Novel Therapies for Triple Negative, HER2+ and ER+ Breast Cancer
Joyce O’Shaughnessy, MDCelebrating Women Chair in Breast Cancer Research
Baylor University Medical CenterTexas Oncology
US OncologyJoyce O’Shaughnessy, MD
Nature, 2012
Subtypes of TNBC and targeted therapy selection
Basal1Basal2
ImmuneModule
Mesenchymal
MesenchymalStem-like
Luminal Apocrine
Cell cycle, DNA damageGFR, glycolysis, p63
B/TCR, cytokines, JAK/STAT
ECM receptorsTGF-βRhoWnt/β-CatEMT
Stem cell markers
Luminal CK’sARFOXA1XBP1
Lehmann BD et. al. J Clin Invest 2011 121(7): 2750
Summary – Triple Negative Breast Cancer
§ Systemic neo/adjuvant chemotherapy• Adjuvant anthracycline (TaxAC vs 6TC) improves DFS in TNBC• Addition of carboplatin to paclitaxel improves pCR rate with as yet
unknown effects on DFS – reasonable for high risk pts• In patients who do not develop a pCR with preoperative chemotherapy,
adjuvant treatment with capecitabine is a reasonable option
§ Promising Approaches• Nab paclitaxel/carboplatin first-line metTNBC• PARP inhibitors gBRCA pts• AKT inhibitors• AR inhibitors • PD-1/PD-L1 inhibitors
4
ABC Trials SchemaNode+ or High Risk Node-Negative
Stratification Variables Number of + Nodes (0, 1-3, 4-9, 10+); Hormone Receptor (ER or PgR+, Both
Negative)
TAC q 3 wk
AC q 2 wk PTX q 2 wk
A
B AC q 3 wk PTX q 1 wk
AC q 2 wk PTX q 1 wkC
D
ARM 1 (TaxAC Options) ARM 2 (TC)
Arm 1 Options Per Study• USOR 06-090 - 1A only• NSABP B-46I/USOR 07132 - 1A only• NSABP B-49 - investigator choice 1A-
1D
Endocrine therapy for ER+ or PgR+ patients for minimum of 5 years
Presented by: Joanne L. Blum, MD, PhD.
TC q 3 wk
ABC Trials: Invasive Disease Free Survival
Presented by: Joanne L. Blum, MD, PhD.
Years from Randomization
0 1 2 3 4 5 6 7
1965 1575 1007 847 566 317 132
2005 1599 1014 858 594 358 136
Aliv
e an
d In
v. D
isea
se-fr
ee (
%)
20
40
60
80
100
0
Δ=2.5%TaxAC 2062 179 90.7%TC 2094 220 88.2%
Treatment N Events IDFS
HR=1.23, 95% CI (1.01-1.50) P=0.04
4 yr
Presented by: Joanne L. Blum, MD, PhD.
ABC Trials: IDFS by Hormone and Nodal StatusExploratory Analysis
Years from Randomization
Ali
ve a
nd
In
v. D
isea
se-f
ree
(%)
0 1 2 3 4 5 6 7
020
4060
8010
0
N- TaxAC, 459 Pts, 37 EventsN- TC, 488 Pts, 52 Events1-3N+ TaxAC, 153 Pts, 21 Events1-3N+ TC, 119 Pts, 28 Events4+N+ TaxAC, 42 Pts, 11 Events4+N+ TC, 40 Pts, 16 Events
Years from Randomization
Ali
ve a
nd
In
v. D
isea
se-f
ree
(%)
0 1 2 3 4 5 6 7
020
4060
8010
0
N- TaxAC, 358 Pts, 29 EventsN- TC, 378 Pts, 22 Events1-3N+ TaxAC, 771 Pts, 46 Events1-3N+ TC, 789 Pts, 53 Events4+N+ TaxAC, 279 Pts, 35 Events4+N+ TC, 280 Pts, 49 Events
HR Negative HR Positive
Role of Neoadjuvant Platinum in TNBC: Randomized Trials
Study No Backbone Regimen No Carbo Carboplatin
GeparSixto 315 Weekly paclitaxel + liposomal dox + bev 38% 59%P< 0.05
C406063 433 Sequential weekly paclitaxel – AC +/- bev 41% 54% P=0.0029
Tamura et al 75 Sequential weekly pacl+/- Carb AUC5 - CEF 26% 62%
Alba et al 94 EC – Doc +/- Carbo AUC6 30% 30%
Von Minckwitz et al. Lancet Oncol 2014; Sikov et al. JCO 2014; Alba et al. BRCT 2012; Tamura et al. ASCO 2014, Abstract 1107GeparSixto C40603 8
9
10
NRG-BR003
Node-Positive or High-Risk Node-NegativeTriple Negative Breast Cancer
ACx4ÚPaclitaxel qwk x 12
Randomization
ACx4 Ú Paclitaxel qwk x 12+ Carboplatin
beginning with WP
AC: 60 mg/m2 /600 mg/m2 (Std or DD AC); Paclitaxel: 80 mg/m2 IV weekly;Carboplatin: AUC of 5 IV q3 weeks for 4 cycles
Efficacy of neoadjuvant carboplatin plus docetaxel in triple negative breast cancer:
Combined analysis of two cohorts• PATIENTS AND METHODS:
– 190 patients with stage I-IIITNBC treated uniformly on two independent prospective cohorts (KU, Spain)
– Treatment regimen: Cb (AUC 6) + D (75mg/m2) given every 21 days X 6 cycles – all received pegfilgrastim or filgrastim
• RESULTS: – median tumor size 35mm, 52% node pos,16% BRCA1/2 mutation– Stage: 33% stage III, 56% stage II, 11% stage I. – pCR and RCB 0+1 rates were 55% and 68%, respectively)– Multivariable analysis - stage III disease (OR 0.35, p<0.001), T3-4 lesion (OR
0.39, p=0.003), associated with a lower pCR, but not age, BRCA ½ mutation, clinical nodal status; KU site associated with higher rate (OR 1.93, p=0.046)
– Toxicity 21% 7% of patients, respectively, experienced at least one grade 3 or 4 adverse event.
