Novedades en Cáncer de Mama del 4º trimestre:

ESMO y SABCS

Dr. José Ángel García Sáenz

• Factores pronósticos : TILs y CTCs

• Terapia antiangiogénica: TRIO012 y BETH

• Enfermedad HER2+: NeoALTTO y TH3RESA

Infiltración linfocitaria tumoral (TILs)

Loi S. SABCS 2013; Denkert C. SABCS 2013; Adams S. SABCS 2013

TRASTUZUMAB NEOADYUVANTE

CBDCA NEOADYUVANTE (Triple Negativo y HER2+)

QT ADYUVANTE (Triple Negativo)

GeparQuattro

GeparSixto

ECOG2197 y 1199

TECNOLOGIA PARA AISLAR Y CUANTIFICAR CTC

TECNOLOGIA PARA AISLAR Y CUANTIFICAR CTC

Célula Epitelial

TECNOLOGIA PARA AISLAR Y CUANTIFICAR CTC

Célula Epitelial

EpCAM

Anti-EpCAM Ferrofluid

TECNOLOGIA PARA AISLAR Y CUANTIFICAR CTC

Célula Epitelial

EpCAM

Anti-EpCAM Ferrofluid

CK

Anti- CK-PE

Nucleus DAPI

TECNOLOGIA PARA AISLAR Y CUANTIFICAR CTC

Célula Epitelial

EpCAM

Anti-EpCAM Ferrofluid

CK

Anti- CK-PE

Nucleus DAPI

Leucocito

TECNOLOGIA PARA AISLAR Y CUANTIFICAR CTC

Célula Epitelial

EpCAM

Anti-EpCAM Ferrofluid

CK

Anti- CK-PE

Nucleus DAPI

Leucocito

Nucleus DAPI

TECNOLOGIA PARA AISLAR Y CUANTIFICAR CTC

Célula Epitelial

CK

Anti- CK-PE

Leucocito

CD45

Anti - CD45-APC

Nucleus DAPI

Nucleus DAPI

EpCAM

Anti-EpCAM Ferrofluid

TECNOLOGIA PARA AISLAR Y CUANTIFICAR CTC

DAPI CK-PE CNTL CD45-APC Comp

Células Tumorales Intactas

Martin M et al. Oncologist 2013

Circulating tumor cells following first chemotherapy

cycle: an early and strong predictor of outcome in patients with metastatic breast cancer.

Time (months) 60 48 36 24 12 0

% o

f p

ati

en

ts

100%

80%

60%

40%

20%

0%

>=5

<5

CTC-21

Overall Survival

P<0.001

Time (months) 60 48 36 24 12 0

%o

f p

ati

en

ts

100%

80%

60%

40%

20%

0%

>=5

<5

CTC-21

Progression Free

Survival

P=0.001

European Pooled Analysis of CTCs in metastatic BC:

findings from 1944 individual pts data

Main inclusion criteria:

MBC patients treated 2003 - 2012 in European centres using CellSearch

CTC count before a new line of therapy +/- during treatment

No change of therapy based on CTC count

Bidard FC y cols. ESMO 2013 & SABC2013

Results – CTC at baseline

≥5 CTC / 7.5mL were detected in 47% of the 1,944 patients at baseline

Results – CTC at baseline

≥5 CTC / 7.5mL were detected in 47% of the 1,944 patients at baseline

CTC count at baseline was associated with

First line (N=1,110) All patients

Performance status p<0.0001 p<0.0001

Liver metastases p<0.0001 p<0.0001

Bone metastases p<0.0001 p<0.0001

Elevated CEA p<0.0001 p<0.0001

Elevated CA15-3 p<0.0001 p<0.0001

Tumor subtype p=0.71 p<0.0001

≥5 CTC

HR+ 51%

HER2+ 38%

T. Neg 44%

Results – CTC at baseline

Prognostic value – univariate analysis

Overall Survival

N= 1,944 patients

HR = 2.77

p<0.0001

Progression-Free Survival

N= 1,899 patients

HR = 1.92

p<0.0001

Kaplan-Meier Curve of PFS by Baseline CTC

PFS

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24

Months

Cohort Patients Events

CTC <5 1014 735

CTC >=5 885 772

1014 685 394 211 115

885 439 174 79 35 CTC >=5

CTC <5

Number at risk

Kaplan-Meier Curve of OS by Baseline CTC Count

OS

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24 30 36

Months

Cohort Patients Events

CTC <5 1033 371

CTC >=5 911 558

1033 896 701 496 333 230 162

911 639 396 237 147 85 53 CTC >=5

CTC <5

Number at risk

CTC < 5 /7.5 ml

CTC ≥ 5 /7.5 ml

CTC < 5 /7.5 ml

CTC ≥ 5 /7.5 ml

Bidard FC y cols. ESMO 2013 & SABC2013

Results – Early CTC changes during treatment

Baseline & week 3-5

Similar OS curves were obtained with later CTC changes (6-8 weeks)

