Transforming patient care through translational research in hormone receptor positive breast cancer

Transforming patient care through translational research in hormone receptor positive

breast cancer

Professor Erik Knudsen

University of Arizona Cancer Center

Tucson United States

Professor Aleix Prat

Hospital Clinic of Barcelona

Barcelona Spain

170271

Disclaimer

ldquoThe statements views and opinions contained in this symposium are

those of the authors and are not endorsed by nor do they necessarily

reflect the opinions of Pfizerrdquo

ldquoThis symposium contains information on investigational products in

development from a research perspective The information aims to be

truthful accurate balanced fair and not misleading It is supported by

relevant scientific data and is non-promotionalrdquo

Agenda

The many faces of CDK46 inhibition

Erik Knudsen

10 minute introduction to the keynote presentation

Transforming patient care through translational research for

HR+ breast cancer

Aleix Prat

40 minute keynote presentation with audience questions

Audience questions and discussion

Closing remarks

Question cards are provided or please raise your hand

Remember to complete your evaluation form





170271

Disclosures

Applicability Company

(1) Advisory role Yes Pfizer Eli Lilly

HTG Diagnostics Novartis

(2) Stock ownershipprofit None

(3) Patent royaltieslicensing fees None

(4) Lecturespeaker engagement fees Yes Pfizer Eli Lilly

(5) Manuscript fees None

(6) Scholarship fund None

(7) Other remuneration None

Erik Knudsen




bull Historical perspective surrounding CDK46 inhibition

bull Translation to the clinic Targeting CDK46 in HR+HER2- breast cancer

bull Key questions related to CDK46 inhibition in breast cancer

ndash Biomarkers determinants of durable response

ndash Nature of progressive disease

ndash Combination approaches to prevent progression

ndash Additional indications in breast cancer

1970-1990 Cell Cycle Experiments

2001 CDKCyclins

1902 Cell Division

1900 2000 1970 1990

CDKCyclins Drive the cell cycle

Cdc2+ encodes a protein kinase regulated by phosphorylation Simanis 1986 Cell

A cytoplasmic factor promoting oocyte maturation Wasserman 1976 Science

Complementation used to clone human cdc2 Lee 1987 Cell

Purified maturation promoting factor contains cdc2+ Gautier 1988 Cell

An essential G1 function for cyclin-like proteins Richardson 1989 Cell

A family of cyclin homologs that control G1 phase Hadwiger 1989 PNAS

Role of CDC28 and cyclins during mitosis Surana 1991 Cell

Cyclin in sea urchin eggs is destroyed at cleavage division Evans 1983 Cell

Genetic control of cell-division cycle in yeast Hartwell 1970 PNAS

Defining CDK in control of proliferation

1992-1994 Discovery of CDK46

CDK4 or CDK6

CycD

1993-1994 Cellular CDK46 Inhibitors

1991 1992 1994

A novel cyclin encoded by a bc1-linked candidate oncogene Motokura Nature 1991

Human D-type cyclin cloned by complementation Xiong 1991 Cell

Expression and amplification of cyclin genes in human breast cancer Buckley 1993 Oncogene

Identification and properties of an atypical catalytic subunit (p34PSK-J3cdk4) Matsushime 1992 Cell

CDK46 define a class of CDK binding to D Cyclins Bates 1994 Oncogene

Deletions of CDK4 inhibitor gene in multiple human cancers Nobori 1994 Nature

1993

1991 Cloning of Cyclin D1

Cyclin D1

CSF-inducible G1 cyclin Matsushime 1991 Cell

CDK4 or CDK6

CycD

A new regulatory motif causing specific inhibition of cyclin DCDK4 Serrano 1993 Nature

Characterisation of CDK46 Kinases cyclins inhibitors

p16INK4A

Dysregulation of Cyclin D CDK46 p16ink4a

in cancer

42017 1246 PMcBioPortal f or Cancer Genomics

of 2ht tp wwwcbiopor talorgcross_cancerdocancer_study_list=ampcanchellip132Cpcnsl_m ayo_20152Cctcl_columbia_20152Cov_tcga2Cov_tcga_pub

Modify Query

cBioPortal (httpcbioportalorg) Version 151 | MSKCC (httpwwwmskccorgmskcchtml44cfm) | TCGA (httpcancergenomenihgov)

Questions and feedback cbioportalgooglegr oupscom (mailtocbioportalgooglegr oupscom) | User discussion gr oup (httpgroupsgooglecomgr oupcbioportal) | BioStars

(httpswwwbiostarsorgtcbioportal)

(indexdo)Data Sets (data_setsjsp) Web API (web_apijsp) RMATLAB (cgds_rjsp) Tutorials (tutorialjsp) FAQ (faqjsp) News (newsjsp) Tools (toolsjsp) About (about_usjsp)

Visualize Your Data (visualize_your_datajsp)

Cross- cancer a lterat ion sum m ary for CCND1 CDK4 CDKN2 A ( 1 5 0 studies 3 genes)

Y-Axis value Alteration frequency Min altered samples 36 Min total samples 0 Show alteration types

Sort alphabetically

PDF SVG

Overview Mutations Expression Download Bookmark

+ + + + + + + + + + + + + + + + + - + + + + + +

+ + + + + + + + + + + + + - + + + + + + + + + +

MP

NS

T (M

SK

CC

)

GB

M (T

CG

A)

GB

M (T

CG

A 2

013)

Head amp

neck (T

CG

A)

GB

M (T

CG

A 2

008)

Eso

phagus (T

CG

A)

Head amp

neck (T

CG

A p

ub)

Mela

nom

a (T

CG

A)

NC

I-60

Pancre

as (U

TS

W)

Bla

dder (T

CG

A)

Pancre

as (T

CG

A)

Lung sq

u (T

CG

A p

ub)

CS

CC

(DFC

I 2015)

Bla

dder (T

CG

A 2

014)

Lung sq

u (T

CG

A)

CC

LE

(Nova

rtisBro

ad 2

012)

Meso

thelio

ma (T

CG

A)

AC

bC

(MS

KC

CB

reast 2

015)

Sto

mach

(TC

GA p

ub)

Bre

ast (B

CC

RC

Xenogra

ft)

NS

CLC

(TC

GA 2

016)

LG

G-G

BM

(TC

GA 2

016)

Sto

mach

Eso

phageal

Cancer type

Mutation data

CNA data

0

10

20

30

40

50

60

70

80

Alte

ratio

n F

req

ue

ncy

Mutation Deletion Amplification Multiple alterations

126 studies ( altered samples lt 36) out of 150 have been filtered out

D1adapi CKD1a CKD1adapi CKdapi

Cas

e 3

C

ase

4

No

rma

l

1992 CDK46 and RB Phosphorylation

1995 Mutual Exclusivity in Cancer

1996-2001 Functions of the RB-Pathway

1992 1994 1996 1998 2000

The RB-pathway and functional interactions

RB

Retinoblastoma-protein-dependent cell-cycle inhibition by the tumor suppressor p16 Lukas 1995 Nature

CDK4 or CDK6

CycD

Co-repressors

RB

E2F RB

P

E2F

p16INK4A

Direct binding of cyclin D to the retinoblastoma product (pRb) and pRb phosphorylation by CDK4 Kato 1993 Genes Dev

Functional interactions of the retinoblastoma protein with D-type cyclins Ewen 1993 Cell

Phosphorylation inactivates RB Livingston Harlow Weinberg Mittnacht Knudsen Bartek Rubin etc

E2F is a critical target of RB Nevins Kaelin Dean Livingston Lukas Farnham Kouzarides etc

Canonical CDK46-pathway

Role of cyclin D1 as therapeutic target Yu 2001 Nature

Mutual exclusivity in cancers Bartek 1995 International Journal of Cancer

Mitogens

Oncogenes

Proliferation

1992 First CDK Inhibitors

2004 First Specific CDK46 Inhibitor

2005-2014 CDK46 Inhibitor Development

2002 2010 Present

Specific inhibition of cyclin-dependent kinase 46 by PD 0332991 Fry 2004 Mol Cancer Ther

Treatment of growing teratoma syndrome Vaughn 2009 N Engl J Med

Phase I study of PD 0332991 a cyclin-dependent kinase inhibitor Schwartz 2011 Br J Cancer

Phase I dose-escalation trial of the oral cyclin-dependent kinase 46 inhibitor PD 0332991 Flaherty 2012 Clin Cancer Res

CDK46 Inhibitors Improve PFS in

HR+HER2- breast cancer

Turner 2015 N Engl J Med

2015 Effectiveness Shown in Breast Cancer

Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275 Kaur 1992 J Natl Cancer Inst

PALOMA 2 PALOMA 3

MONALEESA 2

CDK-inhibitors Start to present

How did CDK46 inhibition emerge in HR+HER2- breast cancer

Many other cancer types show deregulation of CDK46

Many of these tumor types have limited effective therapies

ndash great clinical need

ndash great potential opportunity

ndash why most impactful in HR+HER2-

Witkiewicz et al Nat Comm 2015

Moore et al J Clin Oncol 2007

Excellent example of translational research impacting on

treatment of patients with breast cancer

Luminal

(HR+) Basal

(TNBC)

ER

ER+P

D

0

20

40

60

80

Data 6

TNBC

TNBC

0

20

40

60

80

Data 8HR+ TNBC

K

i67 p

ositiv

e

DMSO PD

K

i67 p

ositiv

e

DMSO PD

HR+HER2- preclinical models are particularly sensitive to CDK46 inhibition

Finn et al 2009 Breast Cancer Research

Witkiewicz et al 2012 Cell Cycle

CDK46 inhibition remains effective in models resistant to endocrine therapy

Proliferation

CDK4 or CDK6

CycD1

ESR1

Oncogenic

Signals

ESR1

mutation Resistant

Model Naive

Model

Xenografts of therapy-resistant disease Fulvestrant resistant cells

ER

antagonists

CDK46

inhibitors


Miller et al 2011 Cancer Discovery

Thangavel et al 2011 Endocrine related cancer

Wardell et al 2015 Clin Can Res

Luminal B

High OncotypeDx RFS

High PAM50 ROR

Luminal A

Low OncotypeDx RS

Low PAM50 ROR

CTL

PD

CTL PD ICI ICI+PD0

200000

400000

600000

RL

U1

00

x1

0^

5 c

ells

ATP Levels

CTL

PD

ICI

ICI+PD

Oncotype Proliferation

Module

PAM50 Proliferation

Genes (Luminal AB)

CTL

PD

CTL

LY

CDK46i

Molecular impact of CDK46 inhibition ldquoLuminal B to Luminal Ardquo transition

Knudsen et al 2016 Oncotarget


Ladd et al 2016 Oncotarget


Oncotarget54130wwwimpactjournalscomoncotarget

the loss of an ER allele the MCF7-Y537SKO cell line

has lower ER expression relative to the parental MCF7

cell line (Figure S6A) Additionally when implanted in

mice supplemented with estrogen pellets we observed

continuous tumor growth of MCF7-Y537SKO cells in

vivo after removing the estrogen pellets (Figure S6B)

which is similar to previous overexpression studies [7]

We then assessed the effica cy of palbociclib or everolimus

in combination with fulvestrant Unlike CTC-174 no

single agent treatments exhibited in tumor regressions

(TGI of 52 50 and 62 for fulvestrant everolimus

and palbociclib respectively) (Figure 7A-7B) The

combination of palbociclib and fulvestrant resulted in a

greater tumor growth inhibition (5 regression) than

either agent alone similar to previous reports in a PDX

model with an ER-Y537S mutation [39] The combination

of everolimus and fulvestrant resulted in a 76 TGI

suggesting the combination of fulvestrant and everolimus

is additive in this model (Figure 7B) Together these data

provide a second ER mutant model demonstrating that

the addition of fulvestrant to palbociclib and everolimus

treatments will provide benefit in ER mutant breast

cancers

dIsc ussIo n

ER+ breast cancers bearing activating ER mutations

represent a new segment of endocrine resistant disease

with an unmet therapeutic need To investigate potential

strategies to target these tumors we developed an ER+

breast cancer CTX model from circulating tumor cells

of a patient that harbors a D538G ER mutation CTC-

174 This mutation promotes estrogen independent ER

activity and have been reported in patients who have

acquired endocrine resistance [7 9 10 40] Indeed

our model recapitulates endocrine therapy resistant

disease as shown by estrogen independent growth and

resistance to tamoxifen Using this model as well as in

vitro approaches we demonstrated that fulvestrant targets

the mutant ER protein for degradation but only provides

modest growth inhibition in vivo suggesting additional

pathways may promote resistance to endocrine therapy

Clinically combinatorial strategies for AI refractory

ER+ breast cancer have yielded encouraging results

The BOLERO-2 and PALOMA-1 trials both achieved

increased progression free survival by combining an

aromatase inhibitor with everolimus or palbociclib

respectively [16 22] Given that activating ER mutations

are acquired most frequently in patients who have

previously received an aromatase inhibitor [40] the

combination of everolimus or palbociclib with a SERD

such as fulvestrant may provide superior effica cy in these

patients by lowering ER expression and could potentially

increase overall survival [18] Recently the PALOMA-3

trial evaluating palbociclib combined with fulvestrant

demonstrated longer progression free survival compared

to fulvestrant alone [41] Future follow-up with these

patients may ultimately determine if this combination

increases overall survival in patients with ER mutations

In support of this hypothesis we demonstrate that our ER

Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination

therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed

in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118

palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p

= 00002

Combination with

Fulvestrant

Combination with

SERD (Bazedoxifine)

