Esophagogastric Cancer CMET as a Novel Target David

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

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

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

Advanced Esophagogastric Cancer Chemotherapy: What Regimen to Use? Oxali: Cape: EOX or EOF ECX or EOX XP FLO Pts 489 513 160 %RR 44% 45% TTP, months 6. 7 OS, months 10. 9 FUFIRI S-1 Cis DCF ECF 109 170 305 221 126 41% 34% 32% 54% 36% 45% 6. 5 5. 6 5. 5 5. 0 6. 0 5. 6 7. 4 10. 5 10. 7 9. 0 13. 0 9. 2 8. 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

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

Does Epirubicin add benefit to Platinum/5 -FU Chemo? 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 3 rd, RJ Mayer, RM Goldberg

CALGB 80403 / ECOG E 1206: ECF vs FOLFOX ARM A: (ECF + cetuximab); 1 cycle = 21 days Cetuximab 400 250 mg/m 2 IV, weekly Epirubicin 50 mg/m 2 IV, day 1 Cisplatin 60 mg/m 2 IV, day 1 Fluorouracil 200 mg/m 2/day, days 1 -21 Stratification: ECOG 0 -1 vs 2 ADC vs. SCC ARM B: (IC + cetuximab); 1 cycle = 21 days Cetuximab 400 250 mg/m 2 IV, weekly Cisplatin 30 mg/m 2 IV, days 1 and 8 Irinotecan 65 mg/m 2 IV, days 1 and 8 ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days Cetuximab 400 250 mg/m 2 IV, weekly Oxaliplatin 85 mg/m 2 IV, day 1 Leucovorin 400 mg/m 2, day 1 Fluorouracil 400 mg/m 2 IV bolus, day 1 Fluorouracil 2400 mg/m 2 IV over 46 hrs (days 1 -2)

CALGB 80403/ECOG 1206: Phase II FOLFOX vs ECF vs Irino/Cis, + Cetuximab 57. 8 45. 6 53. 6 6. 1 5. 3 5. 7 (90% CI) P vs H 0≤ 0. 25 *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 (15 S): Abstract 4006.

CALGB 80403/ECOG 1206: Survival ECF-C N = 67 IC-C N = 71 FOLFOX-C N = 72 Total N = 210 Mos 95% CI 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 (3. 9, 7. 2) 4. 5 (3. 6, 5. 6) 6. 7 (4. 8, 7. 2) 5. 5 (4. 5, 5. 9) OS Median # dead 58 66 64 188 FOLFOX = ECF AE, adverse event; PFS, progression-free survival; TTF, time to treatment failure Enzinger PC, et al. J Clin Oncol. 2010; 28 (15 S): Abstract 4006.

Second Line Chemo Gastric Cancer Phase III Trials Improved Survival Docetaxel vs BSC Docetaxel or Irinotecan vs BSC Paclitaxel vs Irinotecan Patients 84 84 133 69 111 112 RR % 7% -- 13% 17%/10% -- 21% 14% PFS 12. 2 wks NS NS NS 3. 6 mo 2. 3 mo OS 5. 2 mo 3. 6 mo 5. 3 mo (5. 2 -6. 5) 3. 8 mo 9. 5 mo 8. 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

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

en Rep er ro gy g m ram et m ab in ol g is m The hallmarks of cancer: Emerging hallmarks e e un un m m n o iim tion g ucti iin ruc ad st Ev de Evading growth suppressors Resisting cell death The Hallmarks of Cancer Sustaining proliferative Sustaining signaling proliferative signaling Enabling replicative immortality Inducing angiogenesis Activating invasion and metastasis Adapted from Cell, 144, Hanahan D, Weinberg RA, The hallmarks of cancer: the next generation, 646 -674, copyright © 2011, with permission from Elsevier. 2009 Genentech USA, Inc. MBo. C Program

Gene Amplification more common in Esophagogastric Cancer l 296 Esophageal / Gastric Cancers, 190 CRC l Amplified genes in 37% Gas / Eso tumors – FGFR 1 -2 – HER 2 – EGFR – MET l Targetable Receptors and Receptor Tyrosine Kinases l KRAS also amplified l Similar data for a Chinese series Dulak AM et al Can Res 72: 4383; 2012

Gastric Cancer Genomic Analysis: Singapore 193 primaries, 40 cell lines l Common gene amplifications in 5 categories l KRAS: 9% l FGFR 2: 9% l EGFR: 8% l ERBB 2: 7% l 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

Molecular Targets: Esophageal and Gastric Cancer • Except for trastuzumab, there is no identified molecular target in gastric cancer • Except for HER 2, there is no identified biomarker for gastric cancer • Recent Trials of EGFr, VEGFr Targeted Agents – Largely Failed – Unselected patient population

VEGF Revisited? • Ramucirumab: Humanized mo. Ab Targeting VEGr 2 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

