1. Esophagogastric Cancer: CMET as a Novel Target David H. Ilson, M.D., Ph.D. GI Oncology Service Memorial Sloan-Kettering Cancer Center New York, NY

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

3. Esophageal and Gastric Carcinoma US Incidence in 2014 40,390 new cases – Gastric: 22,220 (55%) – Esophagus: 18,170 (45%) Male > Female Decline in Gastric Cancer Incidence Increase in Esophageal, GE JX, cardia adeno OS improvement, 1975-77, 1984-86, 1999-2006 – Gastric: 16%  18%  27% – Esophageal: 5%  10%  19% Siegel et al, CA 64: 9-29; 2014

4. Advanced Esophagogastric Cancer Chemotherapy: What Regimen to Use? Oxali: EOX or EOF Cape: ECX or EOXXPFLOFUFIRI S-1 CisDCFECF Pts489513160109170305221126 %RR44%45%41%34%32%54%36%45% TTP, months 6.76.55.65.55.06.05.67.4 OS, months 10.910.410.510.79.013.09.28.9 Cunningham NEJM 358:36;2008, Kang Annals Oncol 20:666;2009, Al-Batran JCO 26:1435;2008, Dank Annals Oncol 19:450;2008 Koizumi Lancet Oncol 9:215;2008, Van Cutsem JCO 24:4991;2006, Webb JCO 15:61;1997

5. Patient Selection for Chemotherapy 3 drug regimens (DCF, mDCF) – High functional status, younger patients without comorbidities – Willingness to tolerate side effects – Access to frequent follow up and toxicity assessment ECF: does epirubicin add anything but toxicity?

6. CALGB 80403 / ECOG 1206: Randomized Phase II Study of Standard Chemotherapy + Cetuximab for Metastatic Esophageal Cancer PC Enzinger, BA Burtness, DR Hollis, D Niedzwiecki, DH Ilson, AB Benson 3rd, RJ Mayer, RM Goldberg Does Epirubicin add benefit to Platinum/5-FU Chemo?

7. CALGB 80403 / ECOG E1206: ECF vs FOLFOX Stratification: ECOG 0-1 vs 2 ADC vs. SCC ARM A: (ECF + cetuximab); 1 cycle = 21 days Cetuximab 400  250mg/m2 IV, weekly Epirubicin 50 mg/m2 IV, day 1 Cisplatin 60mg/m2 IV, day 1 Fluorouracil 200mg/m2/day, days 1-21 ARM B: (IC + cetuximab); 1 cycle = 21 days Cetuximab 400  250mg/m2 IV, weekly Cisplatin 30 mg/m2 IV, days 1 and 8 Irinotecan 65 mg/m2 IV, days 1 and 8 ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days Cetuximab 400  250mg/m2 IV, weekly Oxaliplatin 85 mg/m2 IV, day 1 Leucovorin 400 mg/m2, day 1 Fluorouracil 400 mg/m2 IV bolus, day 1 Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2)

8. CALGB 80403/ECOG 1206: Phase II FOLFOX vs ECF vs Irino/Cis, + Cetuximab *RECIST - confirmed; restaging every 6 weeks CI, confidence interval; CR, complete response; PD, progressive disease; SD, stable disease Enzinger PC, et al. J Clin Oncol. 2010;28 (15S): Abstract 4006. 57.8 45.653.6 P vs H 0 ≤0.25 (90% CI) 6.15.35.7

9. ECF-C N = 67 IC-C N = 71 FOLFOX-C N = 72 Total N = 210 Mos95% CIMos95% CIMos95% CIMos95% CI OS Median # dead 11.5 51 (8.1, 12.5)8.9 52 (6.2, 13.1)12.4 51 (8.8, 13.9)11.0 154 (8.8, 12.3) PFS Median # dead/pd 5.9 57 (4.5, 8.3)5.0 64 (3.9, 6.0)6.7 63 (5.5, 7.4)5.8 184 (5.1, 6.8) TTF Median # dead/pd/ off for AE 5.5 58 (3.9, 7.2)4.5 66 (3.6, 5.6)6.7 64 (4.8, 7.2)5.5 188 (4.5, 5.9) CALGB 80403/ECOG 1206: Survival FOLFOX = ECF AE, adverse event; PFS, progression-free survival; TTF, time to treatment failure Enzinger PC, et al. J Clin Oncol. 2010;28 (15S): Abstract 4006.