Contr

ol

CDT

01micro

M P

D

CDT+0

1microM

PD

1 microM

PD

CDT+1

0microM

PD

0

10

20

30

40

B

rdU

Po

sitiv

e

Cooperation with

Estrogen withdrawal

Positive interactions between endocrine therapy and CDK46 inhibition

PALOMA2 PALOMA3 MONALEESA-2

FDA-Approval in HR+HER2-

Breast Cancer

Palbociclib

Ribociclib

Abemaciclib Palbociclib

Preferential sensitivity in HR+ 0

10

20

30

40

5

0 6

0

7

0

Ki6

7

C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15

PIK3CA Mutant

PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)

Ki6

7

Ki6

7

0

10

20

30

40

5

0 6

0

7

0

0

10

20

30

40

5

0 6

0

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

Ki6

7

Ki6

7

Ki6

7

LumA

LumB

LumA (n=15) LumB (n=11)


Ki6

7

C0D1 C1D1 C1D15 Surgery

0

10

20

3

0

40

5

0

60

70

Cycle 5

No Cycle 5

C0D1 C1D1 C1D15 Surgery 0

10

20

3

0

40

50

60

70

Ki6

7

Ki6

7

0

10

20 3

0 4

0 50

60

70

No Cycle 5 Cycle 5


A B C

D E F

G H I

Fig 1

Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206

NeoPalAna

Improved progression-free survival in combination with letrozolefulvestrant

Multiple clinical trials

Finn et al 2016 N Engl J Med

Turner et al 2015 N Engl J Med

Hortobagyi et al 2016 N Engl J Med

DeMichele et al 2015 Clin Can Res

Patnaik 2016 Cancer Discovery

Ma et al 2017 Clin Can Res

Complete Cell Cycle Arrest (Ki67lt27)

Anastrazole C1D1 26

Anstrazole+Palbociclib C1D15 87 plt0001)

Abemaciclib and ribociclib are not approved in EU

Rapid progression

Making response more durable

Next steps for treatment

Key questions related to CDK46 inhibition in breast cancer


Pro

ba

bili

ty o

f p

rogre

ssio

n-f

ree s

urv

iva

l (

)

Months

100

90

80

70

60

50

40

20

20

10

0

0 2 4 6 8 10 12

Placebondashfulvestrant (N=174)

Median progression-free survival

38 mo (95 CI 35ndash55)

Palbociclibndashfulvestrant (N=347)


92 mo (95 CI 75ndashNE)

Hazard ratio 042 (95 CI 032ndash056)

Plt0001

Efficacy beyond

HR+HER2-

Biomarkers for use of CDK46 inhibitors

bull Only biomarker routinely used is hormone-receptor positivity

bull There are markers of intrinsic resistance to CDK46 inhibition

ndash Loss of RB and over expression of p16

ndash Very rare in resectedprimary HR+HER2- disease (~1)


Lefebvre C et al 2017 Plos Med

Cohen et al 2016 SABCS Oral Presentation

RB Ki67 +DMSO Ki67 +PD

Sensitive

Resistant

p16ink4a

More common RB loss

in endocrine therapy resistant

metastatic disease

Genetic Events

Acquiredselected Genetic events

Evolution to resistance

RB loss Cyclin E CDK6 amplification

Therapy

Nature of progressive disease with CDK46 inhibition

Herrera-Abreu et al 2016 Cancer Res

Knudsen et al 2017 Trends in Cancer

Jansen et al 2017 Cancer Res

Limited analysis of disease that has progressed on treatment

ndash Insights into next line of treatment

ndash Insights into combination therapy

Adaptive signals

Signaling pathways

Reduce response to CDK46 inhibition

PI3K PDK1 AKT MTOR

CDK4 or CDK6

Cyclin D

Adaptive Responses Acquired Resistance

RB RB

P

CDK46 Inhibitor

PI3K

AKT mTOR

PDK1

CDK2

Cyclin D

CDK2

Cyclin E

Preclinical models support

ndash PI3K inhibitors

ndash MTOR inhibitors

ndash PDK1 inhibitors

Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With

ER+HER2- Breast Cancer

PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)

Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of

Hormone Receptor Positive HER2 Negative Advanced Breast Cancer

Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer

Combinations with CDK46 inhibition (triplet therapy)

Investigational drugs not approved in the EU

Vora et al 2014 Cancer Cell



Other breast cancer indications

Witkiewicz et al 2014 Genes and Cancer

Goel et al 2016 Cancer Cell

Geng et al 2002 Nature

Turner and Rheis-Filo 2013 Clin Can Res

Clinical trialsgov

HER2+ breast cancer

Potent activity in preclinical models

Genetic dependence for cyclin D1

Positive combinatorial interactions

An Open-Label Phase IbII Clinical Trial Of

CDK 46 Inhibitor Ribociclib (Lee011) In

Combination With Trastuzumab Or T-Dm1 For

AdvancedMetastatic Her2-Positive Breast

Cancer

Study of Palbociclib and Trastuzumab With or

Without Letrozole in HER2-positive Metastatic

Breast Cancer (PATRICIA)

Study of Palbociclib and T-DM1 in HER2-

positive Metastatic Breast Cancer Her2

HER2CCND1-

HER2CCND1+

CONTROL PD0

10

20

30

40

Phh3-PD

Legend

Legend

Legend

Legend

Legend

Legend

Legend

Select TNBC subtypes

Generally resistant (clinical experience)

However specific subtypeshellip

Phase III trial of palbociclib in combination with

bicalutamide for the treatment of androgen

receptor (AR)+ metastatic breast cancer

(MBC)

Ribociclib and Bicalutamide in AR+ TNBC

A Phase 2 Study of Abemaciclib for Patients

With Retinoblastoma-Positive Triple Negative

Metastatic Breast Cancer

pH

H3

Investigational drugs not approved in HER2+ disease

Summary

bull Development of CDK46 inhibitors was built upon a strong basis of investigation in

cell cycle control---yeast to man

bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical

data indicating ldquoexceptional sensitivityrdquo in this form of disease

bull Clinical activity related to positive interaction between CDK46 inhibition and

endocrine therapy

bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-

pathway could be considered to define non-responders

bull Knowledge of progressed disease will be important to delineate subsequent

treatments and combination approaches to enhance durability of response

bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond

HR+HER2- breast cancer with endocrine therapies

Questions

Keynote presentation and discussion

bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)

bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)

bull Signalling pathways epigenetics and immunotherapy

bull Conclusions ndash Discussion (10ndash15 minutes)

Aleix Prat


Barcelona Spain

Question cards are provided

Remember to complete your

evaluation form


HR+ breast cancer

Aleix Prat MD PhD

Medical Oncology Department

Hospital Cliacutenic of Barcelona

University of Barcelona

170271

Disclosures


(1) Advisory role Yes Nanostring Technologies



(4) Lecturespeaker engagement fees Yes Pfizer




mRNA microRNA Protein

DNA Copy Number DNA Methylation DNA Mutations

tumour cells features1

TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)

Courtesy of Dr Pedro Fernaacutendez

The biological complexity of HR+ breast cancer

1 Cancer Genome Atlas Network Nature 2012490(7418)61-70

Luminal A and B

Normal-like HER2-enriched

Basal-like Claudin-low

The intrinsic molecular subtypes of breast cancer

Prat A amp Perou CM Mol Oncol 20115(1)5-23

Subtype distribution within HR+HER2ndash disease

Prat A et al Breast 201524 Suppl 2S26-35

51

34

10 5

Luminal A Luminal B HER2-E Basal-like

N=954

Response of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy

Prat A et al BMC Med 201513303

N=451 patients within HR+HER2ndash disease

pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001

(includes tumour size) (includes tumour size

and nodal status)

Dowsett JCO 2013

MammaPrint OncotypeDX PAM50 ROR EndoPredict

Identification of patients with a very low risk of distant recurrence

HR+HER2-negative early breast cancer (T1-20-3 N+)

Patients who can be spared adjuvant multi-agent chemotherapy (or any other

additional drug) due to their low risk (lt10) of distant recurrence at 10-years with

endocrine therapy-only

Paik NEJM 2006 Vijver NEJM 2002 Filipits CCR 2011

What about the prognostic role of the intrinsic subtypes in metastatic

HR+HER2-negative breast cancer

Letrozole+placebo

Letrozole+lapatinib

R bull Phase III clinical trial

bull First-line therapy

bull 1286 patients with HR+ disease

bull No benefit of lapatinib in HR+HER2-

negative disease

bull Survival benefit of lapatinib in

HR+HER2+ disease

Johnston S et al J Clin Oncology 200927(33)5538-46

9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes

EGF30008 Phase III Trial (HR+) distribution of the intrinsic subtypes

Prat A et al JAMA Oncol 20162(10)1287-94

PAM50 and survival in first-line HR+HER2ndash metastatic breast cancer


PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months

P-value lt0001 P-value lt0001

50

Luminal A

Luminal B

Basal-like

HER2-enriched

0

PAM50 and PFS in first-line HR+HER2ndash metastatic breast cancer


Univariate Multivariate

Clinical variables x2 (P) x2 (P)

PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315

Prior endocrine therapy 24933 lt00001 27842 lt00001

Site of metastasis 0490 0484 0539 0463

Performance status 8075 0004 9719 0002

Num of metastases 13327 lt0001 15377 lt00001

Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008

Likelihood (x2) for PFS for all individual clinical variables

Prognosis of HR+HER2ndash advanced breast cancer based on centrally confirmed Ki-67 status (PALOMA-2)

aOnly patients with central laboratory data were included

CI confidence interval HR hazard ratio LET letrozole NE not

estimable PAL palbociclib PCB placebo PFS progression-free survival Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)

PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

Ki-67 le15a Ki-67 gt15a

PF

S

19m 28m 19m 11m

Do intrinsic subtypes change when they recur

Studying the biological differences between primary and metastatic breast cancer

Project Summary

bull 123 patients

bull FFPE paired tumor blocks

bull Primary vs 1 metastatic site

(mostly at first recurrence)

bull 70 HR+HER2-negative

Cejalvo JM et al Cancer Res 2017 [Epub Mar]

Primary Tumour

Gene expression data

Metastatic Site

Pri

ma

ry T

um

or

Studying the biological differences between paired primary and metastatic breast cancer

bull Subtype Concordance=63

bull 54 of primary Luminal A tumors become non-Luminal A

bull 13 of primary Luminal AB become HER2-E


Basal-like HER2-E LumA LumB

Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)

Do other biology-based classifications of

HR+HER2-negative disease exist






TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic

architecture of 2000

breast tumors reveals

novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA

11q133 amplification

(CCND1)

Curtis C et al Nature 2012486(7403)346-52

Discussion

Biological complexity of HR+ breast cancer

Targeting HR+HER2-negative disease beyond

endocrine therapy and chemotherapy

CDK46 inhibitors in breast cancer

bull Resistance to endocrine therapy

presents a major clinical challenge

bull The growth of HR+ breast cancer is

dependent on Cyclin D1 a direct

transcriptional target of ER

bull Cyclin D1 activates CDK 46 resulting in

G1ndashS phase transition and entry into

the cell cycle

bull Cell line models of endocrine resistance

remain dependent on Cyclin D1 and

CDK46

CDK cyclin-dependent kinase ER estrogen receptor

HR+ hormone receptor-positive

Figure adapted from Asghar 2015

Asghar U et al Nat Rev Drug Discov 201514130ndash146

Thangavel C et al Endocr Relat Cancer 201118333ndash345

M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F

S phase transcription program

G1S transition

Mitogenic signalling ERα

CDK2

Cyclin E

CDK46

Cyclin D

PALOMA-2 Subgroup analysis of PFS by biomarker

Finn RS et al Ann Oncol 201627(Suppl 6) (Abstract LBA15)

bull These exploratory analyses did not identify a subgroup of ER+ patients that did not benefit from the

addition of palbociclib to letrozole While the PFS of the control group varied with several of these

markers palbociclib consistently improved PFS

bull Ki-67 by IHC did not further stratify patients

ndash Activity is likely not limited to one ldquoluminal subtype (B)rdquo

n HR (95 CI)

