Phase III Study Comparing Gemcitabine plus Cetuximab versus Gemcitabine in Patients with Locally Advanced or Metastatic Pancreatic Adenocarcinoma Southwest Oncology Group Protocol S0205 PA Philip, J Benedetti, C Fenoglio-Preiser, M Zalupski, H Lenz, E O’Reilly, R Wong, J Atkins, J Abbruzzese, C Blanke On behalf of SWOG, CALGB, NCIC, and the CTSU

Systemic Therapy of Pancreas Cancer Gemcitabine-based cytotoxic combination therapies have demonstrated no significant advantage over gemcitabine alone Combinations of gemcitabine with targeted agents have demonstrated no benefit over gemcitabine alone Gemcitabine plus erlotinib resulted in a marginal survival benefit that was statistically significant 1 1 Moore et al, J Clin Oncol in press

S0205: Background The EGFR pathway is activated in a large proportion of human pancreatic cancers Pre-clinical studies have demonstrated anti-tumor activity of cetuximab in human pancreatic cancer animal models A pilot phase II trial suggested an improvement of one-year survival with the combination of gemcitabine and cetuximab 1 Xiong et al, J Clin Oncol 22:2610, 2004

S0205: Study Schema Stratify Locally advanced versus metastatic Prior pancreatectomy Yes versus No Performance status 0/1 versus 2 Gemcitabine + Cetuximab Gemcitabine + Cetuximab Gemcitabine RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE

S0205: Drug administration Gemcitabine –1000 mg/m 2 IV over 30 minutes weekly x 7 of 8, then –1000 mg/m 2 IV over 30 minutes weekly 3 of 4 Cetuximab –400 mg/m 2 IV loading dose, then –250 mg/m 2 IV weekly

S0205: Study Objectives Primary –Overall survival Secondary –Time to treatment failure –Objective response –Pain and quality of life (QoL) –Toxicity –EGFR expression and its correlation with outcome

S0205: Eligibility Histologically or cytologically confirmed pancreatic adenocarcinoma Incurable locally advanced or metastatic disease Measurable or evaluable disease No prior therapy for metastatic disease –> 6 months from completion of adjuvant therapy ECOG PS 0-2 Adequate organ function Submission of tumor tissue for EGFR assessment Written informed consent

S0205: Statistical Methods Detect a 33% increase in median survival –92% power for the entire population –90% power for the anticipated EGFR positive subset –One-sided significance level Designed to accrue 704 patients/ 5 years

S0205: Statistical Methods Actual accrual accomplished in three years (766 total; 735 eligible) Two interim analyses and a final analysis one year after closure of accrual DSMC recommended study continuation based on formal interim analyses

S0205: Patient Characteristics Gem + Cetux N =366 Gem N = 369 Median Age (years) Female49%46% Performance Status 0/187% Locally Advanced21%22% Measurable Disease86.3%88.3% Prior Pancreatectomy10%11%

S0205 Primary Endpoint: Survival of all Patients HR = 1.09 (95% CI: 0.93, 1.27)

S0205: Progression-Free Survival HR = 1.13 (95% CI: 0.97, 1.31)

S0205: Time to Treatment Failure HR = 1.25 (95% CI: 1.08, 1.45)

S0205: Objective Tumor Response ResponseGem + Cetux (%) N = 316 Gem (%) N = 326 CR01 PR1213 SD3830 CR + PR + SD5044 PD4047

S0205: Grade 3 or 4 Adverse Events Toxicity Gem + Cetux (%) N = 353 Gem (%) N = 353 Grade 3Grade 4Grade 3Grade 4 Neutropenia Fatigue Nausea Vomiting Anemia Rash Anorexia ALT Thrombocytopenia Allergic reaction

S0205: CONCLUSIONS The addition of cetuximab to gemcitabine in patients with advanced pancreas cancer was well tolerated Cetuximab did not significantly improve the overall survival or time to disease progression

S0205: CONCLUSIONS Ongoing analyses will determine the impact of cetuximab on pain and QoL and the contributions of EGFR expression and skin rash on outcome Future studies with targeted agents in pancreas cancer must focus on improving patient selection and/or the adoption of rationally designed multitargeted approaches

Acknowledgements Patients Investigators & clinical trials support personnel Patient advocacy & support groups SWOG operations, data operations, and statistical center personnel NCI ImClone Bristol Myers Squibb