CB-1 Background of Pancreatic Cancer & NCIC CTG PA.3 Study Design Malcolm Moore, MD Professor of Medicine and Pharmacology Princess Margaret Hospital Chair, NCIC Clinical Trials Group—GI Committee

CB-2 Pancreatic Cancer US and Canada – Approximately 35,400 new cases in 2005 – Approximately 35,000 deaths in th-leading cause of cancer-related deaths Most patients are diagnosed with advanced disease 5-year survival < 4%

CB-3 Gemcitabine Registration Study in Pancreatic Cancer †Composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, et al. J Clin Oncol. 1997;15: Gemcitabine N = 63 5-FU N = 63p-value Clinical benefit response † 24%5%0.002 Survival Median survival, months — 5.7 — — 1-year survival18%2%— Partial response5.4%0— Stable disease39%19%— Time to progression, months

CB-4 Pancreatic Cancer 2005 Limited treatment options – Gemcitabine is the only FDA-approved treatment Attempts to improve outcome in advanced disease have been unsuccessful Unmet medical need remains

CB-5 Study NCIC CTG PA.3 A Randomized, Placebo-Controlled Study of OSI-774 (Tarceva) Plus Gemcitabine in Patients with Locally Advanced, Unresectable or Metastatic Pancreatic Cancer

CB-6 Study NCIC CTG PA.3 International study led by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) – Principal Investigator: Malcolm J. Moore, MD – NCIC CTG Physician Coordinator: Wendy Parulekar, MD Co-sponsored by OSI Pharmaceuticals Physicians and patients blinded to treatment assignment

CB-7 Study Conduct Role of NCIC CTG NCIC CTG – Served as overall study-coordinating center – Developed protocol, amendments, and CRFs – Provided medical monitoring and data management across all countries – Managed and monitored Canadian sites – Oversight provided by NCIC DSMC – Maintained clinical database blinded to treatment assignment – Performed statistical analyses after database lock and unblinding Backup Catergories/Study Concuct.ppt

CB-8 Study Conduct Role of OSI Pharmaceuticals OSI Pharmaceuticals – Provided study drug and financial support – Recruited and managed CROs for non-Canadian sites – No access to clinical database prior to database lock and unblinding – Performed the statistical analyses for regulatory filing Backup Catergories/Study Concuct.ppt

CB-9 Key Eligibility Criteria Unresectable, locally advanced or metastatic adenocarcinoma of the pancreas Measurable or nonmeasurable disease ECOG performance status 0 to 2 Prior radiotherapy for local disease allowed No prior chemotherapy, except for 5-FU or gemcitabine as a radiosensitizer Note: EGFR-positive status not required

CB-10 Study Schema Stratified by Center ECOG PS (0/1 vs 2) Stage of disease (locally advanced vs distant metastases) RANDOMIZERANDOMIZE Gemcitabine 1,000 mg/m 2 IV + Tarceva daily PO Gemcitabine 1,000 mg/m 2 IV Cycle 1: Days 1, 8, 15, 22, 29, 36, 43 of an 8-week cycle Cycle 2 onward: Days 1, 8, 15 of a 4-week cycle Gemcitabine 1,000 mg/m 2 IV + Placebo daily PO 1:1

CB-11 Study Endpoints Primary endpoint – Overall survival Key secondary endpoints – Progression-free survival – Response rate – Quality of life (selected countries) – Assess tumor EGFR status with outcomes – Safety

CB-12 Statistical Considerations and Sample Size Hazard ratio (HR): Relative risk of death for patients on Tarceva + gemcitabine, compared to those receiving placebo + gemcitabine Study sample size based on an 80% power to detect hazard ratio of 0.75 (a 33% increase in survival) with a 5% level of significance Minimum of 381 deaths required for an event-driven analysis Sample size initially: 800 patients with accrual over 9 months; minimum follow-up of 2.8 months Modification of sample size to 450 during the study – Extension of follow-up to 18 months – No change in number of deaths for event-driven analysis

CB-13 Tarceva Dosage Initial patients randomized at 100 mg – Plan for interim blinded safety analyses Three safety analyses conducted after 8, 16, 50 patients entered at 100 mg – No safety concerns – Continued accrual worldwide at 100 mg – Entered patients at Canadian centers at 150 mg Interim safety analysis at 150 mg (n = 16) – Over 85% of planned accrual achieved – Continued accrual at 100 mg to sample size of 450

CB-14 Study Timelines 29 Nov 2001—First patient randomized 31 Jan 2003—Last patient randomized (N = 569) 13 Jan 2004—381st death in the 100 mg cohort documented in the NCIC CTG database – Final data cleaning initiated – 444 events occurred prior to 15 Jan Sep 2004 – Database locked and unblinded