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  1. Novel Biologic Therapies for Second-Line Gastric Cancer Charles S. Fuchs, MD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

  2. Second-Line Therapy in Gastric Cancer • No approved 2nd-line chemotherapy • 20-40% patients receiving 1st-line therapy receive 2nd-line • Taxanes and irinotecan most commonly used 2nd-line therapy

  3. Phase II Studies of Taxanes as Second-Line Therapy for Gastric Cancer

  4. Second-Line Therapy in Gastric Cancer • Historically, few randomized phase III trials compared to BSC • Numerous phase II trials: • Variability in response to 1st-line therapy • Variability in prior 1st-line therapy • Publication bias • Small number of patients

  5. Second-Line Therapy in Gastric Cancer • 625 pts who received 1st-line therapy at 3 centers in Italy • 28% (175) received 2nd-line therapy • RR = 16% • Median OS = 6 months • Predictors of poor survival: • ECOG PS  2 • Hgb  11.5 g/l • CEA > 50 ng/ml • >3 to 4 metastatic sites • TTP for 1st-line  6 months Catalano et al. 2008

  6. Second-Line Therapy in Gastric Cancer • 1,080 patients in three 1st-line phase III trials • 20% received 2nd line therapy • RR for 2nd-line therapy = 13% • Median OS = 5.6 months • Independent poor prognostic factors: • ECOG PS ≥ 2 • Liver mets • Peritoneal mets • Serum alkaline phosphatase ≥ 100 U/L Chau et al J Clin Oncol 2004

  7. Chau et al J Clin Oncol 2004

  8. Irinotecan vs. Best Supportive Care in Second-line Gastric Cancer Thuss-Patience et al. ASCO 2009 Median Survival N Irinotecan 250 mg/m2 q 3weeks 21 4.1 mos P = 0.02 Best Supportive Care 19 2.4 mos HR = 0.48 (95% CI, 0.25-0.92)

  9. Cougar-02: Randomized Trial of Docetaxel vs. BSC in Relapsed Esophagogastric Adenocarcinoma 168 patients : R A N D O M I Z E Docetaxel 75 mg/m2 q 3 weeks Primary Endpoint: Overall Survival Best supportive care

  10. Cougar-02: Randomized Trial of Docetaxel vs. BSC in Relapsed Esophagogastric Adenocarcinoma Cook et al. ASCO 2013

  11. K K PI3-K pY pY RAS RAF MEK pY SOS STAT GRB2 PTEN AKT MAPK Gene transcription Cell-cycle progression G2 M S G1 Proliferation/Maturation Metastasis Angiogenesis Survival/Apoptosis EGFR Signal Transduction

  12. Ongoing Randomized Trials in Advanced Esophagogastric Adenocarcinoma R A N D O M I Z E EOX REAL-3 Trial 730 patients EOX Panitumumab Capecitabine Cisplatin R A N D O M I Z E EXPAND Trial 870 patients Capecitabine Cisplatin Cetuximab

  13. PI3K/Akt/mTOR Pathway in Gastric Cancer • In a phase 2 study of 53 patients with previously treated advanced gastric cancer, everolimus showed promising efficacy and acceptable tolerability7 mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase. 1Xu DZ et al. BMC Cancer. 2010;10:536; 2Lang SA et al. Cancer. 2007;120:1803-10; 3Yu G et al. Clin Cancer Res. 2009;15:1821-29; 4Taguchi F et al. Invest New Drugs. 2011;29:1198-205; 5Cejka D et al. Anticancer Res. 2008;28:3901-08; 6Jaeger-Lansky A et al. Cancer Biol Ther. 2010;9:919-27; 7Doi T et al. J Clin Oncol. 2010;28:1904-1910. The PI3K/Akt/mTOR pathway, a key regulator of cell proliferation, growth, survival, metabolism, and angiogenesis, is dysregulated in 50%-60% of gastric cancers1-3 Everolimus, an oral mTOR inhibitor, showed efficacy in preclinical models of gastric cancer1,4-6

  14. Phase 3 GRANITE-1 Study Design Everolimus 10 mg PO daily+ BSC* (n = 439) RANDOMIZE (N = 656) SCREEN Safety follow-up: EOT + 28 d Treatment until disease progression or intolerable toxicity Survival follow-up: every 3 mo 2 1 Placebo PO daily + BSC (n = 217) • Stratification by region: Asia vs rest of world • Stratification by number of lines of previous systemic chemotherapy (1 vs 2) BSC, best supportive care; EOT, end of treatment; PO, orally. ClinicalTrials.gov identifier: NCT00879333.