All patients 666 058 (046ndash072)

ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)

Favors PAL+LET Favors PCB+LET

Percentile n HR (95 CI)


ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)


Qualitative analysis Quantitative analysis

00 05 10 15 0 1 2 3 4

NeoPalAna phase II study

Palbociclib is not approved for use in EBC

C cycle CCCA complete cell cycle arrest D day EBC early breast cancer ECOG PS Eastern Cooperative Oncology Group Performance Status

ER oestrogen receptor HER2 human epidermal growth factor receptor 2

NGS next-generation sequencing PIK3CA phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit alpha

NCT01723774

Ma CX et al Clin Cancer Res 2017 [Epub March 7]

Primary endpoint

Complete cell cycle arrest

(CCCA defined as

Ki67le27) on C1D15

biopsy following 2 weeks of

palbociclib + anastrozole

Secondary endpoints

bull Clinical radiographic and

pathologic responses

bull Safety

bull CCCA rate and changes

in Ki67 by intrinsic

subtype and PIK3CA

mutation status

bull Molecular effect of

palbociclib and NGS of an

83-gene panel to explore

resistance mechanisms

bull Clinical stage II or III

bull ER+ (Allred 6ndash8)

bull HER2ndash breast cancer

bull ECOG PS 0ndash2

Single-arm phase II study

Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10

4 x 28-day cycles (C1ndashC4)

Anastrozole alone induced CCCA

n=11 (26)

Adding P converted non-CCCA to CCCA

n=26 (60)

Persistent non-CCCA on both A + P

n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15

Ki67 Response in Individual Pts

C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10

Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control

NCT01723774


Ki67 Response by

Intrinsic Subtype

Luminal B (n=11) Luminal A (n=18)

0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)

Comparing C1D1 (A alone) and C1D15 (A+P) in cell cycle control based on intrinsic subtype

NCT01723774

Ma CX Presented at SABCS 2015 San Antonio Texas USA

Courtesy of CX Ma

7

12

20


Ki67 recovery at surgery after 4 weeks of palbociclib wash out

NCT01723774


N=4600

bull Histologically

confirmed HR+HER2ndash

early invasive breast

cancer

bull Stage IIa or III

bull Pre- or

postmenopausal

women

bull Men eligible

bull le12 months since initial

pathologic diagnosis

bull Prior chemotherapy

allowed

RA

ND

OM

IZA

TIO

N

Palbociclib (2 years)

+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11

PENELOPE-B phase III study

N=1100 bull Early HR+

breast cancer

lsquohigh riskrsquo (CPS-

EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11

PALLAS phase III study

CDK46 inhibition in the adjuvant setting For how long

NCT01864746 NCT02513394

httpsclinicaltrialsgovct2showNCT01864746

httpsclinicaltrialsgovct2showNCT02513394 Palbociclib is not approved in EBC

Postmenopausal

Untreated BC I-II-III

HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib

Anastrozole 111 Anastrozole +

Abemaciclib

14 weeks

neoMONARCH phase II study

NCT02441946

Hurvitz S et al Presented at ESMO 2016 Abemaciclib is not approved in EBC

neoMONARCH phase II study Results

bull Study met boundary for statistical significance at the interim analysis (boundary plt003)

bull Abemaciclib either in combination with anastrozole or as monotherapy reduced Ki67 more

than anastrozole alone

Abemaciclib is not approved for use in EBC

EBC early breast cancer GMR geometric mean change OR objective response Hurvitz S et al Presented at ESMO 2016

Geometric

mean change


Ki67 index lt27 at 2 weeks

0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19

ndash710 ndash955 ndash931

5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg

Can CDK46 inhibition accomplish similar

results as multi-agent chemotherapy in

HR+HER2-negative early breast cancer

Postmenopausal

Untreated Stage II-IIIA

HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11

Palbociclib is not approved for use in early BC NCT02400567

httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES

Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)

Postmenopausal

Untreated Stage II-III

HR+HER2-

AND

PAM50 LumB

Biopsies PAM50 + RNADNA-seq

Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94

AC ndashgt Paclitaxel

11

Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)

Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES

Can we target HR+HER2+ disease

with CDK46 inhibition

Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease

Prat A et al J Natl Cancer Inst 2014106(8)

Luminal B

HER2-enriched

Basal-like

HER2+ cell lines

CDK46 inhibition in HER2+ breast cancer cell lines

Finn RS et al Breast Cancer Res 200911(5)R77

HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27

Intrinsic subtype distribution within clinically HER2+ disease based on HR status

Combined analyses of reported datasets Cejalvo et al unpublished

MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC

Primary objective

bull Evaluate safety and tolerability

of abemaciclib in combination

with endocrine therapies for

HR+HER2ndash mBC or with

trastuzumab for HER2+ mBC

Secondary objectives

bull Pharmacokinetics

bull Anti-tumour activity

Abemaciclib is not approved for use in mBC

HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016

Part A abemaciclib + letrozole

Part B abemaciclib + anastrozole

Part C abemaciclib + tamoxifen

Part D abemaciclib + exemestane

Part E abemaciclib + exemestane +

everolimus

HR+HER2ndash

mBC

Part F abemaciclib + trastuzumab HER2+

mBC

Key eligibility criteria

bull HR+HER2ndash mBC (parts AndashE) or

HER2+ (both HR+ and HRndash) mBC

(part F)

bull Post-menopausal status (natural

surgical or medical parts AndashE) or

any menopausal status (part F)

bull Parts AndashE no prior systemic

chemotherapy for metastatic disease

bull Part F ge1 chemotherapy regimen for

metastatic disease

bull Patients receiving exemestane-

based therapy must have received

ge1 nonsteroidal aromatase inhibitor

for metastatic disease

Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours

Change in tumour size for patients with measurable disease HER2+ mBC

100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+

+ =HR+ ndash =HRndash

Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)

MonarcHER Anti-tumour activity


Truncated at 100


Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)

Palbociclib is not approved for use in HER2+ disease

BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2

ORR objective response rate pCR pathological complete response defined as absence of invasive

cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily

Gianni L et al SABCS 2016 Poster P4-21-39

NCT02530424 Clinicaltrialsgov

Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve

HPPF x 6 four-weekly cycles Herceptin + Pertuzumab + Palbociclib + Fulvestrant

H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6

P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6

Palbociclib 125 mg orally QD x 21 q 4 wks x 5

Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with

an additional 500 mg dose given two weeks after the initial dose

The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and

fulvestrant (5 administrations every 4 weeks plus the additional dose given two

weeks after the initial dose) was selected to match as closely as possible the total

duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab

HER-2 ER PR and

Ki67 centrally confirmed

Primary endpoints

bull Ki67 changes from

baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability

NA-PHER2 Pathological and clinical response rate

ITT population (n = 30) n ()

pCR (no invasive cells in breast and axilla)

pCR in breast only

8 (27)

9 (30)

Overall clinical response

bull Complete clinical response

bull Partial response

bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)

HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response

defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery




Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)


ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive

HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov

Enrolment criteria

bullHER2+

bullProgressive or recurrent

locally advanced or

metastatic breast cancer

bullHormone receptor

statues known

bullAt least 2 (maximum 4)

prior lines of treatment for


including chemotherapy

and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal

Trastuzumab 8 mgkg (first dose) and 6

mgkg Q3W

+ palbociclib 200 mgday (21 schedule)


mgkg Q3W

+ palbociclib 200 mgday (21 schedule) +

letrozole 25 mgday

R

N=138

Primary endpoint

bullProgression-free survival at 6

months

Secondary endpoints

bullClinical benefit rate

bullObjective response rate

bullProgression-free survival

bullOverall survival

bullBiomarkers (expression levels

of 110 genes)

bullSafety and cardiac profile

HER2+

ERndash


mgkg Q3W


HER2+

ER+

Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC

Discussion

CDK46 inhibitors in the

treatment of breast cancer





tumour cells features1 disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The estrogen receptor (ER) signaling pathway

Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75

Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription

Transcription Transcription

Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA

Cytokines hypoxia stress

Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Drug Pharma Source Target(s)

BYL719 Novartis PI3Kα

GDC-0032 Genentech PI3Kα

MLN-1117 Millenium PI3Kα

CAL-101 Calistoga PI3Kd

XL-147 ExelixisSanofi Pan-PI3K

BKM120 Novartis Pan-PI3K

GDC-0941 Genentech Pan-PI3K

PKI-587 Pfizer Pan-PI3K

XL-765 ExelixisSanofi PI3KmTOR

BEZ235 Novartis PI3KmTOR

GDC-0980 Genentech PI3KmTOR

PF-4691502 Pfizer PI3KmTOR

MLN-128 Millenium TORC12

OSI-027 OSI Pharma TORC12

AZD2014 AstraZeneca TORC12

AZD5363 AstraZeneca AKT (catalytic)

MK-2206 Merck AKT (allosteric)

GDC-0068 Genentech AKT (catalytic)

PI3KmTOR inhibitors

in clinical development

Taselisib

Alpelisib

Courtesy of Dr Johnston

BYL719 (alpelisib) monotherapy

PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer

Bosch A et al Sci Transl Med 20157(283)283

Breast cancer HR+HER2-

locally advanced or metastatic

Postmenopausal

Recurrent or progression

during or after an aromatase

inhibitor

Stratification

1) Visceral disease

2) Endocrine sensitivity

3) Geographic region

480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over

Main endpoint PFS in patients

with a PIK3CA mutation

SANDPIPER Phase III clinical trial (NCT02340221)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007

ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer

Retrospective analyses from SoFEA Phase III trial (n=161723)

Fulvestrant-containing regimen vs Exemestane

Fribbens C et al J Clin Oncol 201634(25)2961-8

ESR1-mut ESR1-WT

GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant

Joseph JD et al Elife 2016 Jul 135 pii e15828

NCT01823835 Phase III GDC-0810 +- palbociclib

NCT02569801 Phase II GDC-0810 vs fulvestrant

Tu

mo

r vo

lum

e (

mm

3)

Days post start of treatment

0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S

ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer

Retrospective Analyses from PALOMA3 Phase III trial (n=360521)

Fulvestrant +- Palbociclib


ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2 MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400

Preliminary analysis SUMMIT phase II trial

NERATINIB +- fulvestrant (N=35)

Activating HER2 mutations in HR+HER2ndash breast cancer

Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]






HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)

HDAC inhibitors (eg entinostat)

Luminal A Luminal B

Chromatin structure regulates transcriptional activity

Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99

ENCORE301 N=130 exemestane +- entinostat

Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer

Yardley DA et al J Clin Oncol 201331(17)2128-35






HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Efficacy of immune checkpoint inhibitors in breast cancer

Study Subtype PDL1 IHC Drug ORR (95 CI)

Keynote-012

(Nanda JCO 2016) TNBC gt1

Pembrolizumab

(PD1) 185 (63-381)

Emens

(AACR 2015) TNBC IHC 2-3

Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)

ER+ gt1 Pembrolizumab

(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256

Tumour infiltrating lymphocytes (TILs) in breast cancer

Loi S et al J Clin Oncol 201331(7)860-7

Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy

Patients treated as per

Investigator

End of participation in

the study

c

ULTIMATE TRIAL DESIGN

NCT02997995 PI Fabrice ANDRE

Take-home messages

bull HR+ is biologically heterogeneous at the DNA RNA and protein level further

subclassifications are needed

bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be

identified within HR+HER2-negative disease

bull Targeting the cell-cycle in luminal disease is a promising strategy

ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy

ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings

ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)

ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit

bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising

bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment

strategy in combination with endocrine therapy A Phase III trial is ongoing

bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-

PD1PDL1 monotherapy is showing weak results

Thank you

Discussion

Please raise your hand if you have a question


Closing remarks

Erik Knudsen


Disclaimer

ldquoThe statements views and opinions contained in this symposium are

those of the authors and are not endorsed by nor do they necessarily

reflect the opinions of Pfizerrdquo

ldquoThis symposium contains information on investigational products in

development from a research perspective The information aims to be

truthful accurate balanced fair and not misleading It is supported by

relevant scientific data and is non-promotionalrdquo

Agenda


Erik Knudsen



HR+ breast cancer

Aleix Prat



Closing remarks







170271

Disclosures










Erik Knudsen












2001 CDKCyclins

1902 Cell Division

1900 2000 1970 1990













CDK4 or CDK6

CycD


1991 1992 1994







1993


Cyclin D1


CDK4 or CDK6

CycD



p16INK4A


in cancer


Page 1 of 2ht tp wwwcbiopor talorgcross_cancerdocancer_study_list=ampcanchellip132Cpcnsl_m ayo_20152Cctcl_columbia_20152Cov_tcga2Cov_tcga_pub

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CC

RC

Xenogra

ft)

NS

CLC

(TC

GA 2

016)

LG

G-G

BM

(TC

GA 2

016)

Sto

mach

Eso

phageal

Cancer type

Mutation data

CNA data

0

10

20

30

40

50

60

70

80

Alte

ratio

n F

req

ue

ncy




Cas

e 3

C

ase

4

No

rma

l




1992 1994 1996 1998 2000


RB


CDK4 or CDK6

CycD

Co-repressors

RB

E2F RB

P

E2F

p16INK4A








Mitogens

Oncogenes

Proliferation




2002 2010 Present










PALOMA 2 PALOMA 3

MONALEESA 2












Luminal

(HR+) Basal

(TNBC)

ER

ER+P

D

0

20

40

60

80

Data 6

TNBC

TNBC

0

20

40

60

80

Data 8HR+ TNBC

K

i67 p

ositiv

e

DMSO PD

K

i67 p

ositiv

e

DMSO PD





Proliferation

CDK4 or CDK6

CycD1

ESR1

Oncogenic

Signals

ESR1

mutation Resistant

Model Naive

Model


ER

antagonists

CDK46

inhibitors





Luminal B

High OncotypeDx RFS

High PAM50 ROR

Luminal A

Low OncotypeDx RS

Low PAM50 ROR

CTL

PD

CTL PD ICI ICI+PD0

200000

400000

600000

RL

U1

00

x1

0^

5 c

ells

ATP Levels

CTL

PD

ICI

ICI+PD


Module

PAM50 Proliferation

Genes (Luminal AB)

CTL

PD

CTL

LY

CDK46i





























cancers

dIsc ussIo n







































= 00002

Combination with

Fulvestrant

Combination with

SERD (Bazedoxifine)

Contr

ol

CDT

01micro

M P

D

CDT+0

1microM

PD

1 microM

PD

CDT+1

0microM

PD

0

10

20

30

40

B

rdU

Po

sitiv

e

Cooperation with

Estrogen withdrawal




Breast Cancer

Palbociclib

Ribociclib



10

20

30

40

5

0 6

0

7

0

Ki6

7


PIK3CA Mutant


Ki6

7

Ki6

7

0

10

20

30

40

5

0 6

0

7

0

0

10

20

30

40

5

0 6

0

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

Ki6

7

Ki6

7

Ki6

7

LumA

LumB



Ki6

7


0

10

20

3

0

40

5

0

60

70

Cycle 5

No Cycle 5


10

20

3

0

40

50

60

70

Ki6

7

Ki6

7

0

10

20 3

0 4

0 50

60

70

No Cycle 5 Cycle 5


A B C

D E F

G H I

Fig 1



NeoPalAna










Anastrazole C1D1 26



Rapid progression





Pro

ba

bili

ty o

f p

rogre

ssio

n-f

ree s

urv

iva

l (

)

Months

100

90

80

70

60

50

40

20

20

10

0

0 2 4 6 8 10 12



38 mo (95 CI 35ndash55)





Plt0001

Efficacy beyond

HR+HER2-










Sensitive

Resistant

p16ink4a

More common RB loss


metastatic disease

Genetic Events




Therapy








Adaptive signals

Signaling pathways


PI3K PDK1 AKT MTOR

CDK4 or CDK6

Cyclin D


RB RB

P

CDK46 Inhibitor

PI3K

AKT mTOR

PDK1

CDK2

Cyclin D

CDK2

Cyclin E





















Clinical trialsgov

HER2+ breast cancer








Cancer






HER2CCND1-

HER2CCND1+

CONTROL PD0

10

20

30

40

Phh3-PD

Legend

Legend

Legend

Legend

Legend

Legend

Legend







(MBC)





pH

H3


Summary






endocrine therapy







Questions






Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen


Agenda


Erik Knudsen



HR+ breast cancer

Aleix Prat



Closing remarks







170271

Disclosures










Erik Knudsen












2001 CDKCyclins

1902 Cell Division

1900 2000 1970 1990













CDK4 or CDK6

CycD


1991 1992 1994







1993


Cyclin D1


CDK4 or CDK6

CycD



p16INK4A


in cancer



Modify Query








Sort alphabetically

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+ + + + + + + + + + + + + + + + + - + + + + + +

+ + + + + + + + + + + + + - + + + + + + + + + +

MP

NS

T (M

SK

CC

)

GB

M (T

CG

A)

GB

M (T

CG

A 2

013)

Head amp

neck (T

CG

A)

GB

M (T

CG

A 2

008)

Eso

phagus (T

CG

A)

Head amp

neck (T

CG

A p

ub)

Mela

nom

a (T

CG

A)

NC

I-60

Pancre

as (U

TS

W)

Bla

dder (T

CG

A)

Pancre

as (T

CG

A)

Lung sq

u (T

CG

A p

ub)

CS

CC

(DFC

I 2015)

Bla

dder (T

CG

A 2

014)

Lung sq

u (T

CG

A)

CC

LE

(Nova

rtisBro

ad 2

012)

Meso

thelio

ma (T

CG

A)

AC

bC

(MS

KC

CB

reast 2

015)

Sto

mach

(TC

GA p

ub)

Bre

ast (B

CC

RC

Xenogra

ft)

NS

CLC

(TC

GA 2

016)

LG

G-G

BM

(TC

GA 2

016)

Sto

mach

Eso

phageal

Cancer type

Mutation data

CNA data

0

10

20

30

40

50

60

70

80

Alte

ratio

n F

req

ue

ncy




Cas

e 3

C

ase

4

No

rma

l




1992 1994 1996 1998 2000


RB


CDK4 or CDK6

CycD

Co-repressors

RB

E2F RB

P

E2F

p16INK4A








Mitogens

Oncogenes

Proliferation




2002 2010 Present










PALOMA 2 PALOMA 3

MONALEESA 2












Luminal

(HR+) Basal

(TNBC)

ER

ER+P

D

0

20

40

60

80

Data 6

TNBC

TNBC

0

20

40

60

80

Data 8HR+ TNBC

K

i67 p

ositiv

e

DMSO PD

K

i67 p

ositiv

e

DMSO PD





Proliferation

CDK4 or CDK6

CycD1

ESR1

Oncogenic

Signals

ESR1

mutation Resistant

Model Naive

Model


ER

antagonists

CDK46

inhibitors





Luminal B

High OncotypeDx RFS

High PAM50 ROR

Luminal A

Low OncotypeDx RS

Low PAM50 ROR

CTL

PD

CTL PD ICI ICI+PD0

200000

400000

600000

RL

U1

00

x1

0^

5 c

ells

ATP Levels

CTL

PD

ICI

ICI+PD


Module

PAM50 Proliferation

Genes (Luminal AB)

CTL

PD

CTL

LY

CDK46i





























cancers

dIsc ussIo n







































= 00002

Combination with

Fulvestrant

Combination with

SERD (Bazedoxifine)

Contr

ol

CDT

01micro

M P

D

CDT+0

1microM

PD

1 microM

PD

CDT+1

0microM

PD

0

10

20

30

40

B

rdU

Po

sitiv

e

Cooperation with

Estrogen withdrawal




Breast Cancer

Palbociclib

Ribociclib



10

20

30

40

5

0 6

0

7

0

Ki6

7


PIK3CA Mutant


Ki6

7

Ki6

7

0

10

20

30

40

5

0 6

0

7

0

0

10

20

30

40

5

0 6

0

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

Ki6

7

Ki6

7

Ki6

7

LumA

LumB



Ki6

7


0

10

20

3

0

40

5

0

60

70

Cycle 5

No Cycle 5


10

20

3

0

40

50

60

70

Ki6

7

Ki6

7

0

10

20 3

0 4

0 50

60

70

No Cycle 5 Cycle 5


A B C

D E F

G H I

Fig 1



NeoPalAna










Anastrazole C1D1 26



Rapid progression





Pro

ba

bili

ty o

f p

rogre

ssio

n-f

ree s

urv

iva

l (

)

Months

100

90

80

70

60

50

40

20

20

10

0

0 2 4 6 8 10 12



38 mo (95 CI 35ndash55)





Plt0001

Efficacy beyond

HR+HER2-










Sensitive

Resistant

p16ink4a

More common RB loss


metastatic disease

Genetic Events




Therapy








Adaptive signals

Signaling pathways


PI3K PDK1 AKT MTOR

CDK4 or CDK6

Cyclin D


RB RB

P

CDK46 Inhibitor

PI3K

AKT mTOR

PDK1

CDK2

Cyclin D

CDK2

Cyclin E





















Clinical trialsgov

HER2+ breast cancer








Cancer






HER2CCND1-

HER2CCND1+

CONTROL PD0

10

20

30

40

Phh3-PD

Legend

Legend

Legend

Legend

Legend

Legend

Legend







(MBC)





pH

H3


Summary






endocrine therapy







Questions






Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen






170271

Disclosures










Erik Knudsen












2001 CDKCyclins

1902 Cell Division

1900 2000 1970 1990













CDK4 or CDK6

CycD


1991 1992 1994







1993


Cyclin D1


CDK4 or CDK6

CycD



p16INK4A


in cancer



Modify Query








Sort alphabetically

PDF SVG


+ + + + + + + + + + + + + + + + + - + + + + + +

+ + + + + + + + + + + + + - + + + + + + + + + +

MP

NS

T (M

SK

CC

)

GB

M (T

CG

A)

GB

M (T

CG

A 2

013)

Head amp

neck (T

CG

A)

GB

M (T

CG

A 2

008)

Eso

phagus (T

CG

A)

Head amp

neck (T

CG

A p

ub)

Mela

nom

a (T

CG

A)

NC

I-60

Pancre

as (U

TS

W)

Bla

dder (T

CG

A)

Pancre

as (T

CG

A)

Lung sq

u (T

CG

A p

ub)

CS

CC

(DFC

I 2015)

Bla

dder (T

CG

A 2

014)

Lung sq

u (T

CG

A)

CC

LE

(Nova

rtisBro

ad 2

012)

Meso

thelio

ma (T

CG

A)

AC

bC

(MS

KC

CB

reast 2

015)

Sto

mach

(TC

GA p

ub)

Bre

ast (B

CC

RC

Xenogra

ft)

NS

CLC

(TC

GA 2

016)

LG

G-G

BM

(TC

GA 2

016)

Sto

mach

Eso

phageal

Cancer type

Mutation data

CNA data

0

10

20

30

40

50

60

70

80

Alte

ratio

n F

req

ue

ncy




Cas

e 3

C

ase

4

No

rma

l




1992 1994 1996 1998 2000


RB


CDK4 or CDK6

CycD

Co-repressors

RB

E2F RB

P

E2F

p16INK4A








Mitogens

Oncogenes

Proliferation




2002 2010 Present










PALOMA 2 PALOMA 3

MONALEESA 2












Luminal

(HR+) Basal

(TNBC)

ER

ER+P

D

0

20

40

60

80

Data 6

TNBC

TNBC

0

20

40

60

80

Data 8HR+ TNBC

K

i67 p

ositiv

e

DMSO PD

K

i67 p

ositiv

e

DMSO PD





Proliferation

CDK4 or CDK6

CycD1

ESR1

Oncogenic

Signals

ESR1

mutation Resistant

Model Naive

Model


ER

antagonists

CDK46

inhibitors





Luminal B

High OncotypeDx RFS

High PAM50 ROR

Luminal A

Low OncotypeDx RS

Low PAM50 ROR

CTL

PD

CTL PD ICI ICI+PD0

200000

400000

600000

RL

U1

00

x1

0^

5 c

ells

ATP Levels

CTL

PD

ICI

ICI+PD


Module

PAM50 Proliferation

Genes (Luminal AB)