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

CMET Receptor Structure

CMET Downstream Signaling Blumenschein JCO 30: 3287; 2012

CMET Downstream Signaling

Tyrosine kinase signaling results in a multitude of cellular effects: HER 2 -3 vs CMET HER 2 HER 3 Met RAS Sos Grb 2 Shc PI 3 K GAB 1 AKT PDK 1 RAF Grb 2 GSK 3 b MEK NFκB m. TOR MAPK Cyclin D 1 BAD p 27 NFκB ↓Apoptosis Cell cycle control Angiogenesis ↑Survival Proliferation HER 2=human epidermal growth factor receptor-2; HER 3=human epidermal growth factor receptor-3; PI 3 K=phosphatidylinositol 3 -kinase; GAB 1=Grb 2 -associated binding protein 1; Grb 2=growth factor receptorbound protein 2; STAT 3=signal transducer and activator of transcription 3; RAS=rat sarcoma; Sos=son of sevenless; PDK 1=phosphoinositide-dependent kinase-1; PTEN=phosphatase and tensin homolog; RAF=rapidly accelerating fibrosarcoma; MEK=mitogen-activated protein kinase; MAPK=mitogen-activated protein kinase; m. TOR=mammalian target of rapamycin; BAD=Bcl-2–associated death promoter; NFκB=nuclear factor kappa–light-chain enhancer of activated B cells; GSK 3β=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. 2012 Genentech USA, Inc. All rights reserved. Nat Rev Mol Cell Biol. 2010; 11: 834 -848. 22

CMET Prognostic in Esophageal Adeno § 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 Tuynman et al BJC 98: 1102; 2008

CMET l Gene amplification is relatively rare (5%) – Rarer are activating TKI and other mutations l Over expression at the protein level is more common (IHC) – Overcrowding of the cell surface with receptors engenders independence of ligand: constitutive activation l 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

CMET l CMET amplified or over expressing tumors appear more aggressive with worse prognosis but appear more sensitive to CMET targeted agents l Paracrine, autocrine activation: Ligand Hepatocyte Growth Factor Receptor dimerization Activation of receptor associated tyrosine kinase l Downstream: PIK 3 CA Kinase, RAS, STAT, RAC

CMET Receptor Cross Talk l Interaction with CMET with other receptors and intra cellular Tyrosine Kinases l Surface Integrin proteins – MET down regulates surface e-Cadherin (tumor suppressor) which increases TCF/Beta catenin nuclear signaling, increases proliferation l HER 1 (EGFR): activates CMET by generation of reactive oxygen species l HER 2: Trastuzumab may upregulate CMET, interacts with HER 3 l RON: shares homology with MET, and the ligand Macrophage Stimulating protein shares homology with HGF

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

Prominent c. MET / HGF Inhibitors Agent Structure Target Rilotumumab Human monoclonal antibody HGF Onartuzumab Humanized monovalent c-MET antibody Tivantinib (ARQ 197) Small molecule c-MET kinase Cabozantinib (XL 184) Small molecule c-MET kinase

Other CMET Agents in Development

Rilotumumab l Humanized monoclonal antibody against HGF l Binds to the HGF ligand light chain l Inhibits binding of HGF to the CMET receptor l AE’s specific to rilotumumab include nausea, fatigue, constipation, and peripheral edema l Toxicities in phase II + ECF, at 7. 5 and 15 mg/kg dosing – Peripheral edema, greater hematologic toxicity, more thromboembolic events

CMET: Rilotumumab: Anti HGF Ligand Antibody, First Line Phase II R A N D O M I ZE Stratification factors: ECOG PS 0 vs 1 LA vs Metastatic ARM A Rilotumumab (15 mg/kg) + ECX Q 3 W (n = 40) ARM B Rilotumumab (7. 5 mg/kg) + ECX Q 3 W (n = 40) ARM C Placebo + ECX Q 3 W (n = 40) 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 Clinical. Trials. gov identifier: NCT 00719550 Zhu M, et al. J Clin Oncol. 2012; 30(Suppl): Abstract 2535.

Analysis of c-Met Expression by IHCa Patientsb, n Acceptable tumor sample available, n (%) c-Met assay failed, n 118 90 (76) 0 c-Met. High, n (%) 38 (42) c-Met. Low, n (%) 52 (58) Evaluable patients in treatment arms A + B: All rilotumumab + ECX, n (%) 62 (78) Arm C: Placebo + ECX, n (%) c-Met defined as >50% of tumor cells express c-Met 28 (74) a b High Per protocol analysis set Zhu M, et al. J Clin Oncol. 2012; 30(Suppl): Abstract 2535.

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.

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

MET TKI’s l 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 l Type II: target a binding site immediately adjacent to the region occupied by ATP characteristic of inactive kinase l Foretinib, Tivantinib (neither Type I or II), Cabozantinib, Crizotinib l AMG 337: a selective inhibitor which inhibits multiple mechanisms of MET activation – Single Agent Phase II – Phase II + FOLFOX (ECOG)

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

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

Crizotinib l Multi national trial l ALK, MET tyrosine kinase inhibitor l 489 pts with EG cancer screened for MET, EGFR, and HER 2 amplification – 10 (2%) CMET+, 23 (4. 7%) EFGR+, 45 (8. 9%) HER 2+ l 2 of 4 CMET amplified patients treated had brief responses (30% tumor reduction for 3. 7 months, 16% reduction for 3. 5 months) l More aggressive clinical course in CMET + patients Lennerz et al JCO 29: 4803; 2011

Resistance to MET Activation l Mutation of the CMET Tyrosine Kinase l Activation of the EGFr pathway – Bypasses CMET by similar downstream signaling via PIK 3 CA Kinase and RAS l KRAS amplification – Constitutive downstream pathway activation l Therapeutic strategies to overcome resistance to CMET inhibitors – Target ligand, receptor, and TK – Target downstream pathways – Target rescue pathways (EGFr, HER 2)

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: HER 2+ / amplified esophagogastric cancers • VEGFR 2: Ramucirumab, active single agent with improved disease control, PFS, OS – + Paclitaxel: Second line all outcomes improved

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 receptor – Rilotumumab: binds HGF – Onartuzumab: blocks ligand binding • Drugs that target the TK – Negative results 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