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

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

Phase II Studies of Taxanes as Second-Line Therapy for Gastric Cancer Drug Author No. of Pts RR PFS (mos) OS (mos) Docetaxel Graziano 21 5% -- 3.5 Giuliani 30 17% 6.0 Jo (S. Korea) 154 14% 2.6 7.2 Paclitaxel Hironka (Japan) 38 24% 5.0 Vinorelbine Kulke 29 7% 1.9 7.8

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

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

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

Chau et al J Clin Oncol 2004

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)

Cougar-02: Randomized Trial of Docetaxel vs 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

Cougar-02: Randomized Trial of Docetaxel vs Cougar-02: Randomized Trial of Docetaxel vs. BSC in Relapsed Esophagogastric Adenocarcinoma Docetaxel BSC P value Response rate 7% NR Overall survival 5.2 months 3.6 months 0.01 Cook et al. ASCO 2013

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

Ongoing Randomized Trials in Advanced Esophagogastric Adenocarcinoma 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

PI3K/Akt/mTOR Pathway in Gastric Cancer 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 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.

Phase 3 GRANITE-1 Study Design Everolimus 10 mg PO daily + BSC* (n = 439) RANDOMIZE (N = 656) SCREEN Treatment until disease progression or intolerable toxicity Safety follow-up: EOT + 28 d 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.

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

Role of VEGF Pathway in Tumor Growth Endothelial cell membrane 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-C VEGF-D Angiogenesis Tumor growth VEGF-A VEGFR2 Ligand binding activates VEGFR2 and p44/p42 MAP kinases Ramucirumab No signaling Inhibit new blood vessel formation and tumor growth Ramucirumab binds to VEGFR2, blocks VEGF ligand binding VEGF binds to VEGFR2 receptor; VEGF-C, -D compete for binding to VEGFR2 VEGF-C VEGF-D Endothelial cell membrane

Tumor assessment, survival, and safety follow-up 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

REGARD: Overall Survival HR (95% CI) = 0.776 (0.603, 0.998) Log rank P-value (stratified) = 0.0473 Ramucirumab Placebo Patients / Events 238 / 179 117 / 99 Median (mos) (95% CI) 5.2 (4.4, 5.7) 3.8 (2.8, 4.7) 6-month OS 42% 32% 12-month OS 18% 11% No. at Risk Ram 238 154 92 49 17 7 3 Plcb 117 66 34 20 4 2 1 Fuchs et al. Lancet 2013

Tumor Response Ramucirumab N=238 Placebo N=117 P-value n (%) Best Overall Response Complete response (CR) 1 (0.4) Partial response (PR) 7 (2.9) 3 (2.6) Stable disease (SD) 108 (45.4) 24 (20.5) Progressive disease 78 (32.8) 63 (53.8) Not evaluable / Not assessed 44 (18.5) 27 (23.1) Response rate: CR + PR 8 (3.4) 0.756 Disease control rate: CR + PR + SD 116 (48.7) <0.0001

REGARD: Progression-free Survival HR (95% CI) = 0.483 (0.376, 0.620) Log rank P-value (stratified) = ≤0.0001 Ramucirumab Placebo Patients / Events 238 / 199 117 / 108 Median (mos) (95% CI) 2.1 (1.5, 2.7) 1.3 (1.3, 1.4) 12-week PFS 40% 16% No. at Risk Ram 238 213 113 65 61 45 30 18 11 5 4 2 1 Plcb 117 92 27 7 Fuchs et al. Lancet 2013

Treatment Emergent Adverse Events * Ramucirumab (N=236) Placebo (N=115) TEAEs* Any Grade (%) Grade ≥3 (%)  Any Grade (%) Fatigue 36 6 40 10 Abdominal pain 29 28 3 Decreased appetite 24 23 Vomiting 20 25 4 Constipation 15 <1 Anemia 8 Dysphagia 11 2 Dyspnea 9 13

Adverse Events of Special Interest Ramucirumab (N=236) Placebo (N=115) Category of event Any Grade Grade ≥3  Any Grade (%) Hypertension * † 16 8 3 Bleeding/Hemorrhage 13 11 Arteriothromboembolic 2 1 Venous thromboembolic 4 7 Proteinuria <1 GI perforation Fistula (GI and non-GI) Infusion-related reaction Cardiac failure † No Grade 4 hypertension was observed among ramucirumab-treated patients Fuchs et al. Lancet 2013

REGARD: Time to Performance Status Deterioration* Ramucirumab Placebo Median 5.1 mos 2.4 mos *Time to deterioration in ECOG PS score of 2 or worse Fuchs et al. Lancet 2013

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.

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.

RAINBOW: Study Design 1:1 Ramucirumab 8 mg/kg day 1&15 + Paclitaxel 80 mg/m2 day 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

ToGA: A Randomized, Open Label Multicenter Phase III Study Capecitabine1 or iv 5-FU2† + cisplatin3 (n=290) HER2-positive* advanced gastric 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. Bang YJ, et al. Lancet. 2010;376:687-697. 27 27 27

ToGA Primary Endpoint: Overall Survival Events Median OS (mo) HR 95% CI p-value FC + Trastuzumab 167 13.8 0.74 0.60, 0.91 0.0046 FC 182 11.1 1.0 0.9 0.8 0.7 0.6 F+C+Trastuzumab F+C 0.5 Probability 0.4 0.3 0.2 11.1 13.8 0.1 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 1 F=fluoropyrimidine (either fluorouracil or capecitabine); C=cisplatin. Bang YJ, et al. Lancet. 2010;376:687-697. 28 28 28

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

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

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

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 docetaxel or irinotecan Addition of ramucirumab to 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

Back-up Slides

Post-discontinuation Treatment Ramucirumab (N=238) Placebo (N=117) n (%) % Patients with any PDT* 75 (31.5) 46 (39.3) Chemotherapy 69 (29.0) 44 (37.6) Biologic therapy 6 (2.5) 1 (0.9) Radiotherapy 4 (1.7) (5.1) Surgery 2 (0.8) *Each patient may have received more than one regimen. PDT = Post-discontinuation Treatment 34

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

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