CTL

PD

CTL

LY

CDK46i





























cancers

dIsc ussIo n







































= 00002

Combination with

Fulvestrant

Combination with

SERD (Bazedoxifine)

Contr

ol

CDT

01micro

M P

D

CDT+0

1microM

PD

1 microM

PD

CDT+1

0microM

PD

0

10

20

30

40

B

rdU

Po

sitiv

e

Cooperation with

Estrogen withdrawal




Breast Cancer

Palbociclib

Ribociclib



10

20

30

40

5

0 6

0

7

0

Ki6

7


PIK3CA Mutant


Ki6

7

Ki6

7

0

10

20

30

40

5

0 6

0

7

0

0

10

20

30

40

5

0 6

0

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

Ki6

7

Ki6

7

Ki6

7

LumA

LumB



Ki6

7


0

10

20

3

0

40

5

0

60

70

Cycle 5

No Cycle 5


10

20

3

0

40

50

60

70

Ki6

7

Ki6

7

0

10

20 3

0 4

0 50

60

70

No Cycle 5 Cycle 5


A B C

D E F

G H I

Fig 1



NeoPalAna










Anastrazole C1D1 26



Rapid progression





Pro

ba

bili

ty o

f p

rogre

ssio

n-f

ree s

urv

iva

l (

)

Months

100

90

80

70

60

50

40

20

20

10

0

0 2 4 6 8 10 12



38 mo (95 CI 35ndash55)





Plt0001

Efficacy beyond

HR+HER2-










Sensitive

Resistant

p16ink4a

More common RB loss


metastatic disease

Genetic Events




Therapy








Adaptive signals

Signaling pathways


PI3K PDK1 AKT MTOR

CDK4 or CDK6

Cyclin D


RB RB

P

CDK46 Inhibitor

PI3K

AKT mTOR

PDK1

CDK2

Cyclin D

CDK2

Cyclin E





















Clinical trialsgov

HER2+ breast cancer








Cancer






HER2CCND1-

HER2CCND1+

CONTROL PD0

10

20

30

40

Phh3-PD

Legend

Legend

Legend

Legend

Legend

Legend

Legend







(MBC)





pH

H3


Summary






endocrine therapy







Questions






Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen


Disclosures










Erik Knudsen












2001 CDKCyclins

1902 Cell Division

1900 2000 1970 1990













CDK4 or CDK6

CycD


1991 1992 1994







1993


Cyclin D1


CDK4 or CDK6

CycD



p16INK4A


in cancer



Modify Query








Sort alphabetically

PDF SVG


+ + + + + + + + + + + + + + + + + - + + + + + +

+ + + + + + + + + + + + + - + + + + + + + + + +

MP

NS

T (M

SK

CC

)

GB

M (T

CG

A)

GB

M (T

CG

A 2

013)

Head amp

neck (T

CG

A)

GB

M (T

CG

A 2

008)

Eso

phagus (T

CG

A)

Head amp

neck (T

CG

A p

ub)

Mela

nom

a (T

CG

A)

NC

I-60

Pancre

as (U

TS

W)

Bla

dder (T

CG

A)

Pancre

as (T

CG

A)

Lung sq

u (T

CG

A p

ub)

CS

CC

(DFC

I 2015)

Bla

dder (T

CG

A 2

014)

Lung sq

u (T

CG

A)

CC

LE

(Nova

rtisBro

ad 2

012)

Meso

thelio

ma (T

CG

A)

AC

bC

(MS

KC

CB

reast 2

015)

Sto

mach

(TC

GA p

ub)

Bre

ast (B

CC

RC

Xenogra

ft)

NS

CLC

(TC

GA 2

016)

LG

G-G

BM

(TC

GA 2

016)

Sto

mach

Eso

phageal

Cancer type

Mutation data

CNA data

0

10

20

30

40

50

60

70

80

Alte

ratio

n F

req

ue

ncy




Cas

e 3

C

ase

4

No

rma

l




1992 1994 1996 1998 2000


RB


CDK4 or CDK6

CycD

Co-repressors

RB

E2F RB

P

E2F

p16INK4A








Mitogens

Oncogenes

Proliferation




2002 2010 Present










PALOMA 2 PALOMA 3

MONALEESA 2












Luminal

(HR+) Basal

(TNBC)

ER

ER+P

D

0

20

40

60

80

Data 6

TNBC

TNBC

0

20

40

60

80

Data 8HR+ TNBC

K

i67 p

ositiv

e

DMSO PD

K

i67 p

ositiv

e

DMSO PD





Proliferation

CDK4 or CDK6

CycD1

ESR1

Oncogenic

Signals

ESR1

mutation Resistant

Model Naive

Model


ER

antagonists

CDK46

inhibitors





Luminal B

High OncotypeDx RFS

High PAM50 ROR

Luminal A

Low OncotypeDx RS

Low PAM50 ROR

CTL

PD

CTL PD ICI ICI+PD0

200000

400000

600000

RL

U1

00

x1

0^

5 c

ells

ATP Levels

CTL

PD

ICI

ICI+PD


Module

PAM50 Proliferation

Genes (Luminal AB)

CTL

PD

CTL

LY

CDK46i





























cancers

dIsc ussIo n







































= 00002

Combination with

Fulvestrant

Combination with

SERD (Bazedoxifine)

Contr

ol

CDT

01micro

M P

D

CDT+0

1microM

PD

1 microM

PD

CDT+1

0microM

PD

0

10

20

30

40

B

rdU

Po

sitiv

e

Cooperation with

Estrogen withdrawal




Breast Cancer

Palbociclib

Ribociclib



10

20

30

40

5

0 6

0

7

0

Ki6

7


PIK3CA Mutant


Ki6

7

Ki6

7

0

10

20

30

40

5

0 6

0

7

0

0

10

20

30

40

5

0 6

0

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

Ki6

7

Ki6

7

Ki6

7

LumA

LumB



Ki6

7


0

10

20

3

0

40

5

0

60

70

Cycle 5

No Cycle 5


10

20

3

0

40

50

60

70

Ki6

7

Ki6

7

0

10

20 3

0 4

0 50

60

70

No Cycle 5 Cycle 5


A B C

D E F

G H I

Fig 1



NeoPalAna










Anastrazole C1D1 26



Rapid progression





Pro

ba

bili

ty o

f p

rogre

ssio

n-f

ree s

urv

iva

l (

)

Months

100

90

80

70

60

50

40

20

20

10

0

0 2 4 6 8 10 12



38 mo (95 CI 35ndash55)





Plt0001

Efficacy beyond

HR+HER2-










Sensitive

Resistant

p16ink4a

More common RB loss


metastatic disease

Genetic Events




Therapy








Adaptive signals

Signaling pathways


PI3K PDK1 AKT MTOR

CDK4 or CDK6

Cyclin D


RB RB

P

CDK46 Inhibitor

PI3K

AKT mTOR

PDK1

CDK2

Cyclin D

CDK2

Cyclin E





















Clinical trialsgov

HER2+ breast cancer








Cancer






HER2CCND1-

HER2CCND1+

CONTROL PD0

10

20

30

40

Phh3-PD

Legend

Legend

Legend

Legend

Legend

Legend

Legend







(MBC)





pH

H3


Summary






endocrine therapy







Questions






Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen


Erik Knudsen












2001 CDKCyclins

1902 Cell Division

1900 2000 1970 1990













CDK4 or CDK6

CycD


1991 1992 1994







1993


Cyclin D1


CDK4 or CDK6

CycD



p16INK4A


in cancer



Modify Query








Sort alphabetically

PDF SVG


+ + + + + + + + + + + + + + + + + - + + + + + +

+ + + + + + + + + + + + + - + + + + + + + + + +

MP

NS

T (M

SK

CC

)

GB

M (T

CG

A)

GB

M (T

CG

A 2

013)

Head amp

neck (T

CG

A)

GB

M (T

CG

A 2

008)

Eso

phagus (T

CG

A)

Head amp

neck (T

CG

A p

ub)

Mela

nom

a (T

CG

A)

NC

I-60

Pancre

as (U

TS

W)

Bla

dder (T

CG

A)

Pancre

as (T

CG

A)

Lung sq

u (T

CG

A p

ub)

CS

CC

(DFC

I 2015)

Bla

dder (T

CG

A 2

014)

Lung sq

u (T

CG

A)

CC

LE

(Nova

rtisBro

ad 2

012)

Meso

thelio

ma (T

CG

A)

AC

bC

(MS

KC

CB

reast 2

015)

Sto

mach

(TC

GA p

ub)

Bre

ast (B

CC

RC

Xenogra

ft)

NS

CLC

(TC

GA 2

016)

LG

G-G

BM

(TC

GA 2

016)

Sto

mach

Eso

phageal

Cancer type

Mutation data

CNA data

0

10

20

30

40

50

60

70

80

Alte

ratio

n F

req

ue

ncy




Cas

e 3

C

ase

4

No

rma

l




1992 1994 1996 1998 2000


RB


CDK4 or CDK6

CycD

Co-repressors

RB

E2F RB

P

E2F

p16INK4A








Mitogens

Oncogenes

Proliferation




2002 2010 Present










PALOMA 2 PALOMA 3

MONALEESA 2












Luminal

(HR+) Basal

(TNBC)

ER

ER+P

D

0

20

40

60

80

Data 6

TNBC

TNBC

0

20

40

60

80

Data 8HR+ TNBC

K

i67 p

ositiv

e

DMSO PD

K

i67 p

ositiv

e

DMSO PD





Proliferation

CDK4 or CDK6

CycD1

ESR1

Oncogenic

Signals

ESR1

mutation Resistant

Model Naive

Model


ER

antagonists

CDK46

inhibitors





Luminal B

High OncotypeDx RFS

High PAM50 ROR

Luminal A

Low OncotypeDx RS

Low PAM50 ROR

CTL

PD

CTL PD ICI ICI+PD0

200000

400000

600000

RL

U1

00

x1

0^

5 c

ells

ATP Levels

CTL

PD

ICI

ICI+PD


Module

PAM50 Proliferation

Genes (Luminal AB)

CTL

PD

CTL

LY

CDK46i





























cancers

dIsc ussIo n







































= 00002

Combination with

Fulvestrant

Combination with

SERD (Bazedoxifine)

Contr

ol

CDT

01micro

M P

D

CDT+0

1microM

PD

1 microM

PD

CDT+1

0microM

PD

0

10

20

30

40

B

rdU

Po

sitiv

e

Cooperation with

Estrogen withdrawal




Breast Cancer

Palbociclib

Ribociclib



10

20

30

40

5

0 6

0

7

0

Ki6

7


PIK3CA Mutant


Ki6

7

Ki6

7

0

10

20

30

40

5

0 6

0

7

0

0

10

20

30

40

5

0 6

0

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

Ki6

7

Ki6

7

Ki6

7

LumA

LumB



Ki6

7


0

10

20

3

0

40

5

0

60

70

Cycle 5

No Cycle 5


10

20

3

0

40

50

60

70

Ki6

7

Ki6

7

0

10

20 3

0 4

0 50

60

70

No Cycle 5 Cycle 5


A B C

D E F

G H I

Fig 1



NeoPalAna










Anastrazole C1D1 26



Rapid progression





Pro

ba

bili

ty o

f p

rogre

ssio

n-f

ree s

urv

iva

l (

)

Months

100

90

80

70

60

50

40

20

20

10

0

0 2 4 6 8 10 12



38 mo (95 CI 35ndash55)





Plt0001

Efficacy beyond

HR+HER2-










Sensitive

Resistant

p16ink4a

More common RB loss


metastatic disease

Genetic Events




Therapy








Adaptive signals

Signaling pathways


PI3K PDK1 AKT MTOR

CDK4 or CDK6

Cyclin D


RB RB

P

CDK46 Inhibitor

PI3K

AKT mTOR

PDK1

CDK2

Cyclin D

CDK2

Cyclin E





















Clinical trialsgov

HER2+ breast cancer








Cancer






HER2CCND1-

HER2CCND1+

CONTROL PD0

10

20

30

40

Phh3-PD

Legend

Legend

Legend

Legend

Legend

Legend

Legend







(MBC)





pH

H3


Summary






endocrine therapy







Questions






Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen



2001 CDKCyclins

1902 Cell Division

1900 2000 1970 1990













CDK4 or CDK6

CycD


1991 1992 1994







1993


Cyclin D1


CDK4 or CDK6

CycD



p16INK4A


in cancer



Modify Query








Sort alphabetically

PDF SVG


+ + + + + + + + + + + + + + + + + - + + + + + +

+ + + + + + + + + + + + + - + + + + + + + + + +

MP

NS

T (M

SK

CC

)