Sharmaetal.Clin CancerRes2016(PMID:27301700)
Lee et al. SABCS 2015 13
Toi M et al. Proc ASCO, 2016
14
15
16
17
Pt is On Study
Weekly paclitaxel ±
New Agent C, D, or EAC
HER2 (+)
HER2(–)
Randomized
I-SPY 2 Adaptive Trial Schema
Weekly paclitaxel & Trastuzumab
±New Agent A, B, or C
AC
Randomized Surgery
Surgery
StratifyingBiomarkers
Biopsyused for
Biomarkers
Stratifying Biomarkers (Established/Approved/IDE) ER, PR
HER2 (IHC, FISH, RPPA, 44K-microarray)MammaPrint 44K microarray
Preoperative MK-2206 AKT inhibitor
• 93 pts MK-2206 + weekly paclitaxel (then AC)• 59 pts weekly paclitaxel alone (then AC)
• pCR TNBC pts 40% with MK-2206 vs 22% control
• 76% probability success MK-2206 phase 3 TNBC –GRADUATED
• RPPA biomarker analyses ongoing
Tripathy D.ASCO2015
Wulfkuhle JD et al ASCO 2015
Preoperative Neratinib
Veliparib/Carboplatin Graduatesin the Triple Negative Signature
SIGNATURE
Estimated pCR Rate(95% probability interval)
Probability Veliparib +Carbo is
Superior to Control
Predictive Probability of Success in
Phase 3Veliparib/
CarboConcurrent
Control
All HER2- 33% (22-43%)
22%(10-35%)
92% 55%
HR+/HER2- 14%(4-27%)
19% (6-35%)
28% 9%
HR-/HER2- 52%(35-69%)
26%(11-40%) 99% 90%
I-SPY 2 Rugo et al, NEJM 2016
Novels Therapies for Metastatic Disease
Tutt et al. SABCS 2014; S3-01
TNT Trial
Tutt et al. SABCS 2014; S3-01
Tutt et al. SABCS 2014; S3-01
Metastatic TNBC Exceptional Responders to First-Line Platinum
Isakoff S et al. J Clin Oncol 2015
4/34 highly durable ORR 11.7 % First-line cisplatin (overall ORR 35%)2/35 highly durable ORR 5.7% First-line carboplatin (overall ORR 23%)
TnAcity: Randomized Phase II Trial of Chemotherapy Doublets for First Line metTNBC
Yardley D et al. SABCS 2016, abst 874
TnAcity: PFS and OS First Line metTNBC
• Breast cancers with BRCA1/2 mutations -- defects in homologous recombination DNA repair mechanisms, are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors
• The PARP inhibitor veliparib effective in early trials in combination with carboplatin and paclitaxel
• BROCADE is a randomised, placebo-controlled Phase II trial of veliparib, carboplatin and paclitaxel in locally recurrent or mBC with a BRCA1/2 mutation
Efficacy and tolerability of veliparib + carboplatin + paclitaxel in patients with BRCA1 or BRCA2
mutations in mBC
HS Han, et al. Oral presentation, Abstract S2-05
LR or mBC with BRCA1/2 mutation
(N = 290)R
Veliparib + carboplatin + paclitaxel (n=97)
Placebo + carboplatin + paclitaxel (n=99)
Veliparib + temozolomide (n=94)
SABCS 2016
Number at riskPlacebo + C/P 98 82 61 35 20 8 4 0 0Veliparib + C/CP
95 80 60 38 22 13 4 2 1
Veliparib + carboplatin + paclitaxel: PFSPrimary analysis
Placebo + C/P Veliparib + C/P
Months since randomisation
Prob
abili
ty o
fpr
ogre
ssio
n-fr
ee s
urvi
val
1.0
0.8
0.6
0.4
0.2
0.0
0 4 12 24
Placebo + C/Pn = 98
Veliparib + C/Pn = 95 HR p value
Median PFS, months 12.3 14.1 0.7890.231
(95% CI) (9.3‒14.5) (11.05‒16.2) (0.536‒1.162)
288 16 20 32
Stage 1 Phase II Trial of Enzalutamide in AR+ metTNBC
71yoTNBC5-yearDFI2prior regimensMBCCR32+weeksonRx
73yoTNBC6-yearDFIFirstLineMBC48+weeksonRX
TrainaT,etal.SABCS,2014
Summary – Triple Negative Breast Cancer
§ Systemic neo/adjuvant chemotherapy• Adjuvant anthracycline (TaxAC vs 6TC) improves DFS in TNBC• Addition of carboplatin to paclitaxel improves pCR rate with as yet
unknown effects on DFS – reasonable for high risk pts• In patients who do not develop a pCR with preoperative chemotherapy,
