Disclosures Consulting fees from: Novartis Contracted research - PDF document

Novel insights into therapy for HER2-positive breast cancer Debates and Didactics in Hematology and Oncology, August 8th, Sea Island, GA Ruth M. O’Regan, MD Professor and Vice-Chair for Educational Affairs, Department of Hematology and Medical Oncology, Emory University, Chief of Hematology and Medical Oncology, Georgia Cancer Center for Excellence, Grady Memorial Hospital Disclosures • Consulting fees from: Novartis • Contracted research from: – Genentech, and Novartis 1

Adjuvant management of HER2- positive breast cancer • The addition of trastuzumab to chemotherapy has clearly improved outcome for patients with early stage HER2-positive breast cancer but …. – Can we do better by adding other targeted agents? – Are we over-treating small HER2-positive cancers? – Do all HER2-positive cancers need trastuzumab, chemotherapy, both…? NeoALTTO Primary Outcome Measure: pCR* 100% 80% 60% Lapatinib n = 154 Trastuzumab n = 149 40% Lapatinib + Trastuzumab n = 152 51% 20% 30% 25% 0% pCR Lapatinib + Lapatinib Trastuzumab Trastuzumab P Value n = 154 n = 149 n = 152 pCR 16% 23% 42% 0.03 HR+ Subset pCR 34% 37% 61% 0.005 HR- Subset *Pathologic complete response (pCR) rate defined as the absence of invasive cancer in the breast at the time of surgery. Baselga J, et al. Lancet. 2012;379(9816):633-640. 2

NeoALTTO : Does pCR Translate Into Improved EFS and OS? Found correlation between • pCR and EFS and OS 3-year EFS was 86% for • those who achieved pCR, 72% for those who did not ( P = 0.0003) OS was 94% for those who • achieved pCR, 87% for those who did not (P = 0.005) Most notable in HR-negative • disease Not powered to detect • difference in survival between study arms Piccart-Gebhart M, et al. Presented at the 2013 San Antonio Breast Cancer Symposium. Abstract S1-01 Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) R Trastuzumab (n=2097) Design 1 A no concurrent N D taxane Surgery O Lapatinib ____________ ____________ M I At least 4 cycles Design 2 Z of (neo) adjuvant Lapatinib (n=2091) Trastuzumab Break A concurrent taxane chemotherapy T 12 weeks 6 weeks 34 weeks I (12 weeks) O Lapatinib + Trastuzumab (n= 2093) N Hormone receptor-positive: ≈ 57% Node-negative: 40% Available at: http://www.cancer.gov/search/clinical_trials/.gov.. 3

DISEASE-FREE SURVIVAL (DFS) ANALYSIS Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting DFS BY Hormone Receptor Status Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting 4

OVERALL SURVIVAL (OS) ANALYSIS Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting MAIN DIFFERENCES IN AEs BY TREATMENT ARM Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting 5

Addition of bevazicumab to trastuzumab- based chemotherapy (BETH): IDFS 1.0 92% 92 0.8 % Estimated probability 0.6 CTx +H CTx + H+ (N=1757) BEV (N=1752) 0.4 145 (8) 147 (8) Median Follow-up: 38 months 1.00 (0.79–1.26) 0.2 0.9789 1.02 (0.81–1.28) 0.8791 0 Time (months) No. at risk: CTxHB-HB 1752 1692 1672 1648 1601 1510 1108 641 287 62 3 CTxH-H 1757 1717 1690 1657 1607 1518 1106 642 282 57 1 Slamon D, et al, SABCS 2013, S1-03 Addition of bevazicumab to trastuzumab- based chemotherapy (BETH): OS 97 1.0 % 96% 0.8 Estimated probability 0.6 CTx + H CTx + H + (N=1757) BEV (N=1752) 0.4 Events, n (%) 62 (4) 54 (3) Median Follow-up: 38 months Stratified HR 0.87 0.2 (95% CI) (0.60–1.25) Log ‐ rank p ‐ 0.4387 value 0 0 6 12 18 24 30 36 42 48 54 60 Time (months) No. at risk: CTHB-HB 1752 1696 1680 1664 1637 1548 1135 660 297 65 3 CTH-H 1757 1722 1702 1690 1660 1565 1153 665 294 58 1 Slamon D, et al, SABCS 2013, S1-03 6

Phase III Trial of Pertuzumab + Chemotherapy + Trastuzumab as Adjuvant Therapy (APHINITY) R Placebo + A Trastuzumab N 6-8 cycles of AC- S D Primary or non-AC-based Non- U O endpoint chemo metastatic R M : node- G I Invasive positive E Z disease Pertuzumab + HER2+ BC R A free Trastuzumab Y T survival I 6-8 cycles of AC- (IDFS) O or non AC-based N chemo 52 weeks http://clinicaltrials.gov/NCT01358877 HER2-Positive Tumors ≤ 2cm 7