GB

M (T

CG

A)

GB

M (T

CG

A 2

013)

Head amp

neck (T

CG

A)

GB

M (T

CG

A 2

008)

Eso

phagus (T

CG

A)

Head amp

neck (T

CG

A p

ub)

Mela

nom

a (T

CG

A)

NC

I-60

Pancre

as (U

TS

W)

Bla

dder (T

CG

A)

Pancre

as (T

CG

A)

Lung sq

u (T

CG

A p

ub)

CS

CC

(DFC

I 2015)

Bla

dder (T

CG

A 2

014)

Lung sq

u (T

CG

A)

CC

LE

(Nova

rtisBro

ad 2

012)

Meso

thelio

ma (T

CG

A)

AC

bC

(MS

KC

CB

reast 2

015)

Sto

mach

(TC

GA p

ub)

Bre

ast (B

CC

RC

Xenogra

ft)

NS

CLC

(TC

GA 2

016)

LG

G-G

BM

(TC

GA 2

016)

Sto

mach

Eso

phageal

Cancer type

Mutation data

CNA data

0

10

20

30

40

50

60

70

80

Alte

ratio

n F

req

ue

ncy




Cas

e 3

C

ase

4

No

rma

l




1992 1994 1996 1998 2000


RB


CDK4 or CDK6

CycD

Co-repressors

RB

E2F RB

P

E2F

p16INK4A








Mitogens

Oncogenes

Proliferation




2002 2010 Present










PALOMA 2 PALOMA 3

MONALEESA 2












Luminal

(HR+) Basal

(TNBC)

ER

ER+P

D

0

20

40

60

80

Data 6

TNBC

TNBC

0

20

40

60

80

Data 8HR+ TNBC

K

i67 p

ositiv

e

DMSO PD

K

i67 p

ositiv

e

DMSO PD





Proliferation

CDK4 or CDK6

CycD1

ESR1

Oncogenic

Signals

ESR1

mutation Resistant

Model Naive

Model


ER

antagonists

CDK46

inhibitors





Luminal B

High OncotypeDx RFS

High PAM50 ROR

Luminal A

Low OncotypeDx RS

Low PAM50 ROR

CTL

PD

CTL PD ICI ICI+PD0

200000

400000

600000

RL

U1

00

x1

0^

5 c

ells

ATP Levels

CTL

PD

ICI

ICI+PD


Module

PAM50 Proliferation

Genes (Luminal AB)

CTL

PD

CTL

LY

CDK46i





























cancers

dIsc ussIo n







































= 00002

Combination with

Fulvestrant

Combination with

SERD (Bazedoxifine)

Contr

ol

CDT

01micro

M P

D

CDT+0

1microM

PD

1 microM

PD

CDT+1

0microM

PD

0

10

20

30

40

B

rdU

Po

sitiv

e

Cooperation with

Estrogen withdrawal




Breast Cancer

Palbociclib

Ribociclib



10

20

30

40

5

0 6

0

7

0

Ki6

7


PIK3CA Mutant


Ki6

7

Ki6

7

0

10

20

30

40

5

0 6

0

7

0

0

10

20

30

40

5

0 6

0

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

Ki6

7

Ki6

7

Ki6

7

LumA

LumB



Ki6

7


0

10

20

3

0

40

5

0

60

70

Cycle 5

No Cycle 5


10

20

3

0

40

50

60

70

Ki6

7

Ki6

7

0

10

20 3

0 4

0 50

60

70

No Cycle 5 Cycle 5


A B C

D E F

G H I

Fig 1



NeoPalAna










Anastrazole C1D1 26



Rapid progression





Pro

ba

bili

ty o

f p

rogre

ssio

n-f

ree s

urv

iva

l (

)

Months

100

90

80

70

60

50

40

20

20

10

0

0 2 4 6 8 10 12



38 mo (95 CI 35ndash55)





Plt0001

Efficacy beyond

HR+HER2-










Sensitive

Resistant

p16ink4a

More common RB loss


metastatic disease

Genetic Events




Therapy








Adaptive signals

Signaling pathways


PI3K PDK1 AKT MTOR

CDK4 or CDK6

Cyclin D


RB RB

P

CDK46 Inhibitor

PI3K

AKT mTOR

PDK1

CDK2

Cyclin D

CDK2

Cyclin E





















Clinical trialsgov

HER2+ breast cancer








Cancer






HER2CCND1-

HER2CCND1+

CONTROL PD0

10

20

30

40

Phh3-PD

Legend

Legend

Legend

Legend

Legend

Legend

Legend







(MBC)





pH

H3


Summary






endocrine therapy







Questions






Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen



CDK4 or CDK6

CycD


1991 1992 1994







1993


Cyclin D1


CDK4 or CDK6

CycD



p16INK4A


in cancer



Modify Query








Sort alphabetically

PDF SVG


+ + + + + + + + + + + + + + + + + - + + + + + +

+ + + + + + + + + + + + + - + + + + + + + + + +

MP

NS

T (M

SK

CC

)

GB

M (T

CG

A)

GB

M (T

CG

A 2

013)

Head amp

neck (T

CG

A)

GB

M (T

CG

A 2

008)

Eso

phagus (T

CG

A)

Head amp

neck (T

CG

A p

ub)

Mela

nom

a (T

CG

A)

NC

I-60

Pancre

as (U

TS

W)

Bla

dder (T

CG

A)

Pancre

as (T

CG

A)

Lung sq

u (T

CG

A p

ub)

CS

CC

(DFC

I 2015)

Bla

dder (T

CG

A 2

014)

Lung sq

u (T

CG

A)

CC

LE

(Nova

rtisBro

ad 2

012)

Meso

thelio

ma (T

CG

A)

AC

bC

(MS

KC

CB

reast 2

015)

Sto

mach

(TC

GA p

ub)

Bre

ast (B

CC

RC

Xenogra

ft)

NS

CLC

(TC

GA 2

016)

LG

G-G

BM

(TC

GA 2

016)

Sto

mach

Eso

phageal

Cancer type

Mutation data

CNA data

0

10

20

30

40

50

60

70

80

Alte

ratio

n F

req

ue

ncy




Cas

e 3

C

ase

4

No

rma

l




1992 1994 1996 1998 2000


RB


CDK4 or CDK6

CycD

Co-repressors

RB

E2F RB

P

E2F

p16INK4A








Mitogens

Oncogenes

Proliferation




2002 2010 Present










PALOMA 2 PALOMA 3

MONALEESA 2












Luminal

(HR+) Basal

(TNBC)

ER

ER+P

D

0

20

40

60

80

Data 6

TNBC

TNBC

0

20

40

60

80

Data 8HR+ TNBC

K

i67 p

ositiv

e

DMSO PD

K

i67 p

ositiv

e

DMSO PD





Proliferation

CDK4 or CDK6

CycD1

ESR1

Oncogenic

Signals

ESR1

mutation Resistant

Model Naive

Model


ER

antagonists

CDK46

inhibitors





Luminal B

High OncotypeDx RFS

High PAM50 ROR

Luminal A

Low OncotypeDx RS

Low PAM50 ROR

CTL

PD

CTL PD ICI ICI+PD0

200000

400000

600000

RL

U1

00

x1

0^

5 c

ells

ATP Levels

CTL

PD

ICI

ICI+PD


Module

PAM50 Proliferation

Genes (Luminal AB)

CTL

PD

CTL

LY

CDK46i





























cancers

dIsc ussIo n







































= 00002

Combination with

Fulvestrant

Combination with

SERD (Bazedoxifine)

Contr

ol

CDT

01micro

M P

D

CDT+0

1microM

PD

1 microM

PD

CDT+1

0microM

PD

0

10

20

30

40

B

rdU

Po

sitiv

e

Cooperation with

Estrogen withdrawal




Breast Cancer

Palbociclib

Ribociclib



10

20

30

40

5

0 6

0

7

0

Ki6

7


PIK3CA Mutant


Ki6

7

Ki6

7

0

10

20

30

40

5

0 6

0

7

0

0

10

20

30

40

5

0 6

0

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

Ki6

7

Ki6

7

Ki6

7

LumA

LumB



Ki6

7


0

10

20

3

0

40

5

0

60

70

Cycle 5

No Cycle 5


10

20

3

0

40

50

60

70

Ki6

7

Ki6

7

0

10

20 3

0 4

0 50

60

70

No Cycle 5 Cycle 5


A B C

D E F

G H I

Fig 1



NeoPalAna










Anastrazole C1D1 26



Rapid progression





Pro

ba

bili

ty o

f p

rogre

ssio

n-f

ree s

urv

iva

l (

)

Months

100

90

80

70

60

50

40

20

20

10

0

0 2 4 6 8 10 12



38 mo (95 CI 35ndash55)





Plt0001

Efficacy beyond

HR+HER2-










Sensitive

Resistant

p16ink4a

More common RB loss


metastatic disease

Genetic Events




Therapy








Adaptive signals

Signaling pathways


PI3K PDK1 AKT MTOR

CDK4 or CDK6

Cyclin D


RB RB

P

CDK46 Inhibitor

PI3K

AKT mTOR

PDK1

CDK2

Cyclin D

CDK2

Cyclin E





















Clinical trialsgov

HER2+ breast cancer








Cancer






HER2CCND1-

HER2CCND1+

CONTROL PD0

10

20

30

40

Phh3-PD

Legend

Legend

Legend

Legend

Legend

Legend

Legend







(MBC)





pH

H3


Summary






endocrine therapy







Questions






Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen





1992 1994 1996 1998 2000


RB


CDK4 or CDK6

CycD

Co-repressors

RB

E2F RB

P

E2F

p16INK4A








Mitogens

Oncogenes

Proliferation




2002 2010 Present










PALOMA 2 PALOMA 3

MONALEESA 2












Luminal

(HR+) Basal

(TNBC)

ER

ER+P

D

0

20

40

60

80

Data 6

TNBC

TNBC

0

20

40

60

80

Data 8HR+ TNBC

K

i67 p

ositiv

e

DMSO PD

K

i67 p

ositiv

e

DMSO PD





Proliferation

CDK4 or CDK6

CycD1

ESR1

Oncogenic

Signals

ESR1

mutation Resistant

Model Naive

Model


ER

antagonists

CDK46

inhibitors





Luminal B

High OncotypeDx RFS

High PAM50 ROR

Luminal A

Low OncotypeDx RS

Low PAM50 ROR

CTL

PD

CTL PD ICI ICI+PD0

200000

400000

600000

RL

U1

00

x1

0^

5 c

ells

ATP Levels

CTL

PD

ICI

ICI+PD


Module

PAM50 Proliferation

Genes (Luminal AB)

CTL

PD

CTL

LY

CDK46i





























cancers

dIsc ussIo n







































= 00002

Combination with

Fulvestrant

Combination with

SERD (Bazedoxifine)

Contr

ol

CDT

01micro

M P

D

CDT+0

1microM

PD

1 microM

PD

CDT+1

0microM

PD

0

10

20

30

40

B

rdU

Po

sitiv

e

Cooperation with

Estrogen withdrawal




Breast Cancer

Palbociclib

Ribociclib



10

20

30

40

5

0 6

0

7

0

Ki6

7


PIK3CA Mutant


Ki6

7

Ki6

7

0

10

20

30

40

5

0 6

0

7

0

0

10

20

30

40

5

0 6

0

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

Ki6

7

Ki6

7

Ki6

7

LumA

LumB



Ki6

7


0

10

20

3

0

40

5

0

60

70

Cycle 5

No Cycle 5


10

20

3

0

40

50

60

70

Ki6

7

Ki6

7

0

10

20 3

0 4

0 50

60

70

No Cycle 5 Cycle 5


A B C

D E F

G H I

Fig 1



NeoPalAna










Anastrazole C1D1 26



Rapid progression





Pro

ba

bili

ty o

f p

rogre

ssio

n-f

ree s

urv

iva

l (

)

Months

100

90

80

70

60

50

40

20

20

10

0

0 2 4 6 8 10 12



38 mo (95 CI 35ndash55)