adjuvant treatment with capecitabine is a reasonable option
§ Promising Approaches• Nab paclitaxel/carboplatin first-line metTNBC and ?neoadjuvant• PARP inhibitors gBRCA pts• AKT, AR and PD-1/PD-L1 inhibitors• ADCs against Trop2 (sacituzumab) and GPNMB (glembatumumab)
32
Optimizing Therapy for HER2+ Breast Cancer
HER2+ Breast Cancer Following Adjuvant Trastuzumab: Risk of Locoregional or Distant Recurrence
� Approximately 20% of patients diagnosed with breast cancer are HER2+a (~35,000 patients annually in the USb)
� Trastuzumab has dramatically improved the outcome of HER2+ breast cancerc
� Despite these advances,
– 16-20+% pts recur with invasive breast cancer within 8 to 10 years after initial diagnosisdd,e
� No proven curative therapy for locally recurrent or metastatic HER2+ breast cancer following adjuvant trastuzumab
a Wolff AC, et al. J Clin Oncol 2013;31:3997-4013; b SEER database, 2015; c Dawood S, et al. J Clin Oncol 2010;28:92-98; d Perez E, et al. J Clin Oncol. 2014;32:3744-3752; e Goldhirsch A, et al. Lancet. 2013;382:1021-1028
Amplified
Not Amplified
Amplified
Not Amplified
Focal HER2 Amplification
CEP17
HER2
Current HER2+ Targeted Treatments
3737
a Yardley DA, et al. ASCO BC 201, Abstract 268; b Osborne CK, et al. Annu Rev Med. 2011;62:233-247; c Yamnik RL, et al. J Biol Chem. 2009;284(10):6361-6369; d den Hollander P, et al. Front Oncol. 2013;3:250; e Kümler I, et al. Cancer Rev Treat. 2014;40:259-270.
ER and PR Negative
AC Ú P
AC Ú P+H
N EventsAC→P 911 175AC→P+H 917 103
21.5%
11.9%
B-31/N9831 Cumulative Incidence of Distant Recurrence as a First Event
ER and/or PR Positive
AC Ú P
AC Ú P+H
Cum
ulat
ive
Inci
denc
e (%
)
N EventsAC→P 1105 216AC→P+H 1110 124
22.3%
12.7%
Years from Randomization
Δ= 9.6%
San Antonio Breast Cancer Symposium, December 4-8, 2012
Δ=9.6%
Slamon DJ, et al. 2015 San Antonio Breast Cancer Symposium. Abstract S5-04.
Disease Free Survival
Standard Trastuzumab-Based Adjuvant Therapy in HER2+ Breast Cancer (BCIRG 006)
One-quarter of patients remain at risk for DFS event after adjuvant trastuzumab therapy
Pertuzumab andtrastuzumab havecomplementarymechanismsofaction
HER2
Dimerisationdomain
Choetal.Nature2003;421:756–760;Fendlyetal.CancerRes1990;50:1550–1558;Franklinetal.Cancer Cell2004;5:317–328;Nahtaetal.CancerRes2004;64:2343–2346;Scheueretal.CancerRes2009;69:9330–9336
Pertuzumab
Trastuzumab
Subdomain IVTrastuzumab:• Inhibitsligand-independent HER2
signaling• ActivatesADCC• PreventsHER2ECDshedding
Pertuzumab:
• Inhibitsligand-dependent HER2dimerizationandsignaling
• Suppresses multipleHERsignallingpathways
• ActivatesADCC
HER1/3/4
CLEOPATRA study design
41HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; PD, progressive disease
Patients withHER2-positive MBC
centrally confirmed(N=808)
Placebo + trastuzumab
1:1
Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not)
Study dosing q3w:- Pertuzumab/Placebo: 840 mg loading dose, 420 mg maintenance- Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance - Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated
Docetaxel≥6 cycles recommended
n=406
n=402
Pertuzumab + trastuzumab
Docetaxel≥6 cycles recommended
PD
PD
Significant improvement in OS in favour of Pertuzumab armConfirmatory Overall survival analysis(Median follow-up: 30 month)
