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David H. Ilson, M.D., Ph.D. GI Oncology Service Memorial Sloan-Kettering Cancer Center

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. DISCLOSURES. Grant/Research Support Amgen Bayer Bristol-Myers Squibb Consultant

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David H. Ilson, M.D., Ph.D. GI Oncology Service Memorial Sloan-Kettering Cancer Center

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  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 CarcinomaUS 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. 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.

  7. AKT RAS PI3K PDK1 Raf Src mTOR MEK MAPK MAPK FAK Dysregulated cancer signaling pathways: Tyrosine kinase signaling examples Ligand-activated receptors ↓ Apoptosis ↑ Survival Cell cyclecontrol Angiogenesis Proliferation

  8. AKT AKT Targeted agents:Crossing the plasma membrane RAS RAS Sos Sos Grb2 Grb2 Shc Shc PI3K PI3K PDK1 PDK1 Raf Raf • 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 Cell surface receptors Cell surface receptors Adjei et al. J Clin Oncol. 2005;23:5386-5403. Imai et al. Nat Rev Cancer. 2006;6:714-727.

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

  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 Incidence of HER2 Expression by IHC or FISH1-5 All GC tumors ── 13% to 23% Histology Intestinal Diffuse Mixed Unknown 16% to 34% 6% to 7% 20% 14% Primary tumor location GEJ Gastric 25% to 34% 9% to 20% 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.

  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 Phase III: Trastuzumab in HER2+ GEJ and Gastric Cancer 5FU or capecitabine + cisplatin (n = 290) 3807 patients screened 810 HER2-positive (22.1%) HER2-positiveadvanced 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

  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) ORR, overall response rate Bang Y, et al. Lancet. 2010;376(9742):687-697.

  16. Primary end point: OS MedianOS 13.811.1 1.0 Event Events 167182 HR 0.74 95% CI 0.60, 0.91 p value 0.0046 0.9 FC + T 0.8 FC 0.7 0.6 0.5 0.4 0.3 0.2 11.1 13.8 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) No. at risk 294 290 277 266 246 223 209 185 173 143 147 117 113 90 90 64 71 47 56 32 43 24 30 16 21 14 13 7 12 6 6 5 4 0 1 0 0 0 T, trastuzumab

  17. Secondary end point: PFS MedianPFS 6.75.5 Event 1.0 Events 226235 HR 0.71 95% CI 0.59, 0.85 p value 0.0002 0.9 FC + T 0.8 FC 0.7 0.6 0.5 0.4 0.3 0.2 5.5 6.7 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Time (months) No. at risk 294 290 258 238 201 182 141 99 95 62 60 33 41 17 28 7 21 5 13 3 9 3 8 2 6 2 6 1 6 1 4 0 2 0 0 0

  18. OS in IHC2+/FISH+ or IHC3+ (exploratory analysis) MedianOS 16.011.8 1.0 Event Events 120136 HR 0.65 95% CI 0.51, 0.83 0.9 FC + T 0.8 0.7 FC 0.6 0.5 0.4 0.3 0.2 11.8 16.0 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) No. at risk 228 218 218 198 196 170 170 141 142 112 12296 100 75 84 53 65 39 51 28 39 20 28 13 20 11 12 4 11 3 5 3 4 0 1 0 0 0

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

  20. 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.

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

  22. Primary Endpoint: Overall Survival 1.0 CapeOx+L CapeOx+P 0.8 0.6 Cumulative survival probability 0.4 0.2 0.0 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 0 5 10 15 20 25 30 35 40 45 Time since randomization (months) ITT analysis HR 0.91 Presented at ASCO 2013

  23. OS by Region ASIA ROW 1.0 1.0 CapeOx+L CapeOx+P 0.8 0.8 0.6 0.6 Cumulative survival probability Cumulative survival probability 0.4 0.4 0.2 0.2 CapeOx+L CapeOx+P 0.0 0.0 0 5 10 15 20 25 30 35 40 45 0 5 10 15 20 25 30 35 40 45 Time since randomization (months) Time since randomization (months) 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 Presented at ASCO 2013

  24. Progression Free Survival (PEP) 1.0 Without Censoring 0.8 0.6 With Censoring Cumulative survival probability 0.4 0.2 CapeOx+L CapeOx+P 0.0 6 0 2 4 10 14 18 22 26 30 34 38 42 46 8 Time since randomization (months) 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 Note: The curve displayed represents data without censoring Presented at ASCO 2013

  25. Best Overall Response Presented at ASCO 2013

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

  27. TYTAN Trial: OS, OS by IHC

  28. Receptor-targeted Antibodies selectively deliver potent cytotoxics: TDM-1 ADC binds to the receptor Receptor-ADC complex is internalized into cell Potent cytotoxic is released once inside the cell ADCs=antibody-drug conjugates.

  29. 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

  30. AKT Targeting mTOR PI3K PDK1 S6 eIF4B Receptor PTEN ↑ Protein synthesis S6K Autophagy mTOR ↑Metabolism 4EBP1 Ribosomebiogenesis

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

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

  33. AKT Targeting the PI3K/AKT axis PI3K PDK1 GSK3b NFκB BAD Cyclin D1 p27 Receptor PTEN S6K Protein translation mTOR 4EBP1 ↓Apoptosis ↑Survival Cell cyclecontrol Proliferation

  34. Trials of Targeted Agents

  35. 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

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