The PI3K-AKT-mTOR pathway regulates cell growth, proliferation and metabolism in sarcoma

1. S. P. Chawla, J. Y. Blay, I. Ray-Coquard, A. Le Cesne, A. P. Staddon, M. M. Milhem, N. Penel, R. F. Riedel, B. Bui Nguyen, L. D. Cranmer, P. Reichardt, E. Bompas, Y. Song, R. M. Lee, J. E. Eid, J. Loewy, F. G. Haluska, P. F. Dodion, G. D. Demetri, on behalf of all SUCCEED investigators Results of the Phase 3, placebo-controlled trial (SUCCEED) evaluating the mTOR inhibitor ridaforolimus as maintenance therapyin advanced sarcoma patientsfollowing clinical benefit fromprior standard cytotoxic chemotherapy

2. PI3K PI3K AKT PTEN 4E-BP1 mTOR TSC Ridaforolimus FKBP The PI3K-AKT-mTOR pathway regulates cell growth, proliferation and metabolism in sarcoma mTOR signaling dysregulated in multiple sarcomas Ridaforolimus: a rapamycin analog and potent mTOR inhibitor Clinical activity in sarcomas in Phase 1 and 2 studies

3. CT PET Baseline Day 5 (53% ) Day 54 (85% ) Ridaforolimus: antitumor activity in sarcoma

4. Ridaforolimus: previous activity demonstrated in sarcomas Clinical benefit rate: CR+PR+SD >4 months

5. Sarcoma standard care and the SUCCEED pivotal Phase III trial design Metastatic sarcoma after 1-3 lines CT, per SOC PD Ineligible IRC CR, PR, SD SOC watchful waiting randomization RidaforolimusPlacebo (40 mg QD x 5 per week)

6. SUCCEED study endpoints • Primary endpoint • Improvement in PFS by independent radiology review • Secondary endpoints • Overall survival • Best target lesion response • Cancer-related symptoms • Safety and tolerability

7. Pivotal Phase III trial design statistics and key features • Statistical design: 650 patients with 90% power to detect 33% improvement in PFS (516 PFS events, =0.025, one-sided) • Stratified for line of therapy, histology, and geography • Two interim analyses • 711 patients enrolled between Oct ‘07 and Jan ‘10; 702 patients received either ridaforolimus or placebo • Largest randomized study ever in the soft tissue and bone sarcoma population

8. Patient characteristics were balanced at study entry

9. PFS per independent radiology review Independent Radiology Review (HR=0.72, p=0.0001) PFS rate Median PFS 3 mon 6 mon Ridaforolimus 17.7 weeks 70% 34% Placebo 14.6 weeks 54% 23% Weeks (Data cut-off date 10-25-2010)

10. PFS per investigator assessment Investigator Assessment (HR=0.69, p<0.0001) PFS rate Median PFS 3 mon 6 mon Ridaforolimus 22.4 weeks 72% 37% Placebo 14.7 weeks 55% 23% Weeks (Data cut-off date 10-25-2010)

11. Consistent progression free survival improvement across multiple subgroup analyses favor placebo favor rida

12. SUCCEED: trend in Overall Survival (OS) HR 0.88, p=0.2256 Median OS ridaforolimus: 21.4 months Placebo: 19.2 months 386 death events based on data cut-off date 4-30-2011 (6 months after PFS data cut-off date)

13. Tumor response: Clinical Benefit Rate (CBR) ≥ 4 months

14. Exploratory analysis of cancer-related symptoms • Questionnaires completed by the patients periodically in 3 categories: pain, cough and shortness of breath • Vast majority (>90%) of patients who stayed on therapy were free of severe symptoms in both treatment groups • Small numerical imbalances favoring placebo at some time points • Large amount of missing information mainly due to treatment discontinuation • Greater in placebo patients over time • Analysis is inconclusive due to large amount of missing information • Following disease progression, no information about cancer-related progression was collected

15. SUCCEED: ridaforolimus inhibited tumor growth Waterfall plots Best target lesion response (mean) Ridaforolimus -1.3% Placebo +10.3% (p<0.0001)

16. Post-progression survival = duration from disease progression to death Survival following disease progression was similar for the ridaforolimus and placebo groups HR=0.94 (95% CI [0.76, 1.18], p=0.6152) Ridaforolimus Placebo Weeks

17. Adverse events noted during SUCCEED trial

18. Adverse events reported with the class of mTOR inhibitors 6 deaths due to “pulmonary disorders” with ridaforolimus vs. none in placebo. 1 drug-related pneumonitis, 2 pleural effusion , 1 pulmonary embolism, 2 respiratory distress

19. Summary: Ridaforolimus improves disease control to maintain benefit of prior therapy • Study met the primary endpoint in PFS improvement (HR 0.72, p=0.0001) • Trend toward OS benefit (HR 0.88, p=0.2256) • Better tumor growth control • No adverse impact on survival following disease progression • No major unexpected AEs, and toxicities similar to other mTOR inhibitors

20. Acknowledgements • All of the sarcoma patients and their families who made this trial SUCCEED • All of the worldwide investigators and study team members • The study sponsors, Merck and Ariad Pharmaceuticals

21. Backup slides

22. Comparison of Independent radiology review and investigator assessment (concordance rate 80%) Independent Radiology Review (HR=0.72, p=0.0001) Ridaforolimus Placebo Investigator Assessment (HR=0.69, p<0.0001) Ridaforolimus Placebo Weeks

23. Ridaforolimus group 7 patients enrolled 64% tumor size reduction in one osteosarcoma patient 1 PR, 4 SD, 2 PD CBR ≥ 4mos: 5/7 = 71% PFS durations: 59, 48, 23, 20, 19, 16, and 8 weeks Placebo group 5 patients enrolled No Responder 1 SD, 4 PD CBR ≥ 4mos: 1/5 = 20% PFS durations: 20, 8, 4, 4, and 4 weeks Efficacy result of pediatric populations