The Gastrointestinal Malignancy Pipeline -What does the future hold for GI Cancers? Targeting the HER-family Receptors David H. Ilson, M.D., Ph.D. GI Oncology Service Memorial Sloan-Kettering Cancer Center New York, NY

DISCLOSURES Grant/Research Support Consultant Speaker’s Bureau Amgen Bayer Bristol-Myers Squibb Consultant Lilly Imclone Speaker’s Bureau Genentech

GI Cancers: US Incidence in 2013 292,200 new cases and 144,570 deaths (49%) Case Fatality Rate: Colorectal: 36% Esophagogastric: 66% Pancreatic: 85% HCC: 70% Male > Female Ongoing rise in Esophageal and GEJ Adenocarcinoma, HCC Siegel et al, CA 63: 11-30; 2013

HER signaling: The network begins with the 4 HER receptors Extracellular ligand-binding domain HER1/EGFR HER2 HER3 HER4 Transmembrane domain Intracellular tyrosine kinase domain HER=human epidermal growth factor receptor; EGFR=epidermal growth factor receptor. Rowinsky EK. Oncologist. 2003;8:5-17. Yarden Y, Sliwkowski MX. Nat Rev Mol Cell Biol. 2001;2:127-137.

HER1/EGFR Signaling Pathways Extracellular Intracellular P P Src PLC GAP Grb2 Shc Nck Vav Grb7 Crk Ras Abl PKC PI3K MAPK JNK Survival, Growth, Proliferation, Adhesion, Migration, Angiogenesis, Metastasis Data from Sedlacek. Drugs. 2000;59:435. Sedlacek Drugs. 2000;59:435.

Integration of EGFR Agents in Colorectal Cancer: KRAS WT tumors First Line: Cetuximab, Panitumumab approved to combine with FOLFIRI or FOLFOX Capecitabine based trials with Cetuximab failed  toxicity Second, Third Line Cetuximab, Panitumumab approved as monotherapy Suggested added benefit when combined with irinotecan or FOLFIRI second line BRAF mutant patients are eligible for EGFR therapy

All RAS Mutant Patients Should Not Get Cetuximab Current testing looks at KRAS exon 2 mutations Trial of FOLFOX + / - Cetuximab An additional 17% had KRAS exon 3/4, NRAS exon 2/3/4 Douillard NEJM 369:11;2013

CALGB 80405: Bevacizumab vs Cetuximab in First-line KRAS WT mCRC Untreated KRAS WT mCRC (n=1500) Bevacizumab + FOLFOX or FOLFIRI Cetuximab + FOLFOX or FOLFIRI PD R Primary endpoint: OS Secondary endpoints: ORR, PFS, TTF, DOR, and safety NCT identifier: NCT00265850. 8

NCI PA.3 Phase III Trial Untreated Advanced Pancreas Ca Gemcitabine + Placebo R A N D O M I Z E Erlotinib Stratify N= 569 LA vs M1 Center PS 0-1 vs 2 Primary Enpoint OS 80% power, 33% increase Moore, et al. J Clin Oncol, 2007

Survival Distribution Function PA.3 Overall Survival Months Survival Distribution Function 1.00 0.75 0.50 0.25 6 12 18 24 G + Erlotinib (N= 261) G + Placebo (N= 260) Med. Survival (mths) 6.24 mths 5.9 mths 1-Year Survival 23% 17% CR + PR 8.6% 8% CR + PR + SD 57% 49% HR= 0.82 (0.69-0.99) p= 0.038 *Adjusted for PS and extent of disease at baseline † From Cox regression model ‡ From 2-sided log-rank test Moore, et al. J Clin Oncol, 2007

S0205 Overall Survival Gemcitabine N = 369 Gem + Cetuximab N = 366 PFS 100% Gemcitabine N = 369 Gem + Cetuximab N = 366 PFS 3.0 months 3.5 months OS 5.9 months 6.4 months 80% 60% 40% HR= 1.09 (95% CI: 0.93, 1.27) 20% 0% 12 24 36 Months After Registration Philip et al. J Clin Oncol 2010; 28:3605-3610

HER2 in Pancreatic Cancer Capecitabine + Trastuzumab: 17 pts with IHC 3+ OS 6.9 months, PFS at 12 weeks 23.5% Gemcitabine + Trastuzumab: 34 pts, 30 IHC 2+, 4 IHC 3+ PR in 6%, OS 7 months, 1 yr OS 19%. Harder et al Br J Cancer 106:1033;2012, Safran et al Cancer Invest 22: 706; 2004

