Is there still a place for chemotherapy in the HER -2 positive breast cancer?

Joelle COLLIGNON

Guy JERUSALEMGuy JERUSALEM

HER2: role in breast cancer

Human epidermal growth factor receptor 2 (HER2) is a transmembrane protein

Overexpression of HER2 occurs in 15% of breast canc ers

HER2 positivity is associated with

- aggressive disease

- a high risk of relapse

- poor survival

50%

25,1

20,3

60

80

100

20

30

Chemotherapy +/- Trastuzumabin Metastatic Breast Cancer

Months (T

TP, survival)

OR

R (

%)

Trastuzumab + Chemotherapy (n=235)

Chemotherapy (n=234)

50%

32%7,4

4,6

0

20

40

60

0

10

ORRP<0.001

MedianTTPP<0.001

MediansurvivalP=0.046

Months (T

TP, survival)

OR

R (

%)

Slamon D et al, N Eng J Med 2001

4 years follow -up joint analysisNCCTG N9831 and NSABP B -31

Kaplan-Meier estimates of overall survival

Perez E A et al. JCO 2011;29:3366-3373

Human Epidermal Growth Factor Receptor (HER) Family of Receptors and Therapeutic Agents Currently Available or in Development.

Gradishar WJ. N Engl J Med 2012;366:176-178 .

C Inhibition of tyrosine kinase activity

A Inhibition through direct antibody binding

B Inhibition throughdimerisation inhibition

ANTI-HER2 THERAPIES

Lapatinib

J. Baselga and S. Swain, Nature Reviews Cancer,2009

NEOADJUVANT TREATMENT:pCR is predictive of outcome

in HER positive disease

Loibl S, et al, SABCS, 2011

N = 66

NEOADJUVANT TREATMENT WITHOUT CHEMOTHERAPY

Chang J et al, ASCO, 2011

NEOADJUVANT TREATMENT Pathologic response

Chang J et al, ASCO, 2011

DUAL Blockade with Taxanes:NeoALLTO and NeoSphere: Study Design

EFFICACY – pCR and tpCR

Baselga J et al, SABCS, 2010

NeoSphere: Primary endpointPathologic complete response

Adjuvant anti-HER2 therapies will be compared in the ALTTO trial

8000 women with HER2-positive breast cancer

CTx

Herceptin®

x 1 year

Lapatinib

x 1 year

Herceptin®

lapatinib

Herceptin®

+ lapatinib

• Includes translational research, eg tumour and bloo d collection

Trastuzumab and pertuzumab in the adjuvant setting: the APHINITY trial

CLEOPATRA trial: Primary endpoint Independently assessed PFS (n = 433 PFS events)

50

60

70

80

90

100 Ptz + T + D: median 18.5 months

Pla + T + D: median 12.4 months∆ = 6.1 months

free

sur

viva

l (%

)

D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab

0 5 10 15 20 25 30 35 40

0

10

20

30

40

n at risk

402 345 267 139 83 32 10 0 0Ptz + T + D

406 311 209 93 42 17 7 0 0Pla + T + D

Time (months)

HR = 0.6295% CI 0.51‒0.75

p<0.0001

Pro

gres

sion

-fr

ee s

urvi

val (

%)

Baselga et al, SABCS, 2011

TAnDEM study: Anastrazole +/- trastuzumab

Kaufman B,J Clin Oncol , 2009, 27:5529-5537

EGF 30008:Letrozole +/- lapatinib

Johnston,J Clin Oncol 2009; 27(33):5538-5546.

HER2+/ ER+ metastatic breast cancerfirst-line treatment

Combination with

Combination with

chemotherapy

HO648g M77001Combination with

aromatase inhibitors

TAnDEMEGF30008 eLEcTRA

Cortes et al. Nat. Rev. Clin. Oncol. 2011;8:307-11

T-DM1: A HER2-Targeted Antibody-Drug Conjugate

Humanized HER2 mAb: trastuzumab

T-DM1 retains antitumor activities of trastuzumab

Cytotoxic drug: DM1

Systemically stable

Nonreducible thioether linker: SMCC T-DM1

Potent cytotoxic agent (inhibitor of tubulin polymerization and

microtubule dynamics)

Progression -Free Survival by InvestigatorP

ropo

rtio

n pr

ogre

ssio

n-fr

ee

1.0

0.8

0.6

MedianPFS, mos

Hazard ratio 95% CI

Log-rank P value

9.214.2

0.5940.364–0.968

0.0353

Time (months)

Pro

port

ion

prog

ress

ion

0.4

0.2

0.00 2 4 6 8 10 12 14 16 18 20

Number of patients at risk

T+D 70 66 63 53 43 27 12 4 2 2 0T-DM1 67 60 51 46 42 35 22 15 6 3 0

Hazard ratio and log-rank P value were from stratified analysis.

Trastuzumab+ docetaxel (n=70)T-DM1 (n=67)

Hurwitz SA et al. ESMO 2011 Abstr 5001

Adverse Event Summary

Safety Evaluable Patients

T-DM1(n=67)

Trastuzumab+Docetaxel(n=68)

Any AE, n (%) 63 (94.0) 68 (100.0)

Grade ≥3 AE 25 (37.3) 51 (75.0)

Serious AE* 13 (19.4) 15 (22.1)Serious AE* 13 (19.4) 15 (22.1)

Three most common AEs (any grade) in T-DM1 armNauseaFatiguePyrexia

32 (47.8)31 (46.3)24 (35.8)

27 (39.7)29 (46.2)14 (20.6)

Three most common AEs (any grade) in trastuzumab + docetaxel arm

AlopeciaNeutropeniaDiarrhea

1 (1.5)5 (7.5)7 (10.4)

45 (66.2)39 (57.4)31 (45.6)

Perez EA, et al. Abstr LBA3. ESMO 2010

First-line HER2-positive mBC

MARIANNE trial

Is there still a place for chemotherapy in the HER2 positive breast cancer?

Chemotherapy should be given to all patients in the adjuvant setting

A high pCR rate is observed with dual HER2 blocade in the neoadjuvant setting. We don’t have predictive facto rs allowing to identify patients who don’t need chemot herapy

Chemotherapy is also indicated for endocrine sensit ive tumors overexpressing HER2