* Stopping boundary for concluding statistical significance at this second interim analysis was p≤0.0138D, docetaxel; Pla, placebo; Ptz, pertuzumab; T, trastuzumab
0 5 10 15 20 25 30 35 400
10
20
30
40
50
60
70
80
90
100
natrisk
0Ptz+T+D
0Pla+T+D
Time(months)
Overallsurvival(%
)
45 50 55
0
0
9
4
33
22
84
67
143
128
230
198
317
285
342
324
371
350
387
383
402
406
89%
94%
1year,Δ 5%
2years ,Δ 12%
69%
81% 3years, Δ 16%
66%
HR=0.6695%CI0.52−0.84
p=0.0008
No. of events%
Median (months)
Ptz + T + D 113 (28%) NR
Pla + T + D 154 (38%) 37.6
50%
Baselga J, et al. N Engl J Med 2012SABCS 2012 P5-18-26
NeoSphere:AdjuvantComponentStudyDesign
GianniL,etal. LancetOncol 2012;13:25–32
FEC,5-fluorouracil, epirubicin, andcyclophosphamide
S
U
R
G
E
R
Y
Studydosing:q3wx4
Patientswithoperableorlocallyadvanced/inflammatoryHER2-positive BC
Chemo-naive&primarytumors>2cm(N=417)
TD(n=107)trastuzumab (8®6mg/kg)docetaxel (75®100mg/m2)
PTD(n=107)pertuzumab (840®420mg)trastuzumab (8®6mg/kg)docetaxel (75®100mg/m2)
PT(n=107)pertuzumab(840®420mg)trastuzumab(8®6mg/kg)
PD(n=96)pertuzumab(840®420mg)docetaxel (75®100mg/m2)
FECq3wx3trastuzumabq3wcycles5–17
FECq3wx3trastuzumabq3wcycles5–17
docetaxelq3wx4® FEC q3wx3trastuzumabq3wcycles5–17
FECq3wx3trastuzumabq3wcycles5–21
44Gianni et al. Lancet Oncol 2012; 13: 25
Gianni et al. Lancet Oncol 2012; 13: 25
Aphinity (IBCSG39-11/BIG4-11)
CU-47WORKING DRAFT
Neratinib is active against metastatic HER2+ BC previously treated with trastuzumaba
aBurstein H et al. J Clin Oncol 28:1301-7, 2010
Trastuzumab Emtansine (T-DM1): Mechanism of Action
Emtansine release
Inhibition of microtubule
polymerization
Internalization
HER2
Adapted from LoRusso PM, et al. Clin Cancer Res 2011.
T-DM1
Lysosome
Nucleus
PP
P
Trastuzumab-specific MOA• Antibody-dependent cellular cytotoxicity (ADCC)
• Inhibition of HER2 signaling• Inhibition of HER2 shedding
Overall Survival:T-DM1 vs capecitabine/lapainib
496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5
Cap + LapT-DM1
No. at risk: Time (months)
78.4% 64.7%
51.8%
85.2%
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 360.0
0.2
0.4
0.6
0.8
1.0
Prop
ortio
n su
rviv
ing
Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012).
Median (months) No. of eventsCap + Lap 25.1 182T-DM1 30.9 149Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006
Efficacy stoppingboundary P=0.0037orHR=0.727
Katherine Study – NSABP/German Breast Group
NCT01772472
• HER2+, T1c-T4 / N0-3 / M0• Neoadjuvant therapy o 6 cycles/16 weekso Trastuzumab x 9 weeks
• Residual Invasive disease
Trastuzumab6 mg/kg q 3 weeks x 14
T-DM13.6 mg/kg q 3 weeks x 14
N = 1484
Enrollment: completed
Primary Endpoint: Invasive-Free SurvivalSecondary Endpoints: DFS, OS, DDFS, Safety, QOL
-100-75-50-25
0255075
100125150175200225250275
• A ≥30% reduction in the SLDs of target CNS lesions was observed in 43% of patients
CBR, the proportion of patients whose best response was CR, PR or SD ≥6 months
KAMILLA CNS metastases: Efficacy with T-DM1Response in brain mets according to clinical benefit rate (in all lesions, systemic and CNS)
% C
hang
e in
sum
of d
imen
sion
sbr
ain
targ
et le
sion
s
CBR responderYes (n=54)No (n=72)
Montemurro, et al. Poster presentation, Abstract P1-12-10, SABCS 2016
25PatientswithHER2SomaticMutations
• Eachbluecirclerepresentsapatient.• From8publicationswithatotalof1,499patients.• 20%ofpatientshavemutationsataminoacids309or310.• 68%ofpatientshavemutationsataminoacids755-781.
