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Eric Van Cutsem*,

Phase 3 Trial of Everolimus in Previously Treated Patients With Advanced Gastric Cancer: GRANITE-1 . Eric Van Cutsem*,

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Eric Van Cutsem*,

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  1. 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.

  2. Background 1Catalano V et al. Crit Rev Hematol Oncol. 2009;71:127-34; 2American Cancer Society. Cancer Facts & Figures 2011; 3Matsuda T et al. Jpn J Clin Oncol. 2011;41:40-51; 4Wagner AD et al. Cochrane Database Syst Rev. 2010;CD004064; 5Field K et al. Drugs. 2008;68:299-317. Gastric cancer is aggressive and difficult to treat1 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 toxicity1,4,5

  3. 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

  4. 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.

  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 Eligibility Criteria Key Inclusion Criteria Key Exclusion Criteria • 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 *Fluoropyrimidine monotherapy was permitted up to 2 weeks before randomization. CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; GEJ, gastroesophageal junction.

  6. Study Endpoints *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. • 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

  7. 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

  8. Patient Disposition 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 = 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 = 217) • Safety set (n = 215) NOS, not otherwise specified.

  9. GRANITE-1: Participating Countries

  10. Baseline Demographics and Disease Characteristics (FAS) FAS, full analysis set.

  11. Baseline Disease Characteristics (FAS)

  12. Exposure to Study Treatment (Safety Set)

  13. 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

  14. Overall Survival by Stratification Factors (FAS) Hazard Ratio (95% CI) All (N = 656) 0.90 (0.75-1.08) Prior chemotherapy 1 (n = 313) 0.94 (0.73-1.23) 2 (n = 343) 0.90 (0.70-1.15) Region Asia (n = 363) 0.96 (0.75-1.23) ROW (n = 293) 0.85 (0.65-1.10) 1 prior chemo & Asia (n = 146) 0.94 (0.63-1.39) Cross-class. of strata 2 prior chemo & Asia (n = 217) 0.98 (0.71-1.35) 1 prior chemo & ROW (n = 167) 0.91 (0.64-1.31) 2 prior chemo & ROW (n = 126) 0.74 (0.50-1.09) 0.6 0.8 1.0 1.2 1.4 Everolimus 10 mg/d Placebo In favor of ROW, rest of world.

  15. Progression-Free Survival (FAS) 100 Censoring Times Everolimus + BSC (n/N = 386/439) Placebo + BSC (n/N = 206/217) 80 Kaplan-Meier medians Everolimus + BSC: 1.68 months Placebo + BSC: 1.41 months 60 Hazard ratio: 0.66 (95% CI, 0.56-0.78) Probability of progression-free survival (%) Log-rank P value < 0.0001 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Time (months) No. of patients still at risk Time (months) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Everolimus 439 367 179 117 92 60 44 37 27 20 13 10 6 5 3 3 2 1 1 0 0 0 217 168 55 28 23 17 8 7 6 3 2 2 2 2 2 2 2 2 2 2 1 0 Placebo

  16. Tumor Response (Patients With Measurable Disease) DCR, disease control rate.

  17. Best Percentage Change From Baseline in Tumor Size 160% 160% º º No change No change 140% 140% 120% 120% 100% 100% 80% 80% Everolimus 10 mg/day (n = 304) Placebo (n = 154) 60% 60% Best % change from baseline (measurable lesions) 40% 40% 20% 20% 0% 0% –20% –20% –40% –40% –60% –60% –80% –80% –100% –100%

  18. Summary of Adverse Events and Deaths (Safety Set) *On-treatment deaths are those that occurred during study treatment and up to 28 days after treatment discontinuation.

  19. Most Common All-Cause Adverse Events (Safety Set)

  20. 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

  21. 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

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