Small HER2-positive Tumor Meta-analysis O’Sullivan SABCS 2013 O’Sullivan CC, et al. SABCS 2013 S6 ‐ 03 Small HER2-positive Tumor Meta-analysis O’Sullivan SABCS 2013 O’Sullivan CC, et al. SABCS 2013 S6 ‐ 03 8

Cumulative Incidence of Recurrence or Death: <br />HR-Positive Disease with Tumors ≤ 2cm Cumulative Incidence of Recurrence or Death: <br />HR-Positive Disease with Tumors ≤ 2cm and N 0/1 9

Cumulative Incidence of Recurrence or Death: <br />HR-Negative Disease with Tumors ≤ 2cm Genomic analysis of immune function genes and clinical outcome in N9831 • Whole gene profiling of 1282 specimens from N9831 trial performed to develop a multi-gene predictive signature of trastuzumab benefit • Identified 6 biological pathways associated with increased RFS in trastuzumab-treated patients – 4 of these pathways linked to immunological functions • Percent immune-response enriched tumors in N9831 DASL cohort – Arm A (no trastuzumab) = 52% – Arm B/C (trastuzumab) = 52% Perez et al Proc ASCO 2014 10

Slide 12 Slide 13 11

Adjuvant Paclitaxel and Trastuzumab T1A/B = 50% T!C/2 = 50% Tolaney S, et al. SABCS 2013, S1-04 12

13

Heterogeneity of HER2-positive cancers 1% 2% 6% HER2 LUM A 31% LUM B 30% Basal Claudin-low Normal 30% N = 265 Carey et al Proc ASCO 2014 Intrinsic subtyping of HER2-positive breast cancers HR-positive HR-negative 1% 3% 5% HER2 17% LUM A 12% LUM B 5% 48% 51% Basal 34% 24% Claudin-low Normal N =109 N = 156 Carey et al Proc ASCO 2014 14

Prognostic ability of 70-gene signature in HER2+, ER+ cancers: untreated patients (n = 89) 21-gene signature not useful as HER2+ cancers have intermediate or high recurrence scores Knauer et al BJC 2010 Bi-directional cross-talk between ER and HER2 • Signaling through EGFR family including HER2 down-regulates ER • Conversely, inhibition of HER2 with trastuzumab or lapatinib increases signaling through ER • ER signaling is increased in HER2-positive cell lines that are resistant to HER2-directed agents • HER2 expression and activity is increased in hormone-resistant cancers, compared to hormone-sensitive cancers Pinzone Mol Cell Biol 2004, Stoia J Endocrinol 2000, Sabnis Cancer Res 2009, Xia PNAS 2006, Valabrega Oncogene 2005 15

HER2 signaling decreases ER activation and inhibition of HER2 increases ER-regulated gene transcription TRAST HER2 HER1/2/3 HER2 HER1/2/3 x x Membrane Membrane TKI PI3-K PI3-K Ras Ras AKT MEK AKT MEK FOXO3a Erk1/2 Erk1/2 Cytoplasm Cytoplasm FOXO3a FOXO3a x ER-regulated ER-regulated gene gene ER Nucleus ER ER ER Nucleus transcription transcription ERE ERE Xia PNAS 2006, Valabrega Oncogene 2005 Clinical relevance of this cross-talk • Inhibition of HER2 without inhibition of ER may increase ER signaling allowing ER to act as an escape mechanism – This could contribute to the lower PCR seen in ER+ HER2+ breast cancers and have potential implications in the metastatic setting – There may be a subset of ER+ HER2+ breast cancers where ER inhibition is critical (more important than chemotherapy) 16

Response to pre-operative trastuzumab and lapatinib ± letrozole (12 weeks) pCR pCR + npCR 70 60 * 50 56 48 53 pCR (%) 40 % % % 40% 30 28 20 % 21% 10 0 All ER+ All ER+ ER - ER- * NeoSphere: PCR 6% with dual HER2 inhibition without ER inhibition Rimawi CCR 2013 npCR = < 1cm residual cancer in the breast TEL trial: Pre-operative Trastuzumab, everolimus and letrozole in HR-positive, HER2- positive breast cancer (PI O’Regan) BX HR+ T T T T T HER2+ Sx* EVEROLIMUS Resectable LET *Further treatment (including chemotherapy at physician’s discretion) Biopsy (Bx) to assess ER and HER2 signaling 17

Summary • Excellent outcomes noted for patients with early stage HER2-positive breast cancer treated with trastuzumab-based chemotherapy • Addition of other growth factor receptor inhibitors has not improved outcome in the adjuvant setting • A “less is more” approach may be appropriate for a subset of HR-positive, HER2-positive cancers but these are not as yet clearly defined 18