BoseRetal,CancerDiscovery2012
27% new HER2 Alterations met ILC
Ross J. Clin Cancer Res 19:2668, 2013
ERBB2-mutantbreastcancer(Neratinibmonotherapy):Tumorassessments
Data cutoff 24-JUN-2016
* * *
* Denotes patient that progressed with amplified ERBB2
Breast Cancer Cohort
57
Summary: HER2+ Breast Cancer• Alternate chromosome 17 probes can resolve equivocal FISH cases
• Preoperative TCHP for T2+ or N1+ disease – APHINITY results soon
• Neratinib extended therapy improves PFS in ER+ HER2+ disease
• Taxane + trastuzumab + pertuzumab standard first line MBC Rx
• T-DM1 second line Rx (no data post-THP)
• Capecitabine + lapatinib or trastutumab + lapatinib --- continue HER2-targeted therapy throughout metastatic course
• HER2 mutations/amplicons detected in MBC – HER2-directed Rx may be of benefit
Clinical Markers Predictors of Resistance to Endocrine Therapy
• Disease free interval from adjuvant therapy• Duration of response• Prior treatment• HER2 amplification• Lower ER expression
Need for improved hormone therapy with minimal toxicity
Comparison of First Line AI ± Fulvestrant Trials
FACT1 SWOG 02262
No. Patients 514 707De Novo Metastatic Disease
13% 39%
Prior Adjuvant Chemotherapy
45% 33%
Prior Adjuvant Endocrine Therapy (TAM)
68% 40%
Prior Adjuvant AI 1.5% excludedMedian TTP/PFS Range (mo)
10–11 13–15
PFS Benefit No YesMedian OS Benefit, (mo) No, 37.8 vs. 38.2
mosYes, 41.3 vs 47.7
mos
Fulvestrant 500 mg IM on Day 0 followed by 250 mg IM Day 14 and 28 then 250 mg every 28 days
1. Bergh J, et al. J Clin Oncol. 2012;30:1919-25 2. Mehta RS, et al. N Engl J Med. 2012;367:435-44
FALCON:(Fulvestrant and AnastrozoLe COmpared in hormonal therapy Naïve advanced breast cancer)
Randomised, double-blind, parallel-group, international, multicentre studyFollow-up for disease progression and survivalRandomisation of 450 patients was planned to achieve 306 progression events; if the true PFS HR was 0.69 this would provide 90% power for statistical significance at the 5% two-sided level (log-rank test)Stratification factors: prior chemotherapy for advanced disease (yes / no); measurable vs. non-measurable disease (at baseline); locally advanced vs. metastatic diseaseSubgroup analysis of PFS for pre-defined baseline covariates
aAssessed via RECIST 1.1, surgery / radiotherapy for disease worsening, or death; bInterim analysis at the time of PFS analysisEDoCB, expected duration of clinical benefit; EDoR, expected duration of response; FACT-B, Functional Assessment of Cancer Therapy – Breast; TOI, Trial Outcome Index
• Postmenopausal women• Locally advanced or
metastatic breast cancer• ER+ and / or PgR+• HER2-• Endocrine therapy-naïve
Fulvestrant 500 mg(500 mg IM on Days 0, 14 and 28, then every 28 days)
+ placebo to anastrozole
Anastrozole 1 mg (daily PO)
+ placebo to fulvestrant
Primary endpoint: PFSa
Secondary endpoints1:1 • OSb
• ORR• CBR• DoR, EDoR
• DoCB, EDoCB
• HRQoL (FACT-B total and TOI)
• Safety
FALCON: PRIMARY ENDPOINT, PFS
A circle represents a censored observation
HR 0.797 (95% CI 0.637, 0.999); p=0.0486
Median PFSFulvestrant: 16.6 monthsAnastrozole: 13.8 months
Number of patients at risk:FulvestrantAnastrozole
230232
187194
171162
150139
124120
110102
9684
8160
6345
4431
2422
1110
20
00
Prop
ortio
n of p
atien
ts ali
ve an
d pr
ogre
ssio
n fre
e
Time (months)
0.9
1.0
0.7
0.8
0.5
0.6
0.3
0.4
0.1
0.00 3 6 9 12 15 18 21 24 27 30 3633 39
0.2
Fulvestrant (n=230)
Anastrozole (n=232)
FALCON: PFS IN PATIENTS WITH OR WITHOUT VISCERAL DISEASE
Post hoc interaction test p<0.01A circle represents a censored observation
Without visceral disease With visceral disease
HR 0.59 (95% CI 0.42, 0.84)
Median PFS Fulvestrant: 22.3 monthsAnastrozole: 13.8 months
Prop
ortio
n of
patie
nts a
live a
nd pr
ogre
ssion
-free
Time (months)
0.9
1.0
0.7
0.8
0.5
0.6
0.3
0.4
0.1
0.0
0.2 Prop
ortio
n of
patie
nts a
live a
nd pr
ogre
ssion
-free
Time (months)
0.9
1.0
0.7
0.8
0.5
0.6
0.3
0.4
0.1
0.00 5 10 15 20 25 30 35 40
0.2
0 5 10 15 20 25 30 35 40
HR 0.99 (95% CI 0.74, 1.33)
Median PFS Fulvestrant: 13.8 monthsAnastrozole: 15.9 months
Fulvestrant (n=135) Anastrozole (n=119)
Fulvestrant (n=95) Anastrozole (n=113)
BOLERO-2: Study Design
EVE 10 mg daily+
EXE 25 mg daily (n = 485)
Placebo+
EXE 25 mg daily (n = 239)
Endpoints•Primary: PFS (local assessment)•Secondary: OS, ORR, CBR, QOL, safety, PK•Exploratory: Biomarkers
Stratification: • Sensitivity to prior hormone therapy • Presence of visceral metastases
65
Abbreviations: BC, breast cancer; CBR, clinical benefit rate; ER+, estrogen receptor-positive; EVE, everolimus; EXE, exemestane; HER2–, human epidermal growth factor receptor-2–negative; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PK, pharmacokinetics; QOL, quality of life.
