Does the addition of erlotinib to gemcitabine improve outcome in patients with advanced pancreatic cancer?

BACKGROUND Advanced pancreatic cancer (APC) has a very poor prognosis. Despite 8 phase III trials over 10 years testing the addition of cytotoxic or biologic agents to gemcitabine, single-agent gemcitabine remains the standard treatment for APC. Pancreatic tumors often overexpress EGFR, which is associated with a worse outcome. OBJECTIVE The aim was to assess the effect on survival of the EGFR-targeted agent erlotinib in combination with gemcitabine in patients with APC. DESIGN AND INTERVENTION From October 2001 to January 2003, this double-blind, placebo-controlled, international phase III trial randomly assigned patients with metastatic or locally advanced pancreatic adenocarcinoma to receive gemcitabine plus either erlotinib or a matched placebo. Gemcitabine (1,000mg/m(2)) was given by 30min intravenous infusion on days 1, 8, 15, 22, 29, 36 and 43 followed by a 1-week rest in cycle 1, and on days 1, 8 and 15 in all subsequent 4-week cycles. Erlotinib was taken orally at 100mg/day or 150mg/day until disease progressed or toxicity became unmanageable. OUTCOME MEASURES Overall survival was the primary end point. Secondary end points included progression-free survival, response rate and duration, toxic effects, quality of life and correlation of baseline tissue EGFR level with outcome. RESULTS In the 569 patients assessed, median overall survival based on an intention-to-treat analysis was longer in patients in the erlotinib plus gemcitabine arm than in those in the placebo plus gemcitabine arm (6.24 versus 5.91 months), with an estimated hazard ratio (HR) of 0.82 (95% Cl 0.69-0.99; P=0.038). One-year survival rates were higher in the erlotinib plus gemcitabine arm than in the placebo plus gemcitabine arm: 23% (95% Cl 18-28%) versus 17% (95% Cl 12-21%; P=0.023). Multivariate Cox regression analysis showed that the factors associated with longer overall survival were erlotinib treatment (P=0.04) and female sex (P = 0.03). Progression-free survival was longer in the erlotinib plus gemcitabine arm than in the placebo plus gemcitabine arm (median 3.75 months versus 3.55 months), with an estimated HR of 0.77 (95% Cl 0.64-0.92; P=0.004). The overall disease control rate was 57.5% for erlotinib plus gemcitabine and 49.2% for placebo plus gemcitabine (P=0.07). Objective response rates did not differ significantly between the treatment arms. No associations were found between EGFR status and either patient response or disease stability. Patients receiving the combination of erlotinib plus gemcitabine had higher frequencies of rash, diarrhea, infection and stomatitis (grade 1 or 2) than did those receiving placebo plus gemcitabine. The presence of a rash was associated with a greater likelihood of achieving disease control (P=0.05), after accounting for other prognostic factors. CONCLUSION In patients with APC, the addition of erlotinib to gemcitabine significantly improves overall and progression-free survival compared with placebo plus gemcitabine, providing a new treatment option.