Trastuzumab plus chemotherapy: the gold standard for HER2 positive early breast cancer

1. Current status of adjuvant HER2 targeting therapyValentina Guarneri, MD, PhDIstituto Oncologico Veneto IRCCSUniversity of Padova

2. Outline • Trastuzumab plus chemotherapy: the gold standard for HER2 positive early breast cancer • Improving on cardiac toxicity: different regimens and different treatment durations • Improving on treatment efficacy: dual blockade and new anti-HER2 agents • Toward personalized cancer medicine: challenging the gold standard for specific patient subgroups

3. Outline • Trastuzumab plus chemotherapy: the gold standard for HER2 positive early breast cancer • Improving on cardiac toxicity: different regimens and different treatment durations • Improving on treatment efficacy: dual blockade and new anti-HER2 agents • Toward personalized cancer medicine: challenging the gold standard for specific patient subgroups

5. Meta-analysis of adjuvant trastuzumab trials: Disease-free Survival MojaL, et al. The CochraneLibrary 2012, Issue4

6. Meta-analysis of adjuvant trastuzumab trials: Overall Survival MojaL, et al. The CochraneLibrary 2012, Issue4

7. DFS : ∆ 11.9% at 6y ∆ 11.5% at 10y OS : ∆ 5.5% at 6y ∆ 8.8% at 10y

8. Sequentialadministration Concurrentadministration Trastuzumab up to 1 yr BCIRG 006 DC x 6+ H AC x 4 D x 4+ H Joint analysis of NSABP B31 & N9831 AC x 4 T x 4 + H N9831 Sequential arm wT x 12 AC x 4 HERA Adjuvant CT (Any) RT FIN-HER D/N+H x 9 wks FECx 3 FEC/ED x 6 RT PACS 04 Are all trastuzumab adjuvant trials the same? Randomization Trastuzumab start T= paclitaxel; D= docetaxel

9. Overall Survival stratified by concurrent or sequential administration MojaL, et al. The CochraneLibrary 2012, Issue4

12. Outline • Trastuzumab plus chemotherapy: the gold standard for HER2 positive early breast cancer • Improving on cardiac toxicity: different regimens and different treatment durations • Improving on treatment efficacy: dual blockade and new anti-HER2 agents • Toward personalized cancer medicine: challenging the gold standard for specific patient subgroups

13. High competing mortality risk score Low competing mortality risk score Cancer ahead pub 2010

14. Congestive heart failure (CHF): all studies. Moja L, et al. The Cochrane Library 2012, Issue 4

15. LVEF decline-all studies.

16. BCIRG 006: Adjuvant Breast Cancer Node Positive and High Risk Node Negative 4x AC60/600 mg/m2 4x Docetaxel 100 mg/m2 ACT HER2+ (central FISH) N+ or High risk N- N=3,222 pts ACTH 1 Year Trastuzumab 6 x Docetaxel 75 mg/m2 +Carboplatin AUC 6 TCH 1 Year Trastuzumab

17. Slamon D, NEJM 2011.

18. Slamon D, NEJM 2011.

19. Slamon et al. SABCS 2006. Abstract 52. Slamon D, NEJM 2011.

20. CHF by trastuzumab duration Moja L, et al. The Cochrane Library 2012, Issue 4

21. DFS by trastuzumab duration Log (Hazard ratio) HR weight HR (IV,random, 95%CI) Moja L, et al. The Cochrane Library 2012

22. Overall survival stratified by duration of trastuzumab treatment Moja L, et al. The Cochrane Library 2012, Issue 4

26. SABCS, 2012

27. SABCS, 2012

29. PHARE* Trial results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancerXavier Pivot, Gilles Romieu, Hervé Bonnefoi, Jean-Yves Pierga, Pierre Kerbrat, Thomas Bachelot, Alain Lortholary, Marc Espié, Pierre Fumoleau, Daniel Serin,Jean-Philippe Jacquin, Christelle Jouannaud, Maria Rios, Sophie Abadie-Lacourtoisie, Nicole Tubiana-Mathieu, Laurent Cany, Stéphanie Catala, David Khayat, Iris Pauporté, Andrew Kramar. • Protocol of • Herceptin® • Adjuvant with • Reduced • Exposure • *lighthouse in French

30. Study design trastuzumab up to 12 months trastuzumab 6 months R Stratification 1. ER pos / neg 2. Chemo: conco/ seq stop trastuzumab Clinical exam LVEF … 0 3 6 9 12 15 18 21 24 30 mos Mammography Up to 60 mos… R: Randomizationafterinformed consent

31. Statistical Methods • Non inferiorityrandomized trial • 2% variation in terms of absolutedifference of recurrence • The 95% CI HR marginsshould not cross the 1.15 boundary • 1040 DFS events required for 80% power at 5% level or 4 years of accrual and at least 2 years of follow-up • HR were estimated from the stratified Cox model • Accrualtarget: 3400 patients