10. Second Line Chemo Gastric Cancer Phase III Trials  Improved Survival Docetaxel vs BSCDocetaxel or Irinotecan vs BSCPaclitaxel vs Irinotecan Patients84 13369111112 RR %7%--13% 17%/10% --21%14% PFS12.2 wksNS 3.6 mo2.3 mo OS5.2 mo3.6 mo5.3 mo (5.2-6.5) 3.8 mo9.5 mo8.4 mo Significance HR 0.67 P = 0.01 HR 0.657 P = 0.007 Ford H Lancet Oncol 15:78; 2014; Kang JH J Clin Oncol 30:1513; 2012 Ueda JCO 31: 4438; 2013

11. Gastric Cancer Second Line Chemo vs BSC: Survival Docetaxel/Irinotecan vs BSCDocetaxel vs BSC

12.  2009 Genentech USA, Inc. MBoC Program The Hallmarks of Cancer Evading growth suppressors Enabling replicative immortality Resisting cell death Sustaining proliferative signaling Inducing angiogenesis Activating invasion and metastasis The hallmarks of cancer: Emerging hallmarks Adapted from Cell, 144, Hanahan D, Weinberg RA, The hallmarks of cancer: the next generation, 646-674, copyright © 2011, with permission from Elsevier. Reprogramming energy metabolism Evading immune destruction The Hallmarks of Cancer Evading growth suppressors Enabling replicative immortality Resisting cell death Sustaining proliferative signaling Inducing angiogenesis Activating invasion and metastasis Reprogramming energy metabolism Evading immune destruction

13. Gene Amplification more common 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 KRAS also amplified Similar data for a Chinese series Dulak AM et al Can Res 72: 4383; 2012

14. Gastric Cancer Genomic Analysis: Singapore 193 primaries, 40 cell lines Common gene amplifications in 5 categories KRAS: 9% FGFR2: 9% EGFR: 8% ERBB2: 7% MET: 4% – Receptor Tyrosine Kinase pathways commonly affected – All upstream from KRAS – 37% targetable by RTK/Ras directed therapy Deng et al Gut 61: 673; 2012

15. Molecular Targets: Esophageal and Gastric Cancer Except for trastuzumab, there is no identified molecular target in gastric cancer Except for HER2, there is no identified biomarker for gastric cancer Recent Trials of EGFr, VEGFr Targeted Agents –Largely Failed –Unselected patient population

16. VEGF Revisited? Ramucirumab: Humanized moAb Targeting VEGr2 receptor REGARD: BSC vs Ramucirumab RAINBOW: 2 nd Line Paclitaxel + / - Ramucirumab Fuchs CS, et al. Lancet. 2014;383(9911):31-39. Wilke GI Symposium 2014 LBA 7

17. CMET Pathway Goyal L, et al. Clin Cancer Res. 2013;19(9):2310-2318.

18. CMET Receptor Structure

19. CMET Downstream Signaling Blumenschein JCO 30:3287;2012

20. CMET Downstream Signaling

22. 22  2012 Genentech USA, Inc. All rights reserved. Tyrosine kinase signaling results in a multitude of cellular effects: HER2-3 vs CMET AKT PDK1 Cell cycle control Proliferation ↓ Apoptosis ↑ Survival Angiogenesis PI3K Cyclin D1 p27 BAD GSK3  NFκB mTOR HER2=human epidermal growth factor receptor-2; HER3=human epidermal growth factor receptor-3; PI3K=phosphatidylinositol 3-kinase; GAB1=Grb2-associated binding protein 1; Grb2=growth factor receptor- bound protein 2; STAT3=signal transducer and activator of transcription 3; RAS=rat sarcoma; Sos=son of sevenless; PDK1=phosphoinositide-dependent kinase-1; PTEN=phosphatase and tensin homolog; RAF=rapidly accelerating fibrosarcoma; MEK=mitogen-activated protein kinase kinase; MAPK=mitogen-activated protein kinase; mTOR=mammalian target of rapamycin; BAD=Bcl-2 – associated death promoter; NFκB=nuclear factor kappa – light-chain enhancer of activated B cells; GSK3β=glycogen synthase kinase 3 beta. Olayioye MA, et al. EMBO J. 2000;19:3159-3167. Rowinsky EK. Oncologist. 2003;8(3):5-17. Trusolino L, et al. Nat Rev Mol Cell Biol. 2010;11:834-848. PTEN Sos Grb2ShcRAS RAF MEK MAPK GAB1 PI3K Grb2 STAT3 NFκB MAPK HER3 HER2 Met