Overall Survival

N= 672 patients; p<0.0001

N Pts N Events

Median OS

months [95%CI]

Stable neg: <5 - <5

327 104 41

[37-53]

Decrease: ≥5 - <5

149 70 27

[22-31]

Increase: <5 - ≥5

17 10 22

[12-NE]

Stable pos: ≥5 - ≥5

179 116 13

[9-16]

Landmark Analysis at 5 Weeks: Kaplan-Meier Curve of OS by Early Change in CTC

OS

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24 30 36

Months

Cohort Patients Events

Decrease: >=5 - <5 149 70

Increase: <5 - >=5 17 10

Stable neg.: <5 - <5 327 104

Stable pos.: >=5 - >=5 179 116

149 135 104 59 36 20 11

17 13 11 7 4 2 1327 296 231 160 102 68 50

179 116 68 36 18 10 5 Stable pos.: >=5 - >=5

Stable neg.: <5 - <5Increase: <5 - >=5

Decrease: >=5 - <5

Number at risk

Conclusions

CTC count (CellSearch®) has reached a level of evidence 1 for clinical validity

Ongoing interventional trials are assessing the CTC clinical utility in breast cancer

SWOG 500

(accrual completed)

CirCe T-DM1 DETECT III

DETECT IV

Chemotherapy

management

Prognostic value STIC CTC

CirCe 01

Targeted therapies

• Objetivo principal: SG

Same 1st Line

Change CHEMO

Smerage JB. SABC2013

120 MBC 1st Line CHEMO

No-CTC response by day 21

SWOG0500 Phase III. Changing versus maintaining therapy for MBC patients who have elevated CTC levels at 1st follow-up assessment

Smerage JB. SABC2013

Study n Treatment OR PFS OS

E2100 722 Paclitaxel +/- BEV 37x21 p<0.001

11.8 x 5.9 p<0.001

27x25 NS

AVADO 736 Docetaxel +/- BEV (LD) 55x44

p:0.029

8.7 x 8.0 p:0.03

NR

Docetaxel +/- BEV (HD) 63x44 p:0.001

8.7 x 8.0 p:0.0099

NR

RIBBON-1 1237 Cape +/- BEV 51x38

p:0.0054

10.7 x 8.3 p:0.04

25x23 NS

A/T +/- BEV 35x27 p:0.0097

9.8 x 6.2 p:0.011

29x21 NS

Miller. NEJM 2007; Miles. JCO 2010; Robert. JCO 2011

• Primary: PFS

• Other: OS, TTP. OR. RD. Safety

Docetaxel

IMC1121B

Docetaxel

Placebo

Mackey. SABC2013

1st Line HER2 MBC

n:1113

ROSE/TRIO-12, a randomized placebo controlled phase III trial evaluating the addition of ramucirumab to first-line

docetaxel chemotherapy in MBC

PD

PD

Mackey. SABC2013

Docetaxel + Ramucirumab

Docetaxel + Placebo

DFS 9.5m 8.2m NS

OS 27.3m 27.2m NS

G3-4 AEs 61.7% 52.1%

FASE III. Docetaxel-Trastuzumab +/- Bevacizumab (AVEREL)

Gianni L. JCO 2013

Docetaxel-Trastuzumab

Docetaxel-Trastuzumab

Bevacizumab

Cancer de mama HER2+ IV

Progression Free Survival E

stim

ate

d p

robabili

ty

Time (months)

0 6 12 18 24 30 36 42 48 54

1.0

0.8

0.6

0.4

0.2

0.0 13.7 16.5

H + DOC

(n=208)

H + DOC + BEV

(n=216)

Events, n (%) 154 (74.0) 153 (70.8)

Median PFS, months

(95% CI)

13.7

(11.4‒16.3)

16.5

(14.1‒19.1)

HR, unstratified

(95% CI)

0.82

(0.65‒1.02)

