Update in the treatment of Her2- overexpressing breast cancers. Fabrice ANDRE Institut Gustave Roussy Villejuif, France

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1 Update in the treatment of Her2- overexpressing breast cancers Fabrice ANDRE Institut Gustave Roussy Villejuif, France

2 Questions Should tumors <1 cm receive trastuzumab? What is the optimal regimen of trastuzumab? Concomitant versus sequential Duration Should patients receive anthracyclines? Which endocrine therapy? Which patients present a high risk of relapse after chemotherapy and trastuzumab? Are dual inhibition ready for prime time in the neoadjuvant setting? Which first line in the metastatic setting? Pertuzumab TDM1 New drugs Everolimus PI3K inh Anti PDL1 / PD1 Brain metastases

3 Should tumors <1 cm receive trastuzumab? Retrospective analysis +++ Most of the guidelines recommend trastuzumab treatment for tumor size ranged between 5 to 10 mm Rodriguez, J Clin Oncol, 2010

4 Questions Should tumors <1 cm receive trastuzumab? What is the optimal regimen of trastuzumab? Concomitant versus sequential Duration Should patients receive anthracyclines? Which endocrine therapy? Which patients present a high risk of relapse after chemotherapy and trastuzumab? Are dual inhibition ready for prime time early breast cancers? Which lines in the metastatic setting? Pertuzumab TDM1 New drugs Everolimus PI3K inh Anti PDL1 / PD1 Brain metastases

5 NCCTG N9831: DFS for sequential vs concurrent trastuzumab No. at risk Alive and disease- -free (%) % 85.7% n Events HR % CI % 79.8% P value* AC TH AC T H Years from randomisation Perez EA, et al *Significant P value pre-defined as P=

6 Are shorter regimen equivalent to 1 year treatment?

7 maybe when T is administered concomitantly to chemotherapy Pivot, SABCS, 2012

8 Take home message Standard of care is 1 year trastuzumab started concomitantly to taxanes Additional studies exploring length of Additional studies exploring length of administration will be reported soon

9 Questions Should tumors <1 cm receive trastuzumab? What is the optimal regimen of trastuzumab? Concomitant versus sequential Duration Should patients receive anthracyclines? Which endocrine therapy? Which patients present a high risk of relapse after chemotherapy and trastuzumab? Are dual inhibition ready for prime time early breast cancers? Which therapies in the metastatic setting? Pertuzumab TDM1 New drugs Everolimus PI3K inh Anti PDL1 / PD1 Brain metastases

10 BCIRG 006: DFS at 5 years of follow-up 100 Alive and disease-f free (%) AC TH TCH AC T n Events HR (ref) 95% CI Years from randomisation P value < AC TH TCH AC T Slamon D, et al. 2009

11 BCIRG 006: Cardiac deaths and CHF (independently adjudicated) Events, n Cardiac-related death AC T n=1050 AC TH n=1068 TCH n=1056 First analysis (23 months) Second analysis (36 months) Third analysis (65 months) Cardiac left ventricular function (CHF) Grade 3/4 First analysis (23 months) Second analysis (36 months) Third analysis (65 months) Slamon D, et al P= P<0.001

12 Should patients receive A? In high risk patients, administration of A is still recommended Open questions: Could A be given concomitantly to trastuzumab in high risk patients? Molecular predictors to define sensitive population to A

13 Questions Should tumors <1 cm receive trastuzumab? What is the optimal regimen of trastuzumab? Concomitant versus sequential Duration Should patients receive anthracyclines? Which endocrine therapy? Which patients present a high risk of relapse after chemotherapy and trastuzumab? Are dual inhibition ready for prime time in the neoadjuvant setting? Which therapies in the metastatic setting? Pertuzumab TDM1 New drugs Everolimus PI3K inh Anti PDL1 / PD1 Brain metastases

14 Lymphocytic infiltration could identify a subset of patients with Low residual risk of relapse after trastuzumab Investigational drugs should be developed in TIL- Her2+++ ebc Loi, ASCO, 2012

15 Take home message TIL could be a good parameter to select patients who present a high risk of relapse after trastuzumab

16 Questions Should tumors <1 cm receive trastuzumab? What is the optimal regimen of trastuzumab? Concomitant versus sequential Duration Should patients receive anthracyclines? Which endocrine therapy? Which patients present a high risk of relapse after chemotherapy and trastuzumab? Are dual inhibition ready for prime time in the neoadjuvant setting? Which therapies in the metastatic setting? Pertuzumab TDM1 New drugs Everolimus PI3K inh Anti PDL1 / PD1 Brain metastases

17 Pertuzumab and trastuzumab bind to different regions on HER2 and have synergistic activity Trastuzumab HER2 receptor Pertuzumab Subdomain IV of HER2 Dimerisation domain of HER2

18 Pertuzumab and trastuzumab in trastuzumab-naive patients : NeoSPHERE trial Adding pertuzumab to trastuzumab and chemotherapy improves pathologic response rates Giani, SABCS, 2010

19 NeoALLTO trial 60% Patholog gic complete response 50% 40% 30% 20% 10% 0% paclitaxel / trastu / lapa paclitaxel / trastu Adding lapatinib to trastuzumab improves the percentage of pathologic complete response Baselga, Lancet 2012

20 Take home message Dual blockade improves pcr rates in the neoadjuvant setting Medical usefulness of such approaches is being evaluated in the adjuvant setting (ALLTO, AFFINITY)