23. CMET Prognostic in Esophageal Adeno Tuynman et al BJC 98: 1102; 2008  145 consecutive patients undergoing surgery  CMET high (54%)by IHC had poorer OS, DSS  Higher rates of local and metastatic recurrence  Higher CMET in higher T stage, N+, poorly differentiated tumors  Independent Prognostic Factor, RR 2.3

24. CMET Gene amplification is relatively rare (5%) – Rarer are activating TKI and other mutations Over expression at the protein level is more common (IHC) – Overcrowding of the cell surface with receptors engenders independence of ligand: constitutive activation CMET activation: cell survival, proliferation, angiogenesis, and invasion and metastasis – Protease activation and increase cell motility – CMET and HGF signaling in vascular endothelium promote angiogenesis – Hypoxia promotes HGF production and upregulates CMET expression

25. CMET CMET amplified or over expressing tumors appear more aggressive with worse prognosis but appear more sensitive to CMET targeted agents Paracrine, autocrine activation: Ligand Hepatocyte Growth Factor  Receptor dimerization  Activation of receptor associated tyrosine kinase Downstream: PIK3CA Kinase, RAS, STAT, RAC

26. CMET Receptor Cross Talk Interaction with CMET with other receptors and intra cellular Tyrosine Kinases Surface Integrin proteins – MET down regulates surface e-Cadherin (tumor suppressor) which increases TCF/Beta catenin nuclear signaling, increases proliferation HER1 (EGFR): activates CMET by generation of reactive oxygen species HER2: Trastuzumab may upregulate CMET, interacts with HER3 RON: shares homology with MET, and the ligand Macrophage Stimulating protein shares homology with HGF

27. How can we inhibit MET? Targeting HGF ligand, preventing receptor binding Blockade of ligand binding to the CMET receptor Inhibition of C-MET receptor trans phosphoyrlation and activation Inhibition of activated kinase activity and phosphorylation of the signal transducer docking site Interference with the docking site and signal transducers

28. Prominent cMET / HGF Inhibitors AgentStructureTarget RilotumumabHuman monoclonal antibody HGF OnartuzumabHumanized monovalent antibody c-MET Tivantinib (ARQ 197) Small moleculec-MET kinase Cabozantinib (XL184) Small moleculec-MET kinase

29. Other CMET Agents in Development

30. Rilotumumab Humanized monoclonal antibody against HGF Binds to the HGF ligand light chain Inhibits binding of HGF to the CMET receptor AE’s specific to rilotumumab include nausea, fatigue, constipation, and peripheral edema Toxicities in phase II + ECF, at 7.5 and 15 mg/kg dosing – Peripheral edema, greater hematologic toxicity, more thromboembolic events

31. CMET: Rilotumumab: Anti HGF Ligand Antibody, First Line Phase II RANDOMIZERANDOMIZE ARM A Rilotumumab (15 mg/kg) + ECX Q3W (n = 40) ARM B Rilotumumab (7.5 mg/kg) + ECX Q3W (n = 40) ARM C Placebo + ECX Q3W (n = 40) Stratification factors: ECOG PS 0 vs 1 LA vs Metastatic E: Epirubicin: 50 mg/m 2 IV, day 1 C: Cisplatin: 60 mg/m 2 IV, day 1 X: Capecitabine: 625 mg/m 2 BID orally, days 1-2 Rilotumumab: IV over 60 ± 10 minutes prior to chemotherapy ClinicalTrials.gov identifier: NCT00719550 Zhu M, et al. J Clin Oncol. 2012;30(Suppl): Abstract 2535.