Baselga J, et al. N Engl J Med. 2012;366(6):520-529.
N = 724• Postmenopausal women• ER+, HER2– unresectable
locally advanced or metastatic BC
• Recurrence or progression after letrozole or anastrozole
Randomize2:1
BOLERO-2 (18-mo): Final PFS Analysis Based on Local Assessment—Met Primary Endpoint (4.6-mo Prolongation of PFS)
1.0
0.8
0.6
Prob
abili
ty o
f Pr
ogre
ssio
n-Fr
ee S
urvi
val
0.4
0.2
02826242220181614
Time, months121086420
00
10
40
101
131
232
426
579
9917
14727
19442
23661
318103
394146
485239
EVE+EXEPBO+EXE
No. at risk
HR = 0.45 (95% CI, 0.38-0.54)Log-rank P < .0001
Kaplan-Meier mediansEVE+EXE: 7.8 monthsPBO+EXE: 3.2 months
Censoring timesEVE+EXE (n/N = 310/485)PBO+EXE (n/N = 200/239)
Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival.
Yardley DA, et al. Adv Ther. 2013;30(10):870-884. 66
PrECOG 0102• Evaluated everolimus and fulvestrant vs
fulvestrant + placebo (N=131)• Advanced ER+, HER2-, post menopausal • Previously treated with AI, or relapsing on AI• PFS: 10.4 mos vs 5.1 mos (p=0.02)• Expected toxicities
Kornblum SABCS2016
Reversible Histone Acetylation Regulates Gene Expression
Yoo CB and Jones PA. Nat Rev Drug Discov.2006;5:37
Histoneacetylation
Pol2 mRNA
Activated Chromatin(hyper-acetylated
histones)
Ac-
Ac-
Ac-
Ac-
Ac-Ac-
Ac-
Ac-
HAT
TranscriptionalFactors
Corehistones
(hypo-acetylated histones)
Repressed Chromatin
Repressed Chromatin
Cofactors
HDACsHistone
deacetylation
HDACInhibitor
Entinostat and Exemestane
• Post-menopausal ER+ advanced breast cancer
• Progressed on/or relapsed while taking a NSAI
exemestane +entinostat
exemestane +placebo
N= 130
1:1
NSAI settingBone onlyRegion
Yardley et al 2013
Entinostat and Exemestane
PFS: 2.3 mos to 4.3 mosHR 0.73 95% CI 0.5-1.07
mOS: 19.8 mos to 28.1 mosHR 0.59 95% CI 0.36-0.97
Yardley et al 2013
Entinostat and Exemestane: Toxicity
Yardley et al 2013
Entinostat and Exemestane: Phase III
0
100
200
300
400
500
600
700
800
900
1000
MB-175
ZR75
-30
CAMA-1
MB134
HCC202
UACC-893
EFM19
SUM190
EFM19
2A
MB-361
HCC1500
HCC1419
HCC38
MB-415
MCF-10A
UACC-812
HCC2218
ZR75
-1
MDAMB453
184A
1T4
7DMCF7
BT-20
MDAMB435
BT474
SKBR3KPL-1
HCC1143
MDAMB231
HCC1395
SUM-225
HS578T
184B
5
UACC732
CAL-51
BT549
COLO82
4
DU4475
HCC1187
HCC1569
HCC1806
HCC1937
HCC1954
HCC70
MB-436
MB157
MDAMB468
SubtypeLuminal Non-luminal/post EMTHER2 amplified Non-luminalImmortalized
Palbociclib: CDK 4/6 Inhibitor – Breast Panel
Finn RS, et al. Breast Cancer Res. 2009;11(5):R77.
