1. Beyond Trastuzumab: The potential for Lapatinib, Pertuzumab, T-DM1 and combinations in GE Adenocarcinoma 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 Globally – Gastric Cancer second leading cause of cancer death U.S. : 40,390 new cases – Gastric: 22,220 (55%) – Esophagus: 18,170 (45%) 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. Exome and Whole Genome Sequencing: Esophageal Adenocarcinoma 149 Tumors Studied 26 significant genes with Mutation or Genomic loss Targetable Genes – CDKN2A – PIK3CA – SMAD4 – ARID1A – TP53 Rarely mutated: KRAS, BRAF ERBB2, EGFR Dulak AM et al Nat Genet 45: 478; 2013

5. 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 KRAS also amplified Similar data for a Chinese series Dulak AM et al Can Res 72: 4383; 2012

6.  2012 Genentech USA, Inc. All rights reserved. 6 HER signaling: The network begins with the 4 HER receptors HER2HER1/EGFRHER4HER3 Transmembrane domain Intracellular tyrosine kinase domain Extracellular ligand-binding 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.

7.  2012 Genentech USA, Inc. All rights reserved. 7 FAK Dysregulated cancer signaling pathways: Tyrosine kinase signaling examples AKT RAS Raf PI3K PDK1 mTOR Cell cycle control Proliferation ↓ Apoptosis ↑ Survival Angiogenesis MAPK MEK MAPK Src Ligand-activated receptors

8.  2012 Genentech USA, Inc. All rights reserved. 8 8 AKT PDK1 Targeted agents: Crossing the plasma membrane RAS Sos Grb2Shc Raf PI3K Cell surface receptors AKT PDK1RAS Sos Grb2Shc Raf PI3K Cell surface receptors Small-molecule inhibitors (SMIs) Generally, chemical agents (~400 daltons) Varying degrees of specificity Penetrate through the plasma membrane Cannot elicit immune response, eg, TKIs Monoclonal antibodies (mAbs) Large proteins (~150,000 daltons) Highly specific Cannot penetrate through the plasma membrane May elicit immune response: ADCC Adjei et al. J Clin Oncol. 2005;23:5386-5403. Imai et al. Nat Rev Cancer. 2006;6:714-727.

9. Targeting the HER2 Hynes et al, 2005; Garrett et al, 2003; Graus-Porta et al, 1997. HER2 Does Not Require A Ligand To Be Primed

10. Trastuzumab  Humanized anti-HER2 antibody  HER2-neu as a biomarker and therapeutic target for gastroesophageal cancers Junttila et al, 2009.

11. Targeting HER2 Meric-Bernstam et al, 2006; Olayioye et al, 2000; Rowinski, 2003.

12. HER2 Expression in Gastric/GEJ Cancer DFS, disease-free survival 1. Bang YJ, et al. Lancet. 2010;6736(10):61121-61132. 2. Gravalos C, et al. Ann Oncol. 2008;19:1523-1529. 3. Yano T, et al. J Clin Oncol. 2004;22(14S): Abstract 4053. 4. Gravolos C, et al. Presented at: 2007 Gastrointestinal Cancer Symposium; January 19-21, 2007: Orlando, Florida. Abstract 89. 5. Lordick F, et al. Eur J Cancer Suppl. 2007;5(4): Abstract 3541. Incidence of HER2 Expression by IHC or FISH 1-5 All GC tumors ── 13% to 23% HistologyIntestinal Diffuse Mixed Unknown 16% to 34% 6% to 7% 20% 14% Primary tumor locationGEJ Gastric 25% to 34% 9% to 20%

13. Is HER2 Prognostic? Mayo Clinic: 787 pts esophageal/GEJ cancer surgery only – HER2+ 17%, better OS, but not independent of path stage – HER3 strongly + in 40% Utrecht: 156 pts esophageal/GEJ cancer surgery only – HER2+ 18%, poorer OS, independent  SISH/IHC but not FISH INT-116: GEJ and gastric cancer, + / - post op FU/RT – HER2+ FISH 11% in 258 pts, IHC 12% in 148 pts – Poorer OS in HER2+ receiving FU/RT: 24 vs 44 mos – No difference in OS for HER2+ with / without FU/RT MAGIC Trial: GEJ and gastric cancer, preop ECF – HER2+ 11% in 156 pts – HER2 neither prognostic for OS nor predictive of chemo benefit EXPAND Trial: Cape-Cis + / - Cetuximab – HER2+ 21% in 679 pts – Superior OS on either arm Yoon Cancer 120: 415; 2014 Prins Ann Oncol 24:1290; 2013 Gordon Ann Oncol 24:1754; 2103 Okines Ann Oncol 24: 1253; 2013 Lordick Lancet Oncol 14: 490; 2013

14. ToGA Trial HER2-positive advanced GC (n = 584) 5FU or capecitabine + cisplatin (n = 290) R 5FU or capecitabine + cisplatin + trastuzumab (n = 294) Phase III: Trastuzumab in HER2+ GEJ and Gastric Cancer 3807 patients screened 810 HER2-positive (22.1%) 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

15. ToGA: Efficacy Outcome 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) Chemotherapy + Trastuzumab (n = 294) Chemotherapy Alone (n = 290)HR (95% CI)P Value Primary endpoint Median OS, months13.811.10.74 (0.60-0.91).0046 Secondary endpoints Median PFS, months6.75.50.71 (0.59-0.85).0002 ORR, %47.334.6-.0017 CR5.42.4-.0599 PR41.832.1-.0145 ORR, overall response rate Bang Y, et al. Lancet. 2010;376(9742):687-697.