32. Patients b, n118 Acceptable tumor sample available, n (%)90 (76) c-Met assay failed, n0 c-Met High, n (%)38 (42) c-Met Low, n (%)52 (58) Evaluable patients in treatment arms Arms A + B: All rilotumumab + ECX, n (%)62 (78) Arm C: Placebo + ECX, n (%)28 (74) Zhu M, et al. J Clin Oncol. 2012;30(Suppl): Abstract 2535. Analysis of c-Met Expression by IHC a a c-Met High defined as >50% of tumor cells express c-Met b Per protocol analysis set

33. PFS and OS in c-Met High Patients Median Months (80% CI)HR (80% CI) 6.9 (5.1, 7.5)0.53 (0.25, 1.13) 4.6 (3.7, 5.2) Median Months (80% CI)HR (80% CI) 11.1 (9.2, 13.3)0.29 (0.11, 0.76) 5.7 (4.5, 10.4) Zhu M, et al. J Clin Oncol. 2012;30(Suppl): Abstract 2535.

34. Ongoing Trials: Met Inhibitors Targeting CMET, + IHC RILOMET-1: Phase III – ECX + / - Rilotumumab (targeting ligand HGF) MetGastric: Phase III – FOLFOX + / - Onartuzumab monovalent anti MET receptor antibody – Blocking ligand binding Tyrosine Kinase Inhibitors – Promising phase I activity in CMET amplified (AMG 337) – Negative trials of earlier agents

35. MET TKI’s Type I: drug targets the ATP binding site  receptor in the active confirmation – After tyrosyl residues in the activation loop have been phosphorylated – Majority of agents Type II: target a binding site immediately adjacent to the region occupied by ATP  characteristic of inactive kinase Foretinib, Tivantinib (neither Type I or II), Cabozantinib, Crizotinib AMG 337: a selective inhibitor which inhibits multiple mechanisms of MET activation – Single Agent Phase II – Phase II + FOLFOX (ECOG)

36. MSKCC: Foretinib (CMET, VEGFr2) Foretinib: muti targeted TKI Targets MET, RON, RON, AXL, TIE-2 Two doses evaluated – 240 mg/d for 5 days every 2 weeks – 80 mg/d 74 patients, 10 with stable disease (23%) median 3.2 months 3 with MET amplification: one with stable disease Shah et al PLoS One 8: Epub 2013

37. Tivantinib Selective, non ATP competitive small molecule inhibitor of CMET Asian trial, daily Tivantinib, phase II 30 patients with gastric cancer, 1-2 prior regimens PFS 43 days No responses No correlation with activity and CMET expression or gene amplification, or HGF Kang YK Invest New Drugs 32: 355; 2014

38. Crizotinib Multi national trial ALK, MET tyrosine kinase inhibitor 489 pts with EG cancer screened for MET, EGFR, and HER2 amplification – 10 (2%) CMET+, 23 (4.7%) EFGR+, 45 (8.9%) HER2+ 2 of 4 CMET amplified patients treated had brief responses (30% tumor reduction for 3.7 months, 16% reduction for 3.5 months) More aggressive clinical course in CMET + patients Lennerz et al JCO 29: 4803; 2011

39. Resistance to MET Activation Mutation of the CMET Tyrosine Kinase Activation of the EGFr pathway – Bypasses CMET by similar downstream signaling via PIK3CA Kinase and RAS KRAS amplification – Constitutive downstream pathway activation Therapeutic strategies to overcome resistance to CMET inhibitors – Target ligand, receptor, and TK – Target downstream pathways – Target rescue pathways (EGFr, HER2)

40. Esophagogastric Cancer: CMET Targeted Agents Chemo: –Two-drug regimens -FOLFOX, Cape-Ox, Cape-Cis Targeted therapies –Biomarkers to identify patients –Gene amplification > mutation in esophagogastric cancer Trastuzumab: HER2+ / amplified esophagogastric cancers VEGFR2: Ramucirumab, active single agent with improved disease control, PFS, OS –+ Paclitaxel: Second line all outcomes improved

41. Esophagogastric Cancer: Targeted Agents MET Pathway key driver in esophagogastric cancer Amplification in some, increased protein expression in many –Poor prognosis Drugs that target the ligand and receptor –Rilotumumab: binds HGF –Onartuzumab: blocks ligand binding Drugs that target the TK –Negative results for foretinib, tivantinib, crizotinib –Rare patients with CMET gene amplification Phase III trials of ECX + Rilotumumab, FOLFOX + Onartuzumab are ongoing in CMET high ICH pts Further trials of TKI’s, CMET gene amplified patients