Plt0001

Efficacy beyond

HR+HER2-










Sensitive

Resistant

p16ink4a

More common RB loss


metastatic disease

Genetic Events




Therapy








Adaptive signals

Signaling pathways


PI3K PDK1 AKT MTOR

CDK4 or CDK6

Cyclin D


RB RB

P

CDK46 Inhibitor

PI3K

AKT mTOR

PDK1

CDK2

Cyclin D

CDK2

Cyclin E





















Clinical trialsgov

HER2+ breast cancer








Cancer






HER2CCND1-

HER2CCND1+

CONTROL PD0

10

20

30

40

Phh3-PD

Legend

Legend

Legend

Legend

Legend

Legend

Legend







(MBC)





pH

H3


Summary






endocrine therapy







Questions






Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen





2002 2010 Present










PALOMA 2 PALOMA 3

MONALEESA 2












Luminal

(HR+) Basal

(TNBC)

ER

ER+P

D

0

20

40

60

80

Data 6

TNBC

TNBC

0

20

40

60

80

Data 8HR+ TNBC

K

i67 p

ositiv

e

DMSO PD

K

i67 p

ositiv

e

DMSO PD





Proliferation

CDK4 or CDK6

CycD1

ESR1

Oncogenic

Signals

ESR1

mutation Resistant

Model Naive

Model


ER

antagonists

CDK46

inhibitors





Luminal B

High OncotypeDx RFS

High PAM50 ROR

Luminal A

Low OncotypeDx RS

Low PAM50 ROR

CTL

PD

CTL PD ICI ICI+PD0

200000

400000

600000

RL

U1

00

x1

0^

5 c

ells

ATP Levels

CTL

PD

ICI

ICI+PD


Module

PAM50 Proliferation

Genes (Luminal AB)

CTL

PD

CTL

LY

CDK46i





























cancers

dIsc ussIo n







































= 00002

Combination with

Fulvestrant

Combination with

SERD (Bazedoxifine)

Contr

ol

CDT

01micro

M P

D

CDT+0

1microM

PD

1 microM

PD

CDT+1

0microM

PD

0

10

20

30

40

B

rdU

Po

sitiv

e

Cooperation with

Estrogen withdrawal




Breast Cancer

Palbociclib

Ribociclib



10

20

30

40

5

0 6

0

7

0

Ki6

7


PIK3CA Mutant


Ki6

7

Ki6

7

0

10

20

30

40

5

0 6

0

7

0

0

10

20

30

40

5

0 6

0

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

Ki6

7

Ki6

7

Ki6

7

LumA

LumB



Ki6

7


0

10

20

3

0

40

5

0

60

70

Cycle 5

No Cycle 5


10

20

3

0

40

50

60

70

Ki6

7

Ki6

7

0

10

20 3

0 4

0 50

60

70

No Cycle 5 Cycle 5


A B C

D E F

G H I

Fig 1



NeoPalAna










Anastrazole C1D1 26



Rapid progression





Pro

ba

bili

ty o

f p

rogre

ssio

n-f

ree s

urv

iva

l (

)

Months

100

90

80

70

60

50

40

20

20

10

0

0 2 4 6 8 10 12



38 mo (95 CI 35ndash55)





Plt0001

Efficacy beyond

HR+HER2-










Sensitive

Resistant

p16ink4a

More common RB loss


metastatic disease

Genetic Events




Therapy








Adaptive signals

Signaling pathways


PI3K PDK1 AKT MTOR

CDK4 or CDK6

Cyclin D


RB RB

P

CDK46 Inhibitor

PI3K

AKT mTOR

PDK1

CDK2

Cyclin D

CDK2

Cyclin E





















Clinical trialsgov

HER2+ breast cancer








Cancer






HER2CCND1-

HER2CCND1+

CONTROL PD0

10

20

30

40

Phh3-PD

Legend

Legend

Legend

Legend

Legend

Legend

Legend







(MBC)





pH

H3


Summary






endocrine therapy







Questions






Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen












Luminal

(HR+) Basal

(TNBC)

ER

ER+P

D

0

20

40

60

80

Data 6

TNBC

TNBC

0

20

40

60

80

Data 8HR+ TNBC

K

i67 p

ositiv

e

DMSO PD

K

i67 p

ositiv

e

DMSO PD





Proliferation

CDK4 or CDK6

CycD1

ESR1

Oncogenic

Signals

ESR1

mutation Resistant

Model Naive

Model


ER

antagonists

CDK46

inhibitors





Luminal B

High OncotypeDx RFS

High PAM50 ROR

Luminal A

Low OncotypeDx RS

Low PAM50 ROR

CTL

PD

CTL PD ICI ICI+PD0

200000

400000

600000

RL

U1

00

x1

0^

5 c

ells

ATP Levels

CTL

PD

ICI

ICI+PD


Module

PAM50 Proliferation

Genes (Luminal AB)

CTL

PD

CTL

LY

CDK46i





























cancers

dIsc ussIo n







































= 00002

Combination with

Fulvestrant

Combination with

SERD (Bazedoxifine)

Contr

ol

CDT

01micro

M P

D

CDT+0

1microM

PD

1 microM

PD

CDT+1

0microM

PD

0

10

20

30

40

B

rdU

Po

sitiv

e

Cooperation with

Estrogen withdrawal




Breast Cancer

Palbociclib

Ribociclib



10

20

30

40

5

0 6

0

7

0

Ki6

7


PIK3CA Mutant


Ki6

7

Ki6

7

0

10

20

30

40

5

0 6

0

7

0

0

10

20

30

40

5

0 6

0

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

Ki6

7

Ki6

7

Ki6

7

LumA

LumB



Ki6

7


0

10

20

3

0

40

5

0

60

70

Cycle 5

No Cycle 5


10

20

3

0

40

50

60

70

Ki6

7

Ki6

7

0

10

20 3

0 4

0 50

60

70

No Cycle 5 Cycle 5


A B C

D E F

G H I

Fig 1



NeoPalAna










Anastrazole C1D1 26



Rapid progression





Pro

ba

bili

ty o

f p

rogre

ssio

n-f

ree s

urv

iva

l (

)

Months

100

90

80

70

60

50

40

20

20

10

0

0 2 4 6 8 10 12



38 mo (95 CI 35ndash55)





Plt0001

Efficacy beyond

HR+HER2-










Sensitive

Resistant

p16ink4a

More common RB loss


metastatic disease

Genetic Events




Therapy








Adaptive signals

Signaling pathways


PI3K PDK1 AKT MTOR

CDK4 or CDK6

Cyclin D


RB RB

P

CDK46 Inhibitor

PI3K

AKT mTOR

PDK1

CDK2

Cyclin D

CDK2

Cyclin E





















Clinical trialsgov

HER2+ breast cancer








Cancer






HER2CCND1-

HER2CCND1+

CONTROL PD0

10

20

30

40

Phh3-PD

Legend

Legend

Legend

Legend

Legend

Legend

Legend







(MBC)





pH

H3


Summary






endocrine therapy







Questions






Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen


Luminal B

High OncotypeDx RFS

High PAM50 ROR

Luminal A

Low OncotypeDx RS

Low PAM50 ROR

CTL

PD

CTL PD ICI ICI+PD0

200000

400000

600000

RL

U1

00

x1

0^

5 c

ells

ATP Levels

CTL

PD

ICI

ICI+PD


Module

PAM50 Proliferation

Genes (Luminal AB)

CTL

PD

CTL

LY

CDK46i





























cancers

dIsc ussIo n







































= 00002

Combination with

Fulvestrant

Combination with

SERD (Bazedoxifine)

Contr

ol

CDT

01micro

M P

D

CDT+0

1microM

PD

1 microM

PD

CDT+1

0microM

PD

0

10

20

30

40

B

rdU

Po

sitiv

e

Cooperation with

Estrogen withdrawal




Breast Cancer

Palbociclib

Ribociclib



10

20

30

40

5

0 6

0

7

0

Ki6

7


PIK3CA Mutant


Ki6

7

Ki6

7

0

10

20

30

40

5

0 6

0

7

0

0

10

20

30

40

5

0 6

0

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

Ki6

7

Ki6

7

Ki6

7

LumA

LumB



Ki6

7


0

10

20

3

0

40

5

0

60

70

Cycle 5

No Cycle 5


10

20

3

0

40

50

60

70

Ki6

7

Ki6

7

0

10

20 3

0 4

0 50

60

70

No Cycle 5 Cycle 5


A B C

D E F

G H I

Fig 1



NeoPalAna










Anastrazole C1D1 26



Rapid progression





Pro

ba

bili

ty o

f p

rogre

ssio

n-f

ree s

urv

iva

l (

)

Months

100

90

80

70

60

50

40

20

20

10

0

0 2 4 6 8 10 12



38 mo (95 CI 35ndash55)





Plt0001

Efficacy beyond

HR+HER2-










Sensitive

Resistant

p16ink4a

More common RB loss


metastatic disease

Genetic Events




Therapy








Adaptive signals

Signaling pathways


PI3K PDK1 AKT MTOR

CDK4 or CDK6

Cyclin D


RB RB

P

CDK46 Inhibitor

PI3K

AKT mTOR

PDK1

CDK2

Cyclin D

CDK2

Cyclin E





















Clinical trialsgov

HER2+ breast cancer








Cancer






HER2CCND1-

HER2CCND1+

CONTROL PD0

10

20

30

40

Phh3-PD

Legend

Legend

Legend

Legend

Legend

Legend

Legend







(MBC)





pH

H3


Summary






endocrine therapy







Questions






Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen




Breast Cancer

Palbociclib

Ribociclib



10

20

30

40

5

0 6

0

7

0

Ki6

7


PIK3CA Mutant


Ki6

7

Ki6

7

0

10

20

30

40

5

0 6

0

7

0

0

10

20

30

40

5

0 6

0

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

0

1

0

20 3

0

40 5

0

60

7

0

Ki6

7

Ki6

7

Ki6

7

LumA

LumB



Ki6

7


0

10

20

3

0

40

5

0

60

70

Cycle 5

No Cycle 5


10

20

3

0

40

50

60

70

Ki6

7

Ki6

7

0

10

20 3

0 4

0 50

60

70

No Cycle 5 Cycle 5


A B C

D E F

G H I

Fig 1



NeoPalAna










Anastrazole C1D1 26



Rapid progression





Pro

ba

bili

ty o

f p

rogre

ssio

n-f

ree s

urv

iva

l (

)

Months

100

90

80

70

60

50

40

20

20

10

0

0 2 4 6 8 10 12



38 mo (95 CI 35ndash55)





Plt0001

Efficacy beyond

HR+HER2-










Sensitive

Resistant

p16ink4a

More common RB loss


metastatic disease

Genetic Events




Therapy








Adaptive signals

Signaling pathways


PI3K PDK1 AKT MTOR

CDK4 or CDK6

Cyclin D


RB RB

P

CDK46 Inhibitor

PI3K

AKT mTOR

PDK1

CDK2

Cyclin D

CDK2

Cyclin E





















Clinical trialsgov

HER2+ breast cancer








Cancer






HER2CCND1-

HER2CCND1+

CONTROL PD0

10

20

30

40

Phh3-PD

Legend

Legend

Legend

Legend

Legend

Legend

Legend







(MBC)





pH

H3


Summary






endocrine therapy







Questions






Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen


Rapid progression





Pro

ba

bili

ty o

f p

rogre

ssio

n-f

ree s

urv

iva

l (

)

Months

100

90

80

70

60

50

40

20

20

10

0

0 2 4 6 8 10 12



38 mo (95 CI 35ndash55)