16. Primary end point: OS Time (months) 294 290 277 266 246 223 209 185 173 143 147 117 113 90 64 71 47 56 32 43 24 30 16 21 14 13 7 12 6 6565 4040 1010 0000 No. at risk 11.113.8 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 024681012141618202224262830323436 Event FC + T FC Events 167 182 HR 0.74 95% CI 0.60, 0.91 p value 0.0046 Median OS 13.8 11.1 T, trastuzumab

18. Secondary end point: PFS 0246810121416182022242628303234 Event 294 290 258 238 201 182 141 99 95 62 60 33 41 17 28 7 21 5 13 3 9393 8282 6262 6161 6161 4040 2020 0000 5.56.7 No. at risk 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Time (months) FC + T FC Events 226 235 HR 0.71 95% CI 0.59, 0.85 p value 0.0002 Median PFS 6.7 5.5

19. 11 3 OS in IHC2+/FISH+ or IHC3+ (exploratory analysis) 1.0 0.8 0.6 0.4 0.2 0.0 363432302826242220181614121086420 Time (months) 11.816.0 FC + T FC Events 120 136 HR 0.65 95% CI 0.51, 0.83 Median OS 16.0 11.8 Event 0.1 0.3 0.5 0.7 0.9 218 198 4040 5353 12 4 20 11 228 218 196 170 170 141 142 112 122 96 100 75 84 53 65 39 51 28 1010 0000 No. at risk 39 20 28 13

20. RTOG 1010: Phase III Study of Neoadjuvant Trastuzumab and Chemoradiation for Esophageal Adenocarcinoma (Siewert I, II) ‘ CHEMORADIATION HER-2 (+) (FISH) HER-2 (+) (FISH) TRASTUZUMAB + CHEMORADIATION TRASTUZUMAB + CHEMORADIATION SURGERY + TRASTUZUMAB (1 YR) SURGERY + TRASTUZUMAB (1 YR) HER-2 (-) (FISH) HER-2 (-) (FISH) ALTERNATIVE STUDIES  Chemoradiation: Carboplatin, Paclitaxel + RT 5040 cGy  Surgery  Maintenance trastuzumab post op  OS Primary Endpoint

21. Targeting the Intracellular Domain of HER2: Lapatinib  Oral dual TKI  Targets EGFR/HER2 –Both frequently overexpressed in various cancers TKI = tyrosine kinase inhibitor; EGFR = epidermal growth factor receptor. Yamauchi et al, 2009.

22. LOGIC Trial: Gastric Cancer RANDOMIZATION Capox + LapatinibCapox Gastric/GEJ Cancer, HER2+, 545 patients Hecht JR, et al. J Clin Oncol. 2013;31(Suppl):Abstract LBA4001

23. Primary Endpoint: Overall Survival CapeOx+L CapeOx+P 1.0 0.8 0.6 0.4 0.2 0.0 Cumulative survival probability 051015202530354045 Time since randomization (months) PEPCapeOx+L N=249 CapeOx+P N=238 Median (95% CI) (mo) 12.2 (10.6, 14.2)10.5 (9.0, 11.3) HR (95% CI)0.91 (0.73, 1.12) p=0.3492 Subjects at risk CapeOx+L 249 199 133 83 47 24 9 3 3 CapeOx+P 238 189 106 53 34 17 11 7 2 2 ITT analysis HR 0.91 Presented at ASCO 2013

24. OS by Region CapeOx+L CapeOx+P 1.0 0.8 0.6 0.4 0.2 0.0 Cumulative survival probability 051015202530354045 Time since randomization (months) ASIAROW Subjects at risk CapeOx+L 100 93 70 49 25 16 7 3 3 141 101 59 30 19 6 2 CapeOx+P 93 77 47 28 19 11 7 5 1 136 104 53 21 12 4 2 1 CapeOx+L N=100 CapeOx+P N=93 Median (95% CI) (mo) 16.5 (13.3,20.2) 10.9 (9.0,14.9) HR (95% CI)0.68 (0.48,0.96) CapeOx+L N=141 CapeOx+P N=136 Median (95% CI) (mo) 10.0 (8.0,12.0) 9.1 (8.3,10.9) HR (95% CI)1.04 (0.79,1.37) 1.0 0.8 0.6 0.4 0.2 0.0 Cumulative survival probability 051015202530354045 Time since randomization (months) CapeOx+L CapeOx+P Presented at ASCO 2013