Gianni L. JCO 2013

• Primary: IDFS

• Other: DFS, OS, Safety

TCH* + Trastuzumab

TCH* + Trastuzumab +

Bevacizumab

Slamon. SABC2013

HER2+ (central) N+ or high-risk N-

n:3600

Phase 3. Adjuvant chemotherapy and trastuzumab ± bevacizumab in HER2-positive, node-positive or high risk node-negative breast cancer

+/- RT

HT

+/- RT

HT

RCP con doble bloqueo de HER2

0 20 40 60 80 100

TP-DC x6

FEC x3 - TPD x3

(FEC-TP x3) - TPD x3

TP

PD

TD

TPD

LT - Pac

T - Pac

L - Pac

LT- Pac

T - Pac

TRYP

HA

ENA

N

EOSP

HER

E N

EOA

LTO

C

ALG

B6

01

Harris L. ASCO 2013

NeoALTTO (n: 455)

Baselga. Lancet 2012

RcP 28%

RcP 20%

RcP 51%

NeoALTTO (n: 455)

Baselga. Lancet 2012

RcP 28%

RcP 20%

RcP 51%

Mutaciones PI3KCA y RCP

Baselga. ESMO 2013

Lapatinib + Trastuzumab

Lapatinib

Trastuzumab

RCP en PI3KCA no mutado

56% 20% 28%

RCP en PI3KCA mutado

20% 15% 20%

EFS OS

Piccart-Gebhart M. SABC2013

Long-term Outcome

DFS and pCR

Emtansine release

Inhibition of microtubule polymerization

Internalization

T-DM1

Lysosome

Nucleus

P P

P

Trastuzumab Emtansine (T-DM1)

2

T-DM1 (optional

crossover)

• Co-primary endpoints: PFS by investigator and OS

• Key secondary endpoints: ORR by investigator and safety

PD

PD T-DM1

3.6 mg/kg q3w IV (n=400)

Treatment of

physician’s

choice (TPC) (n=200)

HER2-positive (central) advanced BC

(N=600) ≥2 prior HER2-directed

therapies for advanced BC Prior treatment with

trastuzumab, lapatinib, and a taxane

1

Wildiers. ESMO 2013

Characteristic

TPC (n=198)

T-DM1 (n=404)

<65 years 82.8 85.4

ECOG 0-1 92% 94%

ER and/or PR-positive, % 52.0 51.5

Visceral mts, % 75.8 74.8

Number of prior regimens MBC 4 4

Brain metastasis at baseline, % 13.6 9.9

Wildiers. ESMO 2013

TPC treatment category TPC Combination with HER2-directed agent, %

Chemotherapyb + trastuzumab

Lapatinib + trastuzumab

Hormonal therapy + trastuzumab

Chemotherapyb + lapatinib

83.2

68.5

10.3

1.6

2.7

Single-agent chemotherapy,b % 16.8

.

T-containing

80.4

Wildiers. ESMO 2013

PFS by Investigator Assessment

198 120 62 28 13 6 1 0

404 334 241 114 66 27 12 0

TPC

T-DM1

No. at risk: Time (months)

14 12 10 8 6 4 2

0.0

0.2

0.4

0.6

0.8

1.0

0

Pro

po

rtio

n p

rog

res

sio

n-f

ree

TPC

(n=198)

T-DM1

(n=404)

Median (months) 3.3 6.2

HR=0.528 (95% CI, 0.422, 0.661)

P<0.0001

Wildiers. ESMO 2013

First Interim OS Analysis

44 patients in the TPC arm received crossover T-DM1 treatment after documented progression.

Unstratified HR=0.57 (P=0.004).

Wildiers. ESMO 2013

ORR in Measurable Disease

Difference: 22.7% (95% CI, 16.2, 29.2)

P<0.0001 P

atie

nts

, %

0

5

10

15

20

25

30

35

40

T-DM1 TPC

31.3%

8.6%

108/345 14/163

Wildiers. ESMO 2013

Grade ≥3 AEs With Incidence ≥2%

TPC (n=184) T-DM1 (n=403)

Any grade Grade ≥3 Any grade Grade ≥3

Nonhematologic AEs, %

Diarrhea 21.7 4.3 9.9 0.7

Hematologic AEs, %

Neutropenia 21.7 15.8 5.5 2.5

Febrile neutropenia 3.8 3.8 0.2 0.2

Anemia 10.3 2.7 8.9 2.7

Leukopenia 6.0 2.7 0.7 0.2

Thrombocytopenia 3.3 1.6 15.1 4.7

Wildiers. ESMO 2013

Conclusions

• T-DM1 demonstrated improved efficacy and safety compared with TPC

• These data reaffirm the results from the EMILIA study