  15. Overall Survival (FAS) 100 Censoring Times Everolimus + BSC (n/N = 352/439) Placebo + BSC (n/N = 180/217) 80 Kaplan-Meier medians Everolimus + BSC: 5.39 months Placebo + BSC: 4.34 months 60 Hazard ratio: 0.90 (95% CI, 0.75-1.08) Probability of overall survival (%) Log-rank Pvalue = 0.1244 40 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (months) No. of patients still at risk Time (months) 0 2 4 6 8 10 12 14 16 18 20 22 24 Everolimus 439 355 253 195 139 87 52 30 13 6 3 1 0 217 172 1 17 82 60 35 28 16 12 8 4 1 0 Placebo

  16. Role of VEGF Pathway in Tumor Growth • Ramucirumab (IMC-1121B; RAM) is a recombinant human IgG1 monoclonal antibody receptor antagonist designed to bind the extracellular domain of VEGF Receptor-2, thereby blocking the binding of VEGF ligands and inhibiting receptor activation. VEGF-A VEGF-A VEGF-CVEGF-D Ramucirumab VEGF-CVEGF-D VEGF binds toVEGFR2 receptor;VEGF-C, -D competefor binding toVEGFR2 Ramucirumabbinds to VEGFR2, blocks VEGFligand binding VEGFR2 VEGFR2 Endothelial cell membrane Ligand binding activates VEGFR2 andp44/p42 MAP kinases No signaling Angiogenesis Tumor growth Inhibit new blood vesselformation and tumor growth

  17. REGARD Study Design Ramucirumab 8 mg/kg q2wk + BSC (n = 238) R A N D O M I Z E Treatment until disease progression or intolerable toxicity Tumor assessment, survival, and safety follow-up 2:1 S C R E EN Placebo q2wk + BSC (n = 117) N = 355 • Multicenter, randomized, double-blind, placebo-controlled, phase 3 trial • Gastric or GEJ adenocarcinoma • Stratification factors: region, weight loss (≥10% vs. <10% over 3 months), location of primary tumor (gastric vs. GEJ) • Global: 6 continents, 30 countries, 120 study centers Abbreviations: BSC=best supportive care; GEJ=gastroesophageal junction Fuchs et al. Lancet 2013

  18. REGARD: Overall Survival No. at Risk Fuchs et al. Lancet 2013

  19. Tumor Response

  20. REGARD: Progression-free Survival No. at Risk Fuchs et al. Lancet 2013

  21. Treatment Emergent Adverse Events *

  22. Adverse Events of Special Interest † No Grade 4 hypertension was observed among ramucirumab-treated patients Fuchs et al. Lancet 2013

  23. REGARD: Time to Performance Status Deterioration* *Time to deterioration in ECOG PS score of 2 or worse Fuchs et al. Lancet 2013

  24. Median OS in randomized 2nd-line gastric cancer studies presented/published in 2009-2013 Ramucirumab vs PBO (BSC) 1 (n=355) 5.2 3.8 Docetaxel vs ASC2 (n=131) 5.2 3.6 CTX [Docetaxel or Irinotecan] vs BSC3 (n=202) 5.3 Irinotecan vs BSC4 (n=40) 1. Fuchs et al. Lancet 2013 2. Ford et al. Proc Gastrointestinal Cancer Symp 2013. LBA4. 3. Kang et al. J Clin Oncol 30:1513-1518, 2012 4. Thuss-Patience et al. EUR J CANCER 47: (2011) 2306-2314.

  25. Response Rates in randomized 2nd-line gastric cancer studies presented/published in 2009-2013 Ramucirumab vs PBO (BSC)1 (n=355) Docetaxel vs ASC2 (n=131) CTX [Docetaxel or Irinotecan] vs BSC3 (n=202) Irinotecan vs BSC4 (n=40) 1. Fuchs et al. Lancet 2013 2. Ford et al. Proc Gastrointestinal Cancer Symp 2013. LBA4. 3. Kang et al. J Clin Oncol 30:1513-1518, 2012 4. Thuss-Patience et al. EUR J CANCER 47: (2011) 2306-2314.

  26. RAINBOW: Study Design 1:1 Ramucirumab 8 mg/kg day 1&15 + Paclitaxel80 mg/m2day 1,8 &15 of a 28-day cycle N = 330 R A N D O M I Z E Treat until disease progression or intolerable toxicity Survival and safety follow-up S C R E EN Placebo day 1&15 + Paclitaxel 80 mg/m2 day 1,8 &15 N = 335 • Important inclusion criteria: • - Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma • - Progression after 1st line platinum/fluoropyrimidine based chemotherapy • Stratification factors: • - Geographic region, • - Measurable vs non-measurable disease, • - Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos) * GEJ=gastroesophageal junction; gastric and GEJ will be summarized under the term GC

