Phase 3 Trial of Everolimus in Previously Treated Patients With Advanced Gastric Cancer: GRANITE-1 Eric Van Cutsem*, K. H. Yeh, Y. J. Bang, L. Shen, J. A. Ajani, Y. X. Bai, H. C. Chung, H. M. Pan, K. Chin, K. Muro, Y. H. Kim, H. Smith, C. Constantini, S. Rizvi, T. Sahmoud, A. Ohtsu On behalf of the GRANITE-1 Investigators * University Hospital Leuven/Belgium Presented at the 2012 Gastrointestinal Cancers Symposium. 1

Background Gastric cancer is aggressive and difficult to treat 1 5-year survival rate for advanced, metastatic disease is <5% 2,3 After failure of first-line chemotherapy, available treatment options provide minimal benefit and are associated with considerable toxicity 1,4,5 2 1 Catalano V et al. Crit Rev Hematol Oncol. 2009;71:127-34; 2 American Cancer Society. Cancer Facts & Figures 2011; 3 Matsuda T et al. Jpn J Clin Oncol. 2011;41:40-51; 4 Wagner AD et al. Cochrane Database Syst Rev. 2010;CD004064; 5 Field K et al. Drugs. 2008;68:

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 cancers 1-3 Everolimus, an oral mTOR inhibitor, showed efficacy in preclinical models of gastric cancer 1,4-6 3 mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase. 1 Xu DZ et al. BMC Cancer. 2010;10:536; 2 Lang SA et al. Cancer. 2007;120: ; 3 Yu G et al. Clin Cancer Res. 2009;15: ; 4 Taguchi F et al. Invest New Drugs. 2011;29: ; 5 Cejka D et al. Anticancer Res. 2008;28: ; 6 Jaeger-Lansky A et al. Cancer Biol Ther. 2010;9:919-27; 7 Doi T et al. J Clin Oncol. 2010;28: In a phase 2 study of 53 patients with previously treated advanced gastric cancer, everolimus showed promising efficacy and acceptable tolerability 7

Phase 3 GRANITE-1 Study Design 4 Everolimus 10 mg PO daily + BSC* (n = 439) Placebo PO daily + BSC (n = 217) SCREEN Treatment until disease progression or intolerable toxicity Stratification by region: Asia vs rest of world Stratification by number of lines of previous systemic chemotherapy (1 vs 2) Safety follow-up: EOT + 28 d Survival follow-up: every 3 mo RANDOMIZE (N = 656) BSC, best supportive care; EOT, end of treatment; PO, orally. ClinicalTrials.gov identifier: NCT

Eligibility Criteria 5 >2 previous systemic therapies for advanced disease Anticancer therapy within 3 weeks* or major surgery within 2 weeks of randomization Chronic treatment with steroids or immunosuppressive agents Enteral feeding CNS metastases Any severe/uncontrolled medical condition Age ≥18 years Confirmed gastric adenocarcinoma –GEJ adenocarcinomas permitted if the majority involved the stomach Documented progression after 1 or 2 lines of previous systemic chemotherapy ECOG performance status ≤2 Adequate bone marrow, renal, and hepatic function Key Inclusion Criteria Key Exclusion Criteria *Fluoropyrimidine monotherapy was permitted up to 2 weeks before randomization. CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; GEJ, gastroesophageal junction.

Study Endpoints Primary: OS Secondary –PFS –ORR* –AEs as assessed by NCI CTCAE, version 3.0 –Time to definitive deterioration of ECOG PS –Time to definitive 5% deterioration in the global health status/quality of life scale of the EORTC QLQ-C30 questionnaire Exploratory –Correlation between biomarkers and clinical endpoints 6 *ORR: overall response rate according to RECIST, version 1.0. AE, adverse event NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; RECIST, Response Evaluation Criteria In Solid Tumors.

Statistical Considerations Between-group OS comparison performed using stratified log- rank test at overall one-sided 2.5% level, stratified by protocol stratification factors Single interim analysis planned after 60% of required deaths observed –At time of interim analysis (cut-off date of Jan 31, 2011), IDMC recommended continuing study without any changes Sample size calculation –Considering randomization scheme and planned interim analysis, estimated that 526 deaths would give study 90% power to detect a 26% difference in the risk of death, corresponding to prolongation in OS from 4.0 months with placebo to 5.4 months with everolimus –Assuming uniform patient accrual over 2 years, 6 months of follow- up, and 5% loss to follow-up, determined that 633 patients needed to be enrolled Hierarchical testing strategy –Formal statistical significance for PFS could be declared only if between-group difference in OS statistically significant 7