32. Primary endpoint scenarii A Equivalent B Superior C D Non Inferior E Inferior .85 1 1.15 1.3 1.45 1.6 HR

33. Patient Characteristics

34. Treatment Characteristics

35. Cardiac toxicity * Investigatorreportedevents (composite withclinical and LFEV finding) ** Based on more than > 25,000 assessments

36. DFS Events 42.5mos. median Follow-up

37. Disease Free Survival 97.0 93.8 90.7 87.8 95.5 91.2 87.8 84.9 EventsHR95%CIp-value H 12m 176 H 6m 219 1.28 (1.05 – 1.56) 0.29 * Cox model stratified by ER status and concomitant chemotherapy

38. 42.5mos. median FU Overall Survival 99.9 98.7 96.9 95.0 99.3 97.2 95.2 93.1 EventsHR95%CIp-value H 12m 66 H 6m 93 1.47 (1.07 – 2.02) * Cox model stratified by ER status and concomitant chemotherapy

39. Primary endpoint scenarii A Equivalent B Superior PHARE trial C D Non Inferior E Inferior .85 1 1.15 1.3 1.45 1.6 HR

40. Trastuzumab duration effects in patient subgroups in the PHARE*trial • Protocol of • Herceptin® • Adjuvant with • Reduced • Exposure Xavier Pivot, Gilles Romieu, Hervé Bonnefoi, Jean-Yves Pierga, Pierre Kerbrat, Thomas Bachelot, Alain Lortholary, Marc Espié, Pierre Fumoleau, Daniel Serin,Jean-Philippe Jacquin, Christelle Jouannaud, Maria Rios, Sophie Abadie-Lacourtoisie, Nicole Tubiana-Mathieu, Laurent Cany, Stéphanie Catala, David Khayat, Iris Pauporté, Andrew Kramar. SABCS 2012 • *lighthouse in French

41. Subgroup Results ER- status & Sequentialmodality Other groups

42.       R      9 mos 3 mos 6 mos 12 mos Trastuzumab 8 mg/kg loading dose  6 mg/kg q 3 wks AC60/600 or EC90/600 Docetaxel 100 FEC (600/60/600) Trastuzumab 4 mg/kg loading dose 2 mg/kg weekly :LVEF measurement Short-HER: study design PI: PF Conte RT/HT Sample size 1250 pts RT/HT 18 mos EUDRACT-2007-004326-25, NCT00629278

43. Enrollment as of May, 2013 • 1176 patients • Arm A (Long) 586 patients • Arm B (Short) 590 patients

44. Outline • Trastuzumab plus chemotherapy: the gold standard for HER2 positive early breast cancer • Improving on cardiac toxicity: different regimens and different treatment durations • Improving on treatment efficacy: new anti-HER2 agents and multiple dual blockade • Toward personalized cancer medicine: challenging the gold standard for specific patient subgroups

45. TEACH Trial • Eligibility • HER2+ Local IHC3+ or FISH +ve • Resected Stage I-IIIc primary BRCA • No prior trastuzumab • Neo-/adjuvant chemotherapy (CMF, anthracycline, or taxane) • Appropriate endocrine therapy • Stratification • Time from diagnosis ≤4 vs >4 yrs • Lymph node +ve vs -ve • ER+ and/or PgR+ vs ER–/PgR– R A N D O M I Z E Lapatinib 1500 mg qd × 1 yr N=3147 Aug 2006-May 2008 33 countries Placebo qd × 1 yr 4 yr Diagnosis • Disease-free survival (DFS):local, regional, distant recurrence,contralateralBRCA,other 2nd primary cancers,death from any cause Goss, SABCS 2011

46. TEACH Primary Endpoint: K-M Plot of DFS inITT Population—Time From Randomization Lapatinib HR 0.83 (0.70-1.00); p=0.053a Placebo Median Follow up: 4 years 0.0 • No improvement in OS demonstrated with use of lapatinib:HR: 0.99 (95% CI: 0.74-1.31; P = .966) Goss, SABCS 2011 ap value based on 2-sided stratified log-rank test

47. TEACH: Forest Plot of DFS for Subgroups in ITT Population L=lapatinib; P=placebo. Goss, SABCS 2011

48. Dual anti-HER2 blockade (neoadjuvant studies) Phase III NeoALLTO study Phase II CHER-LOB study

49. Dual Anti-HER2 blockade significantly increases the pCR rate 60 Exploratory p=0.0187 50 40 46.7% 30 20 25% 26.3% 10 0 Arm A: CT + T Arm B: CT + L Arm C: CT + T + L pCR (breast & axilla) Guarneri V et al, J Clin Oncol 2012 Baselga J et al. Lancet 2012

50. ALTTO study design (8000 patients)