Disrupting Cytokine Signaling in Pancreatic Cancer A Phase I/II Study of Etanercept in Combination With Gemcitabine in Patients With Advanced Disease

Objectives: Etanercept blocks tumor necrosis factor alpha (TNF-alpha), a proinflammatory cytokine that plays a role in cancer-related cachexia and tumor growth. A phase I/II study was conducted to assess the tolerability and efficacy of gemcitabine and etanercept in advanced pancreatic cancer. Methods: Twenty-five patients received etanercept 25 mg subcutaneously twice weekly with gemcitabine. A control cohort of 8 patients received gemcitabine alone. The primary end point was progression-free survival at 6 months. Blood specimens were analyzed for TNF-alpha, IL-1 beta, IL-6, interferon-gamma, IL-10, and NF-kappa beta activation. The trial is registered with ClinicalTrials.gov, number NCT00201838. Results: Thirty-eight patients participated in this study. In the gemcitabine-etanercept cohort, grade 3/4 drug-related toxicities included leucopenia (3) and neutropenia (6). There were 3 (12%) patients with partial response and 8 (32%) patients with stable disease. The rate of progression-free survival at 6 months was 28% [n = 7; 95% confidence interval (CI), 20%-36%]. Median time to progression was 2.23 months (95% CI, 1.86-4.36 months) and median overall survival was 5.43 months (95% CI, 3.30-10.23 months). Clinical benefit rate was 33% of the evaluable patients. A correlation was seen between IL-10 levels and clinical benefit. Conclusions: Etanercept added to gemcitabine is safe but did not show significant enhancement of gemcitabine in patients with advanced pancreatic cancer.