HCC: Sorafenib is the Standard for Advanced Disease SHARP TRIAL ASIA PACIFIC TRIAL OS 7.9  10.7 months, HR 0.69 OS 4.5  6.2 months, HR 0.68 Llovet NEJM 359: 378; 2008 Chang Lancet Oncol 10:25; 2009

HCC: Failed Phase III Trials Agent Target Number Overall Survival First Line Sunitinib vs Sorafenib VEGFr, PDGFr, C-KIT, FLT3 1074 8.1 vs 10 months, HR 1.31 Brivanib vs Sorafenib VEGFr, FGFr 1155 9.5 vs 9.9 months, HR 1.07 Erlotinib/Sorafenib vs Placebo/Sorafenib EGFR 720 9.5 vs 8.5 months, HR 0.929 Linifanib vs Sorafenib VEGFr, PDGFr 1035 9.1 vs 9.8 months, HR 1.046 Second Line Brivanib vs BSC 395 9.4 vs 8.2 months, HR 0.89

Gene Amplification: The Driver in Esophagogastric Cancer 296 Esophageal / Gastric Cancers, 190 CRC Amplified genes in 37% Gas / Eso tumors FGFR1-2 HER2 EGFR MET Targetable Receptors and Receptor Tyrosine Kinases Similar data for a Chinese series Dulak AM et al Can Res 72: 4383; 2012

Targeted Agents Phase III: Negative Trials for EGFr REAL 3: ECX + / - Panitumumab (U.K.) Negative: Panitumumab had inferior outcomes EXPAND: Cape-Cis + / Cetuximab (E.U.) Negative: Cetuximab trended inferior COG: BSC vs Gefitinib (U.K.): Negative Trials conducted with no biomarker selection of patients No biomarker identified in EG Cancer Waddell T Lance Oncol 14: 481; 2013 Lordick F et al Lancet 14:490; 2013 Sutton JCO 30: 2012 (suppl 34 abstr 6)

EGFr: Cetuximab in Gastric Cancer: EXPAND Trial Untreated Gastric/GEJ Cancer RANDOMIZATION:904pts Patients with advanced gastric cancer refractory to prior FP were randomly assigned into weekly paclitaxel or irinotecan group. Stratification factors were institution, performance status and target lesion. Paclitaxel 80mg/m2 was administered weekly for consecutive three weeks with one-week rest. And irinotecan 150mg/m2 was administered bi-weekly. Cape-Cis Cape-Cis + Cetuximab Lordick F et al Lancet 14:490; 2013

EXPAND Trial: Cetuximab in Gastric Cancer OS PFS

R REAL3 Trial Design Arm A: EOC Arm B: mEOC-P EOC (Arm A): Untreated advanced adenocarcinoma or undifferentiated carcinoma of the oesophagus, OGJ or stomach EOC (Arm A): Epirubicin 50mg/m2 IV D1 Oxaliplatin 130mg/m2 IV D1 Capecitabine 1250mg/m2/day PO in two divided doses D1-21 mEOC-P (Arm B)1: Epirubicin 50mg/m2 IV D1 Oxaliplatin 100mg/m2 IV D1 Capecitabine 1000mg/m2/day PO in two divided doses D1-21 Panitumumab 9mg/kg IV D1 Okines et al, JCO 2010 Presented at ASCO 2012

Primary Endpoint – OS Based on 251 OS events 100 Median OS (95% CI) % alive at 1 year 11.3m (9.6 – 13.0) 46% (38% - 54%) 8.8m (7.7 – 9.8) 33% (26% - 41%) HR 1.37, p = 0.013 80 60 Probability of Survival (%) 40 EOC HR 1.37 (95% CI: 1.07 – 1.76) 20 EOC-P 6 12 18 24 30 36 Months from Randomisation Number at risk EOC 275 49 3 EOC-P 278 38 2 Presented at ASCO 2012 Based on 251 OS events

Trial Results - PFS Based on 333 PFS events 100 Median PFS (95% CI) % alive and progression-free at 1 year 7.4m (6.3 – 8.5) 21% (14% - 27%) 6.0m (5.5 – 6.5) 20% (14% - 26%) HR 1.22, p = 0.068 80 60 Probability of Survival (%) 40 EOC 20 EOC-P HR 1.22 (95% CI: 0.98 – 1.52) 6 12 18 24 30 Months from Randomisation Number at risk EOC 275 25 2 EOC-P 278 24 Presented at ASCO 2012 Based on 333 PFS events