25. Progression Free Survival (PEP) CapeOx+L N=249 CapeOx+P N=238 Median (95% CI) (mo)6.0 (5.6, 7.0)5.4 (4.4, 5.7) HR (95% CI)0.86 (0.71, 1.04) p= 0.1026 Subjects at risk CapeOx+L 249 212 180 121 95 63 43 35 27 17 9 9 5 4 4 3 2 1 1 1 1 0 0 0 0 CapeOx+P 238 205 157 91 54 36 25 20 18 15 11 9 7 6 6 6 5 4 3 2 1 1 1 1 0 Without Censoring CapeOx+L N=249 CapeOx+P N=238 Median (95% CI) (mo)6.0 (5.6, 7.0)5.4 (4.4, 5.7) HR (95% CI)0.82 (0.68, 1.00) p=0.0381 With Censoring CapeOx+L CapeOx+P 1.0 0.8 0.6 0.4 0.2 0.0 Cumulative survival probability 041014182630343846 Time since randomization (months) 2 6 8 2242 Note: The curve displayed represents data without censoring Presented at ASCO 2013

26. Best Overall Response CapeOx + Lapatinib N=249 CapeOx + Placebo N=238 Complete response6 (2%)5 (2%) Partial response126 (51%)90 (38%) Stable Disease70 (28%)94 (39%) Disease Progression20 (8%)22 (9%) Not evaluable/unknown27 (11%) Overall RR53% (95%CI : 46.6−59.3)40% (95% CI : 33.6−46.4) Median Duration of Response (month) 7.3 (95%CI : 6.4–8.4)5.6 (95%CI : 4.8–6.0) ORR by region North America63 %56 % Asia65 %39 % ROW44 %40 % Presented at ASCO 2013

27. TYTAN Trial: Gastric Cancer RANDOMIZATION Weekly Paclitaxel + Lapatinib Weekly Paclitaxel Gastric/GEJ Cancer POD prior FP, HER2+ Bang YJ, et al. J Clin Oncol. 2012;30(15S): Abstract 11

28. TYTAN Trial: OS, OS by IHC

29.  2012 Genentech USA, Inc. All rights reserved. 29 Receptor-ADC complex is internalized into cell Potent cytotoxic is released once inside the cell ADC binds to the receptor Receptor-targeted Antibodies selectively deliver potent cytotoxics: TDM-1 ADCs=antibody-drug conjugates.

30. HER2-Directed Therapy Trials Ongoing HER2 Trials –Second-line: -GATSBY: Paclitaxel vs TDM-1 –First-line -JACOB: Cape-Cis-Trastuzumab + / - Pertuzumab (HER2-3), 780 patients -HELOISE: Cape-Cis + 2 dose levels of Trastuzumab, 400 patients

31.  2012 Genentech USA, Inc. All rights reserved. 31 31 eIF4B Targeting mTOR AKT PDK1 ↑ Metabolism PI3K ↑ Protein synthesis Receptor mTOR PTEN S6K 4EBP1 S6 Ribosome biogenesis Autophagy

32. mTOR: Everolimus in Gastric Cancer: GRANITE-1 Trial RANDOMIZATION, 656 patients BSC + Everolimus Ohtsu A, et al. J Clin Oncol. 2013;31(31):3935-3943. Refractory Gastric/GEJ Cancer BSC + Placebo

33. Gastric Cancer: GRANITE-1, Everolimus GRANITE-2: Paclitaxel + / - Everolimus second line Ohtsu A, et al. J Clin Oncol. 2013;31(31):3935-3943.

34.  2012 Genentech USA, Inc. All rights reserved. 34 34 Targeting the PI3K/AKT axis AKT PDK1 Cell cycle control Proliferation ↑ Survival PI3K Cyclin D1p27BAD GSK3  NFκB ↓ Apoptosis Receptor mTOR PTEN S6K 4EBP1 Protein translation

35. Trials of Targeted Agents 1 st Line TargetAgentTrialRegimenNumberStatus HER2PertuzumabJACOBXP + T +/- Pertuzumab 780Ongoing HER2TrastuzumabHELOISEXP + T (2 doses)400Ongoing CMETRilotumumabRilomet-1ECX + / - Rilo650Ongoing CMETOnartuzumabMetGastricFOLFOX + /- O800Ongoing EGFrPanitumumab NCT01627379 5-FU-Cis + / - Pan 300Ongoing VEGFrPazopanibPaFLOFLO + / - Pazop75Ongoing 2 nd Line mTOREverolimus AIOST00111 Pac + / - Evero665Ongoing HER2TDM-1GATSBYPac vs TDM-1412Ongoing EGFrNimotuzumab NCT01813253 Irino + / - Nimo400Ongoing PARPOlaparibPac + / - OlapPlanned

36. Esophagogastric Cancer: Targeted Agents Biomarkers to identify patients more likely to respond Gene amplification > mutation in esophagogastric cancer: EGFr and HER2 are key pathways 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