ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 1 Temozolomide Oncology Drug Advisory Committee March 13, 2003 Craig L. Tendler, M.D. Vice President, Oncology Clinical Research

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 2 Agenda Basis for the accelerated approval of Temozolomide in refractory Anaplastic Astrocytoma (94-123) Post-approval commitment study (98-13) –Design –Key study milestones –Current status Ongoing challenges associated with post-approval commitment study Initiatives to expedite completion of post approval commitment Schering-Plough development programs with temozolomide in primary brain tumors

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 3 Temozolomide NDA Submission for Recurrent Glioma (at first relapse) Recurrent Glioblastoma Multiforme –Phase 2 randomized study temozolomide vs procarbazine (94-091) –Phase 2 single arm study (94-122) Recurrent Anaplastic Astrocytoma –Phase 2 single arm study Anaplastic Astrocytoma (94-123)

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 4 Temozolomide Indication (August 1999) Adult patients with refractory anaplastic astrocytoma, i.e. patients at first relapse who have experienced disease progression on a regimen containing a nitrosourea and procarbazine

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 5 Basis for Temozolomide Accelerated Approval for Refractory Anaplastic Astrocytoma Study Design (94-123) –single arm study (n=162) –adult anaplastic astrocytoma patients at first relapse ≤ 1 prior chemotherapy regimen Study conduct –32 institutions –February 1995 – April 1998

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 6 Basis for Temozolomide Accelerated Approval for Refractory Anaplastic Astrocytoma Primary endpoint – PFS at 6 months assessed by Gd MRI (confirmed by central review) Secondary endpoints –response rate –overall survival Objective –to show 6 month PFS rate lower boundary of 95% CI of at least 10%

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 7 Basis for Temozolomide Accelerated Approval for Refractory Anaplastic Astrocytoma Overall results: ITT Population (94-123) –PFS 6 Months:51% (95% CI: 43-59%) –Median Survival:13.6 months –Response Rate:33% (CR + PR: 5%+28%)

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 8 Basis for Temozolomide Accelerated Approval for Refractory Anaplastic Astrocytoma Results: Patients Refractory to Procarbazine Plus a Nitrosourea (n = 54 ) –Objective Response Rate:22% (CR = 9%) –Median Duration of Response:50 weeks ( weeks) –Duration of Response in Complete Responders: weeks –Median Survival:15.9 months

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 9 Temozolomide Safety in Malignant Glioma Safety database: 1,017 temozolomide treated patients (400 GBM & AA) Temozolomide was administered with few dose reductions or dose delays Most adverse events were mild to moderate in severity Study treatment discontinuation due to adverse events was infrequent Grade 3/4 myelosuppression was also infrequent and non-cumulative

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 10 Unanimous ODAC Opinion Patients with relapsed anaplastic astrocytoma after procarbazine and a nitrosourea are considered unresponsive to other therapies –Unmet medical need Objective response in this setting could be an adequate surrogate for clinical benefit if well defined and of sufficient magnitude

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 11 Unanimous ODAC Opinion Efficacy: –Temozolomide is effective for the treatment of anaplastic astrocytoma in patients previously treated with a nitrosourea and procarbazine Safety: –Safety of Temozolomide is acceptable for this indication

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 12 Temozolomide Anaplastic Astrocytoma Post Approval Commitment Planning for first-line study with RTOG already underway at time of the ODAC accelerated approval recommendation Design (98-13) –Population: First-line anaplastic astrocytoma –Primary endpoint: Overall Survival RT + TMZ Randomization RT + BCNU RT + TMZ/BCNU Rationale for TMZ/BCNU Combination –AGAT depletion

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 13 FDA Agreed Commitments Commitment Date Status Randomized phase III (98-13) to be preceded by additional safety assessment of TMZ/BCNU in the study population June ’01Submitted July ‘01 Submission of pediatric study reports -I H Dec. ‘02Submitted Sept. ‘02 Submission of final study report (Anaplastic Astrocytoma first-line study 98-13) June ‘07Project ongoing

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 14 Temozolomide Anaplastic Astrocytoma Post Approval Commitment: Key Milestones 6/99Protocol first submitted to FDA 8/99Accelerated approval granted 10/99Revised protocol incorporating FDA comments submitted to FDA 12/99FDA indicated that the protocol should not proceed until additional safety data on the TMZ + BCNU in the study population was submitted 2/00Agreement on design of phase I safety assessment 4/00IND filed by RTOG

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 15 Key Milestones - Continued 6/00Initiation of Phase I safety assessment with TMZ/BCNU 3/01Completion of enrollment for safety assessment 7/01Submission of safety data to FDA 9/01Enrollment initiated for second safety cohort 1/02Completion of enrollment for 2 nd safety cohort 6/02Combination arm discontinued due to safety profile 1/03Randomized Phase 3 opened

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 16 RTOG 98-13: Status March ‘03 RT + TMZ Study design RT + BCNU Phase 3 opened to enrollment Jan. ‘03 Projected enrollment 24 patients/month for total of 454 patients Inter-group study infrastructure provides broadest access to U.S. and Canadian investigators –RTOG, ECOG, SWOG, NCCTG (>300 sites) (HR target 1.5; median OS 36 vs. 54 months)

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 17 Temozolomide Post-Approval Commitment: Estimates of Interim Analyses and Study Completion Protocol-specified objective: survival HR = 1.5 Protocol Specified Analyses Projected Time from Study Initiation (Jan. ’03) Survival HR Required to Cross Boundary * Interim 1: 63 events’ Interim 2: 126 events’ Interim 3: 188 events’ Final: 251 events’ * Boundaries at interims are one sided p values , , , final analysis Overall significance levels.05 (one sided)

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 18 Challenges of Survival Trial in First- Line Anaplastic Astrocytoma Low and declining annual incidence (~3,000 newly diagnosed U.S.patients/year) Long median survival (3-4 years)

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 19 Schering-Plough and RTOG Initiatives to Expedite Study Completion Communications: –Investigators: investigator meetings, target neuro-surgeons, monthly teleconference with the lead investigators at each cooperative group, cooperative group newsletters –Patients: internet listing, patient brochures, patient brain tumor support groups (National Brain Tumor Foundation and American Brain Tumor Foundation) Project Management: –RTOG HQ staff –Monthly progress reviews (SPRI / Inter-group PIs) –Institutional data management support International Sites

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 20 Temozolomide Additional Initiatives in Malignant Gliomas SPRI-supported EORTC/NCIC phase 3 study of Temozolomide plus radiation versus radiation in newly diagnosed Glioblastoma Multiforme Enrollment completed March ‘02 (573 patients) Primary endpoint is overall survival

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 21 Temozolomide Development Programs in Primary Brain Cancer Phase 3 Newly diagnosed Anaplastic Astrocytoma (98-13) Phase 3 Newly diagnosed Glioblastoma Multiforme Phase 2 Anaplastic Oligodendroglioma-RTOG Phase 3 Low Grade Glioma-EORTC Phase 1/2 studies in recurrent pediatric CNS tumors