Patient Disposition 8 Patients randomly assigned (N = 656) Everolimus + BSC (n = 439) Placebo + BSC (n = 217) Ongoing (n = 11; 2.5%) Discontinued treatment (n = 428; 97.5%) –Disease progression (n = 292; 66.5%) –AEs (n = 94; 21.4%) –Abnormal laboratory values (n = 1; 0.2%) –Withdrew consent (n = 20; 4.6%) –Administrative problems (n = 2; 0.5%) –Death NOS (n = 16; 3.6%) –Lost to follow-up (n = 2; 0.5%) –Protocol deviation (n = 1; 0.2%) Ongoing (n = 11; 2.5%) Discontinued treatment (n = 428; 97.5%) –Disease progression (n = 292; 66.5%) –AEs (n = 94; 21.4%) –Abnormal laboratory values (n = 1; 0.2%) –Withdrew consent (n = 20; 4.6%) –Administrative problems (n = 2; 0.5%) –Death NOS (n = 16; 3.6%) –Lost to follow-up (n = 2; 0.5%) –Protocol deviation (n = 1; 0.2%) Ongoing (n = 0; 0%) Discontinued treatment (n = 217; 100%) –Disease progression (n = 169; 77.9%) –AEs (n = 34; 15.7%) –Abnormal laboratory values (n = 0; 0%) –Withdrew consent (n = 7; 3.2%) –Administrative problems (n = 0; 0%) –Death NOS (n = 5; 2.3%) –Lost to follow-up (n = 1; 0.5%) –Protocol deviation (n = 1; 0.5%) Ongoing (n = 0; 0%) Discontinued treatment (n = 217; 100%) –Disease progression (n = 169; 77.9%) –AEs (n = 34; 15.7%) –Abnormal laboratory values (n = 0; 0%) –Withdrew consent (n = 7; 3.2%) –Administrative problems (n = 0; 0%) –Death NOS (n = 5; 2.3%) –Lost to follow-up (n = 1; 0.5%) –Protocol deviation (n = 1; 0.5%) Full analysis set (n = 439) Safety set (n = 437) Full analysis set (n = 439) Safety set (n = 437) Full analysis set (n = 217) Safety set (n = 215) Full analysis set (n = 217) Safety set (n = 215) NOS, not otherwise specified.

GRANITE-1: Participating Countries 9

Baseline Demographics and Disease Characteristics (FAS) 10 Everolimus + BSC (n = 439) Placebo + BSC (n = 217) Age, yrs, median (range)62.0 ( )62.0 ( ) Age <65 yrs260 (59.2)129 (59.4) Male, n (%)322 (73.3)161 (74.2) Race, n (%) Caucasian166 (37.8)75 (34.6) Asian251 (57.2)126 (58.1) Other22 (5.0)16 (7.4) Region, n (%) Asia243 (55.4)120 (55.3) Rest of world196 (44.6)97 (44.7) ECOG performance status, n (%) 0144 (32.8)70 (32.3) 1269 (61.3)120 (55.3) 225 (5.7)27 (12.4) FAS, full analysis set.

Baseline Disease Characteristics (FAS) 11 Everolimus + BSC (n = 439) Placebo + BSC (n = 217) Anatomical site, n (%) Proximal162 (36.9)94 (43.3) Distal276 (62.9)123 (56.7) GEJ involvement, n (%)118 (26.9)69 (31.8) Lauren classification, n (%) Adenocarcinoma, diffuse93 (21.2)37 (17.1) Adenocarcinoma, intestinal82 (18.7)50 (23.0) Adenocarcinoma, mixed29 (6.6)18 (8.3) Adenocarcinoma, NOS105 (23.9)45 (20.7) Other129 (29.4)67 (30.9) Previous gastrectomy, n (%) Partial126 (28.7)60 (27.6) Total97 (22.1)46 (21.2) Previous lines of chemotherapy, n (%) 1210 (47.8)103 (47.5) 2229 (52.2)114 (52.5)

Exposure to Study Treatment (Safety Set) 12 Everolimus + BSC (n = 437) Placebo + BSC (n = 215) Duration, wks, median (range)7.1 ( )6.4 ( ) Duration, wks, mean (SD)11.5 (12.09)8.5 (8.76) Duration of exposure, wks, n (%) <484 (19.2)49 (22.8) 4 to <8163 (37.3)101 (47.0) 8 to <1255 (12.6)23 (10.7) 12 to <1646 (10.5)20 (9.3) 16 to <2026 (5.9)7 (3.3) 20 to <2412 (2.7)3 (1.4) 24 to <289 (2.1)5 (2.3) 28 to <327 (1.6)2 (0.9) ≥3235 (8.0)5 (2.3)

