1 Results of the Phase 3, placebo-controlled trial (SUCCEED) evaluating the mTOR inhibitor ridaforolimus as maintenance therapy in advanced sarcoma patients following clinical benefit from prior standard cytotoxic chemotherapy 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

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

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

4 Ridaforolimus: previous activity demonstrated in sarcomas Route of ridaforolimus Number and diagnosis Clinical benefit rate Rate of 6 months Phase 1/2oral147 all tumors (85 sarcomas) 27%23% Phase 2IV212 sarcomas29%23% EORTC historical review of sarcoma database for “active” agents (Glabbeke, European Journal of Cancer 38 (2002) 543–549 14% Clinical benefit rate: CR+PR+SD >4 months

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

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 Placebo (N=364) Ridaforolimus (N=347)P-Value Age mean (SD)50.6 (15.0)52.0 (16.0) Gender Male/Female (%)43/5745/ ECOG 0/1 (%)50/ Histology soft tissue/bone (%)91/989/ Prior chemo 1 st /2 nd or 3 rd (%)62/3861/ Sarcoma grade high/low (%)73/674/ Metastatic sites lung/liver (%)64/1967/

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

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

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

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

13 Tumor response: Clinical Benefit Rate (CBR) ≥ 4 months CBR (CR+PR+SD) Ridaforolimus40.6% Placebo28.6% p-Value0.0009

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

17 Adverse events noted during SUCCEED trial MedDRA System Organ Class Preferred Term Placebo (N=359)Ridaforolimus (N=343) All Grades (%) Grade ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) PERCENT of Patients with ≥ 1 Adverse Event Stomatitis18<1619 Infections (all sites included) Fatigue Thrombocytopenia Diarrhea Cough16<131<1 Rash6028<1

18 Adverse events reported with the class of mTOR inhibitors MedDRA System Organ Class Preferred Term Placebo (N=359)Ridaforolimus (N=343) All Grades (%) Grade ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) Anemia Hypertriglyceridemia9<1272 Hypercholesterolemia5021<1 Hyperglycemia3<1147 Renal and other urinary disorders7<1163 Pneumonitis< 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%) Weeks Investigator Assessment (HR=0.69, p<0.0001) Ridaforolimus Placebo Independent Radiology Review (HR=0.72, p=0.0001) Ridaforolimus Placebo

23 Efficacy result of pediatric populations 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