IMPROVED OVERALL SURVIVAL IN PATIENTS WITH ADVANCED SOFT-TISSUE OR BONE SARCOMAS WHO ACHIEVED A CLINICAL-BENEFIT RESPONSE WHEN TREATED WITH AP23573, A NOVEL MTOR INHIBITOR: UPDATE OF A PHASE 2 TRIAL G.Z. D’Amato, S.P. Chawla, A.W. Tolcher, A.P. Staddon, S.M. Schuetze, J.Y. Blay, J. Loewy, R. Kan, G.D. Demetri, and the AP23573 Sarcoma Study Group CTOS Seattle, 2007 Oncology 1, Friday November 2 CONFIDENTIAL ®

2 11/02/07 DEFOROLIMUS (AP23573, MK-8669) l Potent mTOR inhibitor l Non-prodrug rapamycin analog l Product of structure-based drug design l Exquisite specificity for mTOR l Compatible with i.v. or oral delivery l Crosses blood-brain barrier l Combinations possible –In vitro with targeted and cytotoxic agents –In patients with cytotoxic agents FKBP mTOR (fragment)

3 11/02/07 Trial Design l Patients with any form of advanced soft-tissue or bone sarcomas (metastatic and/or unresectable) l No restriction on prior therapy l Open-label, non-randomized trial, Simon 2-stage design l Deforolimus daily for 5 consecutive days i.v. (12.5 mg fixed dose, could be reduced for significant AE), every 2 weeks in repeating 4-week cycles l Four independent parallel groups based on histological subtype l Primary end-point –Clinical-benefit response (CBR) = objective response (complete or partial), or stable disease for ≥ 16 weeks –Criterion of success: CBR ≥ 25% (per histological subgroup) l Secondary end-point – progression-free survival (PFS)

4 11/02/07 Trial Schema Metastatic / Unresectable Soft-tissue and Bone sarcomas Age ≥15 years No restriction on prior therapy Measurable disease Bone Sarcomas Leiomyosarcoma Liposarcoma Other soft-tissue sarcoma Deforolimus i.v. QDx5 q2wks

5 11/02/07 ANALYSIS OBJECTIVES l Describe Overall Survival (OS) in overall population l Determine if Clinical-Benefit Response (CBR) is a prognostic factor for OS –CBR defined as complete response, partial response, or stable disease ≥ 16 weeks

6 11/02/07 METHODS l Kaplan-Meier curves plotted to describe Overall Survival (OS) in 2 populations –All treated (deforolimus) patients (N=212) –Subset of treated patients surviving ≥ 16 weeks (n=169)* l OS described in both populations for – those achieving CBR and, – those not achieving CBR l Cox regression analysis on patients surviving ≥ 16 weeks to determine –If selected baseline characteristics predictive of OS –To determine if CBR is predictive of OS across all subgroups * to adjust for any potential bias introduced by patients who expired or withdrew from study prior to evaluation for CBR

7 11/02/07 PATIENT CHARACTERISTICS Total Number of Patients Median Age (yrs) Age Range (yrs) Number of Males Number of Females Number of Prior Chemo – therapy Regimens (50%) > 4 (7%) (16%) (39%) At least 90% of patients had disease progression prior to enrollment

8 11/02/07 SURVIVAL PREDICTORS Overall Survival Hazard Ratios (95% CI) for Selected Baseline Characteristics (n=169) Cox proportional hazards models performed on potential predictors of survival For all characteristics CBR most predictive of survival HR = Hazard ratio for CBR robust in all patients treated (N=212). HR= [not shown] CBR:Yes rt No Bone Mets.: ECOG: Regimen: Lung Mets.: Liver Mets. : Age: TS Diag. (wks): Histology: Gender: No rt Yes 0 rt 1 0 & 1 rt >1 Yes rt No <65 rt ≥65 >208 rt ≤208 Bone rt STS Male rt Female 012 Hazard Ratio rt=relative to

9 11/02/07 Overall Survival – Entire Population

10 11/02/07 Overall Survival – Subset of Patients Surviving ≥ 16 Weeks

11 11/02/07 SURVIVAL PREDICTORS the data in the overall population hold true in a majority of subgroups sample size in some categories leads to wide confidence intervals Overall Survival Hazard Ratios (95% CI) for CBR in Patient Subgroups (n=169) Histology: Age: Gender: Regimen: TS Diag. (wks): Lung Mets.: Liver Mets.: Bone Mets.: ECOG: Bone STS <65 ≥65 Male Female 0 & 1 >1 ≤208 >208 Yes No Yes No Yes No NE Hazard Ratio 012

12 11/02/07 SUMMARY l Median OS was 40 weeks for all treated patients –72 vs 26 weeks for CBR and non-CBR patients, respectively l Median OS was 52 weeks in the subset of patients surviving ≥ 16 weeks –72 vs 38 weeks for CBR and non-CBR patients, respectively l OS did not differ by histological category l CBR status found to be associated with OS duration –Finding consistent for all patients and in subset of patients on trial ≥ 16 weeks

13 11/02/07 CONCLUSION l This exploratory analysis suggests that patients who achieve a CBR on deforolimus will have an overall survival duration at least double that of those with non-CBR l Additional studies are needed to further investigate this observation

14 11/02/07 ACKNOWLEDGEMENTS G.D. DemetriA. Elias M. Von MehrenD. Quinn W. ChowJ. Moore S. UndeviaS.P Chawla A.W. TolcherA.P. Staddon S.M. SchuetzeJ.Y. Blay A. Le CesneP. Schoffski G. EdelmanJ. Germino AP23573 Sarcoma Study Group