21 Questions Should tumors <1 cm receive trastuzumab? What is the optimal regimen of trastuzumab? Concomitant versus sequential Duration Should patients receive anthracyclines? Which endocrine therapy? Which patients present a high risk of relapse after chemotherapy and trastuzumab? Are dual inhibition ready for prime time early breast cancers? Which therapies in the metastatic setting? Pertuzumab TDM1 New drugs Everolimus PI3K inh Anti PDL1 / PD1 Brain metastases

22 CLEOPATRA: Registration trial pertuzumab HER2+ MBC (n=800) 1:1 randomization Docetaxel + trastuzumab + placebo Docetaxel + trastuzumab + pertuzumab

23 Primary endpoint: Independently assessed PFS Progression-f free survival (%) 100 Ptz + T + D: median 18.5 months n at risk Ptz + T + D Pla + T + D D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Pla + T + D: median 12.4 months Time (months) = 6.1 months HR = % CI p< Stratified by prior treatment status and region Baselga J, et al.2011 SABCA.abstr S5-5

24 T-DM1: Mechanism of Action HER2 T-DM1 Emtansine release Inhibition of microtubule polymerization Lysosome P P P Internalization Nucleus Adapted from LoRusso PM, et al. Clin Cancer Res 2011.

25 EMILIA Study Design HER2+ (central) LABC or MBC (N=980) T-DM1 3.6 mg/kg q3w IV PD Prior taxane and trastuzumab Progression on metastatic tx or within 6 mos of adjuvant tx 1:1 Capecitabine 1000 mg/m 2 orally bid, days 1 14, q3w + Lapatinib 1250 mg/day orally qd PD

26 Proportion progression-free Progression-Free Survival by Independent Review Median (mos) No. events Cap + Lap T-DM Stratified HR=0.650 (95% CI, 0.55, 0.77) P< Time (mos) No. at risk by independent review: Cap + Lap T-DM Unstratified HR=0.66 (P<0.0001). Blackwell, ASCO, 2012

27 Questions Should tumors <1 cm receive trastuzumab? What is the optimal regimen of trastuzumab? Concomitant versus sequential Duration Should patients receive anthracyclines? Which endocrine therapy? Which patients present a high risk of relapse after chemotherapy and trastuzumab? Are dual inhibition ready for prime time early breast cancers? Which therapies in the metastatic setting? Pertuzumab TDM1 New drugs Everolimus PI3K inh Anti PDL1 / PD1 Brain metastases

28 Rapalogs + Her2 inhibitors: Phase I/II Data Study/Patient population Treatments N Outcome Disease progression on/after trastuzumab (Morrow, J Clin Oncol, 2012) Everolimus, trastuzumab (without chemotherapy) 47 Clinical benefit:34% ORR: 15% PD on/after trastuzumab (Andre, J Clin Oncol, 2010) Everolimus, trastuzumab, paclitaxel 33 ORR: 44% PD on/after trastuzumab Everolimus, trastuzumab, 50 ORR: 19% (Jerusalem, BCRT, 2011) vinorelbine Refractory to trastuzumab AND taxanes (Dalenc, ASCO, 2011) Everolimus, trastuzumab, paclitaxel 55 Clinical benefit:40% ORR: 20% PD after trastu (Gajria, ASCO, 2011) Temsirolimus / neratinib 6 4 PR / 6 mtor inhibitors overcome resistance to trastuzumab in phase I/II trials Is it medically useful?

29 Registration trials in the Her2 segment BOLERO I Phase 3 study; N = 717 Her2-overexpressing mbc Not pretreated with trastuzumab in the metastatic setting Everolimus 10 mg/d+ paclitaxel/ trastuzumab Placebo + paclitaxel/ trastuzumab Primary endpoint: PFS BOLERO III Phase 3 study; N = 572 Her2-overexpressing mbc Pretreated with trastuzumab Everolimus 5 mg/d+ vinorelbine/ trastuzumab Placebo + vinorelbine/ trastuzumab Primary endpoint: PFS

30 BKM120 + Trastuzumab Saura et al. SABCS 2011.

31 Rationale for anti-pd1 in trastuzumab-resistant tumors Established tumors in transgenic MMTV/HER2 mice were treated with combinations Stagg, Loi et al PNAS 2011

32 Questions Should tumors <1 cm receive trastuzumab? What is the optimal regimen of trastuzumab? Concomitant versus sequential Duration Should patients receive anthracyclines? Which endocrine therapy? Which patients present a high risk of relapse after chemotherapy and trastuzumab? Are dual inhibition ready for prime time early breast cancers? Which therapies in the metastatic setting? Pertuzumab TDM1 New drugs Everolimus PI3K inh Anti PDL1 / PD1 Brain metastases

33 Should medical treatment start before radiation therapy? Efficacy of lapatinib and capecitabine given before radiation therapy for brain metastases CNS Volumetric change n = 44 % CNS objective response 29 66% (95% CI: ) 80% Reduction 9 20% 50- <80% Reduction 20 46% 20- <50% Reduction 6 14% > 0- <20% Reduction 2 5% Progression* 7 16% Bachelot, ESMO, 2012

34 Conclusions Adjuvant therapy is still one year trastuzumab started concomitantly to chemotherapy Anthracyclines is still mandatory in patients with high risk of relapse Dual blockade should improve outcome in early breast cancer Pertuzumab and TDM1 have shown efficacy in the metastatic setting New targeted agents and immunotherapeutics are being developed