FinnRSetalNEJM2016
Subgroup Analysis of PFS by Biomarker
HR=hazard ratio; LET=letrozole; PAL=palbociclib; PCB=placebo; PFS=progression-free survival.
n HR (95% CI)
All patients
666
0.58 (0.46–0.72)
ER+ER–
504 62
0.57 (0.44–0.74)
0.41 (0.22–0.75)
Rb+Rb–
512 51
0.53 (0.42–0.68)
0.68 (0.31–1.48)
CyclinD1+
CyclinD1–
54915
0.56 (0.44–0.71)
1.0 (0.29–3.46)
p16+p16–
46684
0.52 (0.40–0.67)
0.73 (0.39–1.36)
Ki-67 ≤20%Ki-67 >20%
318235
0.53 (0.38–0.74)
0.57 (0.41–0.79)
0 1 2 3 4
HR (95% CI)
Favors PAL+LET Favors PCB+LET
Percentile n HR (95% CI)
All patients 666
0.58 (0.46–0.72)
ER status
≤25th
>25th to <75th
≥75th
142282142
0.50 (0.32–0.78)
0.53 (0.37–0.74)
0.65 (0.41–1.05)
Rbstatus
≤25th
>25th to <75th
≥75th
154249160
0.57 (0.36–0.88)
0.46 (0.32–0.67)
0.63 (0.42–0.95)
CyclinD1 status
≤25th
>25th to <75th
≥75th
141247176
0.41 (0.26–0.65)
0.69 (0.48–1.00)
0.52 (0.34–0.78)
p16 status
≤25th
>25th to <75th
≥75th
14025815
0.74 (0.46–1.20)
0.62 (0.44–0.89)
0.33 (0.21–
0 .0 0 .5 1 .0 1 .5HR (95% CI)
Favors PAL+LET Favors PCB+LET
Qualitative Analysis Quantitative Analysis
Placebo (3 wks on/ 1wk off)
+ Fulvestrant†
(500 mg IM q4w)
Palbociclib (125 mg QD;
3 wks on/1 wk off)+
Fulvestrant†
(500 mg IM q4w)
†administered on Days 1 and 15 of Cycle 1.
● Visceral metastases● Sensitivity to prior hormonal
therapy● Pre-/peri- vs Post-menopausal
Clinicaltrials.gov NCT01942135
2:1 Randomization
N=521
Stratification:
• Post-menopausal patients must have progressed on prior aromatase inhibitor therapy.
n=347
n=174
• HR+, HER2– ABC• Pre-/peri-* or post-menopausal • Progressed on prior endocrine
therapy:– On or within 12 mo adjuvant– On therapy for ABC
• ≤1 prior chemotherapy regimen for advanced cancer
*All received goserelin.
Design of Phase III Study in Recurrent MBC (1023)-PALOMA-3
0 2 4 6 8 10 12Time (Month)
0
10
20
30
40
50
60
70
80
90
100
PFS
Prob
abili
ty (%
)
347 279 132 59 16 6PAL+FUL
174 109 42 16 6 1PCB+FUL
Number of patients at risk
PALOMA3: Primary Endpoint: PFS (ITT Population)
CI=confidence interval; HR=hazard ratio; ITT=intent-to-treat; NE=not estimable; PFS=progression-free survival.
Palbociclib + Fulvestrant
n=347
Placebo + Fulvestrant
n=174
Median PFS, months(95% CI)
9.2(7.5, NE)
3.8(3.5, 5.5)
HR (95% CI) 0.422 (0.318, 0.560)2-sided P value <0.000001
Turner N et al NEJM 2015
Regardless of study treatment relationshipNON-HEMATOLOGIC ADVERSE EVENTS
Adverse Event≥15% in Either Arm, %
Ribociclib + Letrozolen=334
Placebo + Letrozolen=330
All Grade 3 Grade 4 All Grade 3 Grade 4Nausea 52 2.4 0 29 0.6 0Infections 50 3.6 0.6 42 2.1 0.3Fatigue 37 2.1 0.3 30 0.9 0Diarrhea 35 1.2 0 22 0.9 0Alopecia 33 – – 16 – –Vomiting 29 3.6 0 16 0.9 0Arthralgia 27 0.6 0.3 29 0.9 0Constipation 25 1.2 0 19 0 0Headache 22 0.3 0 19 0.3 0Hot flush 21 0.3 0 24 0 0Back pain 20 2.1 0 18 0.3 0Cough 20 0 – 18 0 –Decreased appetite 19 1.5 0 15 0.3 0Rash 17 0.6 0 7.9 0 0ALT increased 16 7.5 1.8 3.9 1.2 0AST increased 15 4.8 0.9 3.6 1.2 0
u In the ribociclib arm 10 (3.0%) patients experienced Grade 2 QTcF (481–500 ms) and 1 (0.3%) patient experienced Grade 3 QTcF (>500 ms); no dose reductions were required
MONALEESA-3
NCT02422615
MONALEESA-7
NCT02278120
MONARCH 1: Phase 2 Study Design
Previously-treated
HR+/HER2- MBC
Abemaciclib 200 mg orally
Q12H
Treatment continued until unacceptable toxicity or PD
♦ Primary objective• To evaluate abemaciclib with respect to confirmed objective response rate
based on investigator assessment (per RECIST v1.1)
♦ Secondary objectives• Duration of response, progression-free survival, overall survival, clinical
benefit rate, safety