  27. ToGA: A Randomized, Open Label Multicenter Phase III Study Capecitabine1 or iv 5-FU2†+ cisplatin3 (n=290) HER2-positive* advancedgastric or GEJ cancer (n=584) 3807 patients screened 810 HER2-positive (22.1%) R Capecitabine or iv 5-FU2†+ cisplatin3+trastuzumab (n=294) • Stratification factors • Advanced vs. metastatic disease • GC vs. GEJ • Measurable vs. non-measureable • ECOG PS 0-1 vs. 2 • Capecitabine vs. 5-FU • †Chosen at investigator’s discretion • 1 1000 mg/m2 bid d1-14 q3w x 6 cycles • 2 800 mg/m2/day continuous iv infusion d1-5 q3w x 6 cycles • 3 80 mg/m2 q3w x 6 cycles • 4 8 mg/kg loading dose followed by 6 mg/kg q3w until disease progression *IHC 3+ or FISH+5-FU=5-fluorouracil; GEJ=gastroesophageal junction; R=randomization; ECOG PS =Eastern Cooperative Oncology Group performance score. 27 Bang YJ, et al. Lancet. 2010;376:687-697.

  28. ToGA Primary Endpoint: Overall Survival 1.0 0.9 0.8 0.7 F+C+Trastuzumab 0.6 F+C 0.5 Probability 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 F=fluoropyrimidine (either fluorouracil or capecitabine); C=cisplatin. 28 Bang YJ, et al. Lancet. 2010;376:687-697.

  29. T-DM1 structure Target expression: HER2 Monoclonal antibody: Trastuzumab Cytotoxic agent: DM1 Highly potent cytotoxic agent T-DM1 Linker: MCC Systemically stable T-DM1 is a novel ADC Trastuzumab Average drug:antibody ratio ≅3.5:1

  30. Phase III Study of T-DM1 Versus Taxane in Patients With HER-2 Gastric Cancer 412 HER-2 pts following first-line therapy: T-DM1 q 3 weeks R A N D O M I Z E Primary endpoint: Overall Survival T-DM1 weekly Paclitaxel or Docetaxel

  31. MET Amplification as a Predictor of Drug Sensitivity in Gastric and Esophageal Adenocarcinoma Graziano et al J Clin Onc 2011: 230 pts: 10% MET amplifications Worse prognosis Yapp et al J Clin Onc 2011: Phase I trial of ARQ197 Minor regression in gastric cancer Smollen et al PNAS, 2006

  32. Second-Line Therapy for Gastric Cancer: 2014 • For all patients, 2nd-line ramucirumab significantly improves overall survival • Survival benefit for ramucirumab appears comparable to 2nd-line docetaxelor irinotecan • Addition of ramucirumabto 2nd-line paclitaxel significantly improves overall survival • Other novel targeted approaches that may emerge: • HER-2 directed therapy • C-MET pathway directed therapy • Ongoing mining of genomic data may generate the next generation of targets

  33. Back-up Slides

  34. Post-discontinuation Treatment *Each patient may have received more than one regimen. PDT = Post-discontinuation Treatment

  35. REGARD: Subgroup Analysis for OS N(Ram) N(Plcb) Category Subgroup Overall 238 117 Age Group <65 156 71 ≥65 82 46 Sex Male 169 79 Female 69 38 Race White 181 91 Asian 39 17 Other 18 9 Ethnicity 41 19 Hispanic 197 98 Not Hispanic ECOG PS 0 67 31 ≥1 171 86 Measurable Tumor Yes 218 106 No 20 11 Prior Therapy First-Line 199 103 Adjuvant/Neo 39 14 First-Line Type Doublets 99 63 Triplets 92 36 Hist. Subtype 96 44 Diffuse 52 35 Intestinal 90 38 Unknown # Metastatic Sites 163 71 0-2 75 46 ≥3 Peritoneal 64 45 Yes No 174 72 Progression-free Interval <6 months 132 74 65 28 ≥6 months Weight Loss ≥10% 37 17 <10% 201 100 Primary Tumor Gastric 179 85 59 32 GEJ Geo Region NA 165 80 LA 55 29 Asia 18 8

  36. REGARD: Subgroup Analysis for PFS N(Ram) N(Plcb) Category Subgroup Overall 238 117 Age Group <65 71 156 ≥65 82 46 Sex Male 169 79 Female 69 38 Race White 181 91 Asian 39 17 Other 18 9 Ethnicity Hispanic 41 19 Not Hispanic 197 98 ECOG PS 0 67 31 ≥1 171 86 Measurable Tumor Yes 218 106 No 20 11 Prior Therapy First-Line 199 103 Adjuvant/Neo 14 39 First-Line Type Doublets 63 99 Triplets 36 92 Hist. Subtype Diffuse 96 44 Intestinal 52 35 Unknown 90 38 # Metastatic Sites 71 0-2 163 46 ≥3 75 Peritoneal Yes 64 45 No 174 72 Progression-free Interval <6 months 132 74 28 ≥6 months 65 Weight Loss ≥10% 17 37 <10% 201 100 Primary Tumor Gastric 85 179 32 59 GEJ Geo Region NA 80 165 LA 29 55 Asia 8 18