Overall Survival (FAS) 13

Overall Survival by Stratification Factors (FAS) 14 ROW, rest of world. Prior chemotherapy Region Cross-class. of strata Hazard Ratio (95% CI) Everolimus 10 mg/d Placebo In favor of All (N = 656)0.90 ( ) 2 (n = 343)0.90 ( ) Asia (n = 363)0.96 ( ) ROW (n = 293)0.85 ( ) 1 prior chemo & ROW (n = 167)0.91 ( ) 2 prior chemo & ROW (n = 126)0.74 ( ) 1 (n = 313)0.94 ( ) 0.98 ( )2 prior chemo & Asia (n = 217) 0.94 ( )1 prior chemo & Asia (n = 146)

Progression-Free Survival (FAS) 15

Tumor Response (Patients With Measurable Disease) 16 DCR, disease control rate. Everolimus + BSC (n = 379) Placebo + BSC (n = 191) Best overall response, n (%) CR1 (0.3)0 PR16 (4.2)4 (2.1) SD147 (38.8)38 (19.9) PD157 (41.4)119 (62.3) Unknown58 (15.3)30 (15.7) ORR (CR + PR), n (%)17 (4.5)4 (2.1) DCR (CR + PR + SD), n (%)164 (43.3)42 (22.0)

Best Percentage Change From Baseline in Tumor Size 17 Best % change from baseline (measurable lesions) 160% 140% 120% 100% 80% 60% 40% 20% 0% –20% –40% –60% –80% –100% 160% 140% 120% 100% 80% 60% 40% 20% 0% –20% –40% –60% –80% –100% Everolimus 10 mg/day (n = 304)Placebo (n = 154) º No change º Everolimus + BSC (n = 304) Placebo + BSC (n = 154) Decrease in best percentage change from baseline, n (%)115 (37.8)19 (12.3) Zero change in best percentage change from baseline, n (%)16 (5.3)2 (1.3) Increase in best percentage change from baseline, n (%)109 (35.9)98 (63.6) Best % change from baseline available but contradicted by overall lesion response of progressive disease, n (%) 64 (21.1)35 (22.7)

Summary of Adverse Events and Deaths (Safety Set) Everolimus + BSC (n = 437) Placebo + BSC (n = 215) Any AE, n (%)433 (99.1)208 (96.7) Any grade 3/4 AE, n (%)310 (70.9)115 (53.5) Any serious AE, n (%)207 (47.4)89 (41.4) AE leading to discontinuation, n (%)94 (21.5)34 (15.8) AE requiring dose interruption/reduction, n (%)242 (55.4)46 (21.4) AE requiring additional therapy, n (%)395 (90.4)174 (80.9) All deaths, n (%)352 (80.5)179 (83.3) On-treatment deaths*, n (%)88 (20.1)49 (22.8) Study indication as primary cause79 (18.1)45 (20.9) Other primary cause9 (2.1)4 (1.9) 18 *On-treatment deaths are those that occurred during study treatment and up to 28 days after treatment discontinuation.

Most Common All-Cause Adverse Events (Safety Set) Adverse Event, n (%) Everolimus + BSC (n = 437) Placebo + BSC (n = 215) All gradesGrade 3/4All gradesGrade 3/4 Nonhematologic Decreased appetite208 (47.6)48 (11.0)78 (36.3)12 (5.6) Stomatitis174 (39.8)20 (4.6)23 (10.7)0 Fatigue150 (34.3)34 (7.8)65 (30.2)11 (5.1) Nausea132 (30.2)16 (3.7)69 (32.1)8 (3.7) Diarrhea115 (26.3)15 (3.4)33 (15.3)2 (0.9) Hematologic Anemia114 (26.1)70 (16.0)42 (19.5)27 (12.6) Thrombocytopenia80 (18.3)22 (5.0)5 (2.3)3 (1.4) Neutropenia47 (10.8)17 (3.9)6 (2.8)1 (0.5) Abnormal biochemistry Hypokalemia52 (11.9)26 (5.9)9 (4.2)2 (0.9) Blood alkaline phosphatase increased34 (7.8)20 (4.6)6 (2.8)3 (1.4) Aspartate aminotransferase increased34 (7.8)14 (3.2)8 (3.7)2 (0.9) 19

Conclusions Compared with BSC, everolimus did not significantly reduce the risk of death in patients with advanced gastric cancer Everolimus did reduce the risk of progression or death compared with BSC The safety profile of everolimus was similar to that observed with everolimus in other cancers, with no new safety signals identified Biomarker analysis is ongoing 20

Acknowledgements The patients participating in this trial and the study investigators Independent data monitoring committee –Roberto Labianca (chair) –Ichinosuke Hyodo (member) –Ian Ford (biostatistician) The Novartis teams Steering committee members –Eric Van Cutsem (co-chair) –Atsushi Ohtsu (co-chair) –Jaffer Ajani –Yung-Jue Bang –Lin Shen –Kun-Huei Yei –Chiara Constantini –Syed Rizvi –Tarek Sahmoud –Heind Smith 21