♦ Statistical design• A sample size of 128 patients provides 82% power, assuming a true response
rate of 25%, to exclude an ORR of ≤15 % on the lower bound of the 95 % CI at 12 months follow-up
♦ Clinical trial ID: NCT02102490
MONARCH 1: Prior Therapies♦ Median number of prior systemic regimens (any setting) was 5 (range 2-11)
♦ 100% of patients received taxanes in any setting
♦ Median number of prior systemic regimens for metastatic disease was 3 (range 1-8) Chemotherapy
for Metastatic Disease
N = 132n (%)
# of Regimens
1 67 (50.8)
2 64 (48.5)
3 1 (0.8)
Taxanes 91 (68.9)
Endocrine Therapy for Metastatic Disease
N = 132n (%)
# of Regimens1 48
(36.4)2 25
(18.9)3 24
(18.2)≥ 4 18
Cha
nge
from
Bas
elin
e (%
)
100
0
-100
-50
-30
50
20
Disease Control Rate (CR + PR + SD) = 67.4%
Progressive disease (n = 34)Stable disease (n = 63)Partial response (n = 26)Not assessed (n = 9) aAssessments based on independent review
were comparable
Investigator Assessed ResponseaAbemaciclib
200 mg (N = 132)
Confirmed Objective Response Rate (ORR = CR + PR)(95 % CI)
19.7% (13.3, 27.5)
CRPR
0%19.7%
Stable Disease ≥ 6 months 22.7%Clinical Benefit Rate (CBR = ORR +SD ≥ 6 mos)
42.4 %
MONARCH 1: Response Summary
Dickler M. et al. J Clin Oncol 34, 2016 (suppl; abstr 510)
MONARCH 1: Kaplan-Meier Plots
A. Progression-free Survival
Patients/Events 132/100
Median, months 5.95
95% CI 4.21, 7.50
89 54132 72 43 38 25 1010 10 7 6Pts at Risk:
2 0
Surv
ival
Pro
babi
lity
Pts = patients, NR = not reached
Months MonthsPts at Risk:
132
128
121
116
111
105
92
85
76
65
39
22
8 2 0
B. Overall Survival
Patients/Events 132/62
Median, months 22.32
95% CI 17.7, NR
Surv
ival
Pro
babi
lity
Abemaciclib 200 mg
1.0
0 2 4 6 8 10 12
14
16
18
20
22
24
26
0.0
0.2
0.4
0.6
0.8
0.1
0.3
0.5
0.7
0.9
IIIIIIIII
III
II
IIII
I I IIII
I I I I I I II
aCTCAEVersion4.03,bN = 130forlababnormalities listed,except plateletcount decreased(N = 128), cAbemaciclibisacompetitive inhibitor ofOCT2,MATE1,andMATE2-K,effluxtransporters ofcreatinine;cystatinCcalculatedGFRwasnotraised,dOnepatient whoreceivedcytotoxic chemotherapywithin the30dayfollowupwindow experienced febrileneutropenia
MONARCH 1: Most Common Adverse Events
Investigator Assessed TEAEsa >20% (N = 132)
Grade 1%
Grade 2%
Grade 3%
Grade 4%
All Grades
%Diarrhea 41.7 28.8 19.7 0 90.2Nausea 39.4 21.2 4.5 0 65.2Fatigue 20.5 30.3 13.6 0 64.4Decreased appetite 28.0 14.4 3.0 0 45.5Abdominal pain 22.0 14.4 2.3 0 38.6Vomiting 23.5 10.6 1.5 0 35.6Headache 13.6 6.8 0 0 20.5Pain 12.1 6.8 1.5 0 20.5Lab abnormalitiesb TEAEsa > 40% Creatinine increasedc (CTCAE v 4.03: over baseline) 46.9 50.8 0.8 0 98.5White blood cell decreased 20.0 44.6 27.7 0 92.3Neutrophil count decreased 16.9 43.8 22.3 4.6 87.7d
Anemia 30.0 39.2 0 0 69.2Lymphocyte count decreased 4.6 23.1 13.8 0.8 42.3Platelet count decreased 28.9 10.2 2.3 0 41.4
Abemaciclib (LY2835219): MONARCH 2
Primary endpoint: Progression-Free Survival (PFS)
Women with HR+, HER2-Locally Advanced or
Metastatic Breast Cancer(N=550)
R
LY2835219 + Fulvestrantuntil PD
Placebo + Fulvestrant until PD
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant with or without LY2835219, a CDK4/6 Inhibitor, for Women with Hormone Receptor Positive, HER2 Negative
Locally Advanced or Metastatic Breast Cancer
2:1
NCT02107703
MARCH 20, 2017: Met its Primary Endpoint
Evolution of ER+ Breast Cancer
1977 1995 2012 201519991997 20102002
Modifeid from Chemlowski epub 2012
20051970
Tamoxifen(1977)
Anastrazole(1995)
Examestane(1999)
Palbociclib(2015)
Toremifene(1997)
Letrozole(1997)
19901980
Everolimus(2012)
Fulvestrant 250 mg(2002)
Fulvestrant 500 mg(2010)
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