Phase II study of pemetrexed plus gemcitabine in advanced pancreatic cancer

Background: Gemcitabine is the standard chemotherapy for the treatment of advanced pancreatic cancer. The novel multitargeted antifolate pemetrexed (Alimta®) has also demonstrated activity in this disease. These two drugs are synergistic in vitro, and a phase I study has demonstrated activity of single-agent pemetrexed in pancreatic cancer. Aim: To evaluate pemetrexed plus gemcitabine in a multicenter phase II study in patients with advanced pancreatic cancer. Patients and methods: Chemonaive patients with advanced pancreatic adenocarcinoma, metastatic or locally advanced, not amenable to curative resection, received intravenous gemcitabine 1250 mg/m² over 30 minutes on days 1 and 8 and intravenous pemetrexed 500 mg/m² over 10 minutes on day 8 every 21 days. The primary endpoint was objective response rate. Patients were evaluated for time-to-event variables including overall survival, time-to progression, time-to-treatment failure, and duration of response. Patients who were symptomatic were evaluated weekly for clinical benefit response. CT scans were obtained every two cycles. Results: Forty-two patients were treated; 41 were evaluable for efficacy. Ninety-five percent of patients had metastatic disease. There were five partial responses (objective response rate 12%), and 44% of patients had stable disease. The 1-year survival rate was 32%; median survival was 6.6 months (95% CI 4.4, 9.9). Of 30 eligible patients, four (13%) had a clinical benefit response. Grade 3 and 4 hematologic toxicities included neutropenia (84%), febrile neutropenia (12%), and thrombocytopenia (33%). Non-hematologic toxicities were minimal. Conclusion: The combination of pemetrexed and gemcitabine is active in advanced pancreatic cancer, and has acceptable toxicity; a 1-year survival rate of 32% is encouraging. A phase III trial comparing pemetrexed plus gemcitabine with gemcitabine has completed accrual.