Plt0001

Efficacy beyond

HR+HER2-










Sensitive

Resistant

p16ink4a

More common RB loss


metastatic disease

Genetic Events




Therapy








Adaptive signals

Signaling pathways


PI3K PDK1 AKT MTOR

CDK4 or CDK6

Cyclin D


RB RB

P

CDK46 Inhibitor

PI3K

AKT mTOR

PDK1

CDK2

Cyclin D

CDK2

Cyclin E





















Clinical trialsgov

HER2+ breast cancer








Cancer






HER2CCND1-

HER2CCND1+

CONTROL PD0

10

20

30

40

Phh3-PD

Legend

Legend

Legend

Legend

Legend

Legend

Legend







(MBC)





pH

H3


Summary






endocrine therapy







Questions






Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen











Sensitive

Resistant

p16ink4a

More common RB loss


metastatic disease

Genetic Events




Therapy








Adaptive signals

Signaling pathways


PI3K PDK1 AKT MTOR

CDK4 or CDK6

Cyclin D


RB RB

P

CDK46 Inhibitor

PI3K

AKT mTOR

PDK1

CDK2

Cyclin D

CDK2

Cyclin E





















Clinical trialsgov

HER2+ breast cancer








Cancer






HER2CCND1-

HER2CCND1+

CONTROL PD0

10

20

30

40

Phh3-PD

Legend

Legend

Legend

Legend

Legend

Legend

Legend







(MBC)





pH

H3


Summary






endocrine therapy







Questions






Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen


Genetic Events




Therapy








Adaptive signals

Signaling pathways


PI3K PDK1 AKT MTOR

CDK4 or CDK6

Cyclin D


RB RB

P

CDK46 Inhibitor

PI3K

AKT mTOR

PDK1

CDK2

Cyclin D

CDK2

Cyclin E





















Clinical trialsgov

HER2+ breast cancer








Cancer






HER2CCND1-

HER2CCND1+

CONTROL PD0

10

20

30

40

Phh3-PD

Legend

Legend

Legend

Legend

Legend

Legend

Legend







(MBC)





pH

H3


Summary






endocrine therapy







Questions






Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen






















Clinical trialsgov

HER2+ breast cancer








Cancer






HER2CCND1-

HER2CCND1+

CONTROL PD0

10

20

30

40

Phh3-PD

Legend

Legend

Legend

Legend

Legend

Legend

Legend







(MBC)





pH

H3


Summary






endocrine therapy







Questions






Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen


Summary






endocrine therapy







Questions






Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen


Questions






Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen







Aleix Prat


Barcelona Spain



evaluation form


HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen



HR+ breast cancer

Aleix Prat MD PhD




170271

Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen


Disclosures












TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen





TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen


Luminal A and B







51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen




51

34

10 5


N=954




pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen





pCR RD Total

Luminal A 12 5 227 95 239

Luminal B 21 15 122 85 143

HER2-E 4 16 21 84 25

Basal-like 16 36 28 64 44

Plt0001


and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen



and nodal status)

Dowsett JCO 2013










Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen




Letrozole+placebo

Letrozole+lapatinib





negative disease


HR+HER2+ disease


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen


9161286 (71)

FFPE

821 (64)

RNA

Pre-treated

Luminal

Disease

nCounter

80 PRIMARY

TUMOURS

HR+HER2-neg (N=644)

PAM50 subtypes





PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen




PFS OS

Letrozole (n=644)

Pro

gre

ss

ion

-fre

e s

urv

iva

l p

rop

ort

ion

10

08

06

04

02

00

10 20 30 40

Months

Luminal A

Luminal B

Basal-like

HER2-enriched

Ove

rall

su

rviv

al

pro

po

rtio

n

10

08

06

04

02

00

10 20 30 40

Months


50

Luminal A

Luminal B

Basal-like

HER2-enriched

0





PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen






PAM50 subtype 35572 lt00001 31589 lt00001

Treatment 0648 0421 1010 0315





Age 1603 0206 0875 0350

Type of tissue 3950 0047 6934 0008






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen






PAL+LET (n=179)

PCB+LET (n=75)

Median (95 CI)

PFS mo

NE

(242ndashNE)

192

(163ndash239)

HR (95 CI)

P value

054 (036ndash079)

00015

PAL+LET (n=189)

PCB+LET (n=110)

Median (95 CI)

PFS mo

192

(141ndash222)

110

(82ndash137)

HR (95 CI)

P value

060 (045ndash081)

00006

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months

0

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Time months


PF

S

19m 28m 19m 11m



Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen




Project Summary

bull 123 patients






Primary Tumour


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen


Metastatic Site

Pri

ma

ry T

um

or







Basal-like 12 (92) 1 (8) 0 0

HER2-E 2 (15) 10 (77) 1 (8) 0

LumA 1 (2) 6 (13) 21 (46) 18 (39)

LumB 0 4 (13) 5 (17) 21 (70)








TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen









TCGA Nature 2012

disease today

HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen


The genomic and

transcriptomic



novel subgroups

Basal-like

HER2E

LumA

(1q16q)

LumB

LumA


(CCND1)


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen


Discussion












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen












the cell cycle



CDK46






M

G1 G2

S

CDK1

Cyclin B

CDK12

Cyclin A

pRB

P P P

E2F

pRB

E2F


G1S transition


CDK2

Cyclin E

CDK46

Cyclin D








n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen









n HR (95 CI)


ER+

ERndash

504

62

057 (044ndash074)

041 (022ndash075)

Rb+

Rbndash

512

51

053 (042ndash068)

068 (031ndash148)

Cyclin D1+

Cyclin D1ndash

549

15

056 (044ndash071)

10 (029ndash346)

p16+

p16ndash

466

84

052 (040ndash067)

073 (039ndash136)

Ki-67 le20

Ki-67 gt20

318

235

053 (038ndash074)

057 (041ndash079)

HR (95 CI)




ER status

le25th

gt25th to lt75th

ge75th

142

282

142

050 (032ndash078)

053 (037ndash074)

065 (041ndash105)

Rb status

le25th

gt25th to lt75th

ge75th

154

249

160

057 (036ndash088)

046 (032ndash067)

063 (042ndash095)

Cyclin D1

status

le25th

gt25th to lt75th

ge75th

141

247

176

041 (026ndash065)

069 (048ndash100)

052 (034ndash078)

p16 status

le25th

gt25th to lt75th

ge75th

140

258

152

074 (046ndash120)

062 (044ndash089)

033 (021ndash052)

HR (95 CI)



00 05 10 15 0 1 2 3 4






NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen







NCT01723774


Primary endpoint


(CCCA defined as

Ki67le27) on C1D15



Secondary endpoints



bull Safety



subtype and PIK3CA

mutation status










Anastrozole

(1 mg)

Palbociclib

(125 mg)

28-day (C0)

BIO

PS

Y

C0D1

SU

RG

ER

Y

BIO

PS

Y

C1D1

BIO

PS

Y

C1D15 Surgical

specimen

Off study

Ki67gt10



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen



n=11 (26)


n=26 (60)


n=6 (14)

0

10

20

30

40

50

60

70

80

90

C0D1 C1D1 C1D15


C1D15 gt 10

Off study

C1D15 gt 27

27

N=43

10


NCT01723774


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen


Ki67 Response by

Intrinsic Subtype


0

20

40

60

80

C0D1 C1D1 C1D15

0

20

40

60

80

C0D1 C1D1 C1D15

Geo

metr

ic M

ean

s K

i67

Geo

metr

ic M

ean

s K

i67

0

20

40

60

80

100

C0D1 C1D1 C1D15

Basal-like

HER2-E

Rb E323fs

Non-luminal (n=2)


NCT01723774


Courtesy of CX Ma

7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen


7

12

20



NCT01723774


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen


N=4600

bull Histologically



cancer


bull Pre- or

postmenopausal

women

bull Men eligible




allowed

RA

ND

OM

IZA

TIO

N


+ Endocrine therapy

(5ndash10 years)

Endocrine therapy

(5ndash10 years)

11



breast cancer


EG ge3)

bull Premenopausal

postmenopausal

bull Completed

taxane-based

neoadjuvant

therapy surgery

radiotherapy

RA

ND

OM

IZA

TIO

N

Palbociclib

(1 year)

+ SOC

Placebo

(1 year)

+ SOC

11



NCT01864746 NCT02513394



Postmenopausal


HR+HER2-

Biopsies

Anastrozole +

Abemaciclib

TREATMENT

S

U

R

G

E

R

Y

15 days

N=220

Abemaciclib


Abemaciclib

14 weeks


NCT02441946








Geometric

mean change



0

ndash20

ndash40

ndash60

ndash80

ndash100

100

80

60

40

20

0

n=22 n=23 n=19


5 16 13 Responders

227 696 684

Me

an

ch

an

ge

in

K6

7

exp

ressio

n (

)

Com

ple

te c

ell

Cycle

resp

on

se

ra

te (

)

GMR=022 (013 039)

Plt0001

024 (013042)

Plt0001

OR=78 (20 308)

0003

72 (20 267)

0000

Anastrozole 1 mg

Abemaciclib 150 mg

+ anastrozole 1 mg

Abemaciclib 1 mg




Postmenopausal


HR+HER2-

AND

PAM50 LumA Node+

or LumB Node+-

Letrozole 25 mg +

Palbociclib 125 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

18 weeks

N=132

FEC x 3 ndashgt

Docetaxel x3 11




Postmenopausal


HR+HER2-

AND

PAM50 LumB


Letrozole 25 mg +

Ribociclib 600 mg

TREATMENT

S

U

R

G

E

R

Y

RCB 0-1

6 months

N=94


11







Luminal B

HER2-enriched

Basal-like

HER2+ cell lines



HR+HER2+

N=1648

HR-HER2+

N=1213

360

318

300

22

751

148

74 27




Primary objective
















everolimus

HR+HER2ndash

mBC


mBC




(part F)







metastatic disease







100

50

0

ndash50

ndash100

Change f

rom

baselin

e (

)

20 increase

30 decrease

-

-

- + + + + + + +

+ +

+


Abemaciclib

+ letrozole

Part A (n = 8)

Abemaciclib

+ anastrozole

Part B (n = 8)

Abemaciclib

+ tamoxifen

Part C (n = 7)

Abemaciclib

+ exemestane

Part D (n = 8)

Abemaciclib

+ exemestane

+ everolimus

Part E (n = 10)

Abemaciclib

+ trastuzumab

Part F (n = 13)



Truncated at 100









Patients with

early and locally

advanced HER2+

and ER+ (gt10)

BC chemo-naiumlve











HER-2 ER PR and


Primary endpoints


baseline before

therapy at 2

weeks and at

surgery

bull Change in

apoptosis from

baseline before

therapy and at

surgery

Secondary

endpoints

bull pCR

bull ORR

bull Tolerability




pCR in breast only

8 (27)

9 (30)




bull Stable disease

29 (97)

15 (50)

14 (47)

3 (3)










Enrolment criteria

bullHER2+


locally advanced or



statues known





and trastuzumab

treatment

bullECOG PS 0ndash1

bullLVEF ge50

bullPostmenopausal


mgkg Q3W



mgkg Q3W


letrozole 25 mgday

R

N=138

Primary endpoint


months

Secondary endpoints






of 110 genes)


HER2+

ERndash


mgkg Q3W


HER2+

ER+


Discussion








HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

AP1 or SP1



Estradiol

ERE CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus




















PI3KmTOR inhibitors


Taselisib

Alpelisib







Postmenopausal



inhibitor

Stratification

1) Visceral disease



480 Patients

with a PIK3CA

mutation

120 Patients

without a

PIK3CA

mutation

Taselisib 4 mg 1

vd + Fulvestrant

Placebo 1 vd +

Fulvestrant

Taselisib 4 mg QD

+ Fulvestrant

Placebo QD +

Fulvestrant

21 randomization

21 randomization

Treatment

until

progression of

disease or

unacceptable

toxicity

No cross-over







Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H

IGF1R EGFR HER2

MET FGFR

p38 JNK

CoA


Cytosol

Nucleus

Interaction

P=007





ESR1-mut ESR1-WT





Tu

mo

r vo

lum

e (

mm

3)


0 7 14 21 28

0

200

400

600

800

1000

Vehicle (-E2)

Tamoxifen 60mgkg

Fulvestrant 200mgkg

GDC-0810 100mgkg

MCF-7HA-ERY537S





ESR1-mut ESR1-WT

Interaction

P=074



Estradiol

ERE

AP1 or SP1

CoA

CoA CoR ERE

Transcription


Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

N

O

T

C

H


p38 JNK

CoA


Cytosol

Nucleus

Freq 2-23

Response N

CR 5 143

PR 9 257

ORR 14 400










HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)


Histone

Acetyltransferases

(HAT)

Histone

Deacetylases

(HDAC)


Luminal A Luminal B











HER2 +3 HER2 ISH+

Ki67-low Ki67-high

tumour

microenvironment

Tumor

Infiltrating

Lymphocytes

(TILs)




Keynote-012


Pembrolizumab

(PD1) 185 (63-381)

Emens


Atezolizumab

(PDL1) 24 (8-47)

Javelin

(Dirix SABCS

2015)

ER+TNBC

HER2+ Any

Avelumab

(PDL1) 54 (25-99)

Keynote -028

(Rugo SABCS

2015)


(PD1) 12 (25-312)

N=2009 N=1079 N=297 N=256





Investigator


the study

c



Take-home messages















Thank you

Discussion



Closing remarks

Erik Knudsen


Transforming patient care through translational research in hormone receptor positive breast cancer

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