EGFr: Definitive Cetuximab + Chemo RT SCOPE-1 Cape-Cis  Cape-Cis- RT + / - RT 258 pts (65 AC,188 SCC) RTOG 0436 Pac-Cis-RT + / - Cetuximab 328 pts (203 AC,125 SCC) Crosby Lancet 14: 627; 2013 Suntha JCO 32: 2014 (suppl 3; abstr LBA6)

EGFr: Gefitinib vs BSC, COG Trial 766 pts Esophageal and GEJ Adeno pts refractory to chemotherapy Placebo vs Gefitinib No difference in OS Sutton JCO 30: 2012 (suppl 34 abstr 6)

ToGA Trial Design Phase III, randomized, open-label, international, multicenter study: Trastuzumab 5FU or capecitabine + cisplatin (n = 290) 3807 patients screened 810 HER2-positive (22.1%) HER2-positive advanced GC (n = 584) R 5FU or capecitabine + cisplatin + trastuzumab (n = 294) Stratification factors Advanced vs metastatic GC vs GEJ Measurable vs nonmeasurable ECOG PS 0-1 vs 2 Capecitabine vs 5-FU Bang Y, et al. Lancet. 2010;376(9742):687-697

ToGA: Efficacy Outcome Chemotherapy + Trastuzumab (n = 294) Chemotherapy Alone (n = 290) HR (95% CI) P Value Primary endpoint Median OS, months 13.8 11.1 0.74 (0.60-0.91) .0046 Secondary endpoints Median PFS, months 6.7 5.5 0.71 (0.59-0.85) .0002 ORR, % 47.3 34.6 - .0017 CR 5.4 2.4 .0599 PR 41.8 32.1 .0145 Preplanned subgroup analysis indicated improved OS benefit with increasing HER2 expression by IHC Exploratory analysis of IHC 2+/FISH+ and IHC 3+ cohort demonstrated a 4-month increase in OS with trastuzumab HR: 0.65 (95% CI: 0.51-0.83) ORR, overall response rate Bang Y, et al. Lancet. 2010;376(9742):687-697.

Targeted Agents Phase III: HER2: Met Disease LOGIC: Cape-Ox + / - Lapatinib (HER2+) First line Negative trial for OS Benefit in Asian pts TYTAN: Paclitaxel + / - Lapatinib (HER2+) Second Line: Negative Trial PFS and Survival Benefit in subset of patients IHC 3+ for lapatinib Novel HER2 targeted agents, Phase III: Second line: TDM-1 vs paclitaxel First line: Trastuzumab + / - pertuzumab Hecht JR, et al. J Clin Oncol. 2013;31(Suppl):Abstract LBA4001 Bang et al GI Cancers Symposium 2013 Abstract 11

Trials of Targeted Agents 1st Line Target Agent Trial Regimen Number Status HER2 Pertuzumab JACOB XP + T +/- Pertuzumab 780 Ongoing Trastuzumab HELOISE XP + T (2 doses) 400 EGFr Panitumumab NCT01627379 5-FU-Cis + / - Pan 300 2nd Line TDM-1 GATSBY Pac vs TDM-1 412 Nimotuzumab NCT01813253 Irino + / - Nimo mTOR Everolimus AIOST00111 Pac + / - Evero 665

GI Cancers: HER Family Targeted Agents Biomarkers to identify responding patients Colorectal Cancer EGFr blocking antibodies active as monotherapy, and + chemotherapy first and second line Benefit limited to RAS type wild type Testing beyond exon 2 KRAS required Pancreatic Cancer Marginal benefit for erlotinib + gemcitabine Negative trial for cetuximab + gemcitabine Negative phase II trials of trastuzumab

GI Cancers: HER Family Targeted Agents HCC: Large phase III trial of erlotinib + sorafenib negative Gene amplification > mutation in esophagogastric cancer EGFR Negative trials in EG Cancer No Biomarker Trastuzumab: improves outcome in HER2+ / amplified esophagogastric cancers Lapatinib + chemo: failed to improve OS Newer HER2 agents, TDM-1 and pertuzumab, will be studied