Intermittent Erlotinib in Combination with Pemetrexed: Phase I Schedules Designed to Achieve Pharmacodynamic Separation

Introduction:Epidermal growth factor receptor tyrosine kinase inhibitors given concurrently with chemotherapy do not improve patient outcomes compared with chemotherapy alone in advanced non-small cell lung cancer (NSCLC). Pharmacodynamic separation by intermittent delivery of epidermal growth factor receptor tyrosine kinase inhibitors with chemotherapy may increase efficacy by overcoming hypothesized antagonism.Methods:Two dose-escalating phase I trials (arm A and arm B) were conducted simultaneously. Pemetrexed was given every 21 days (500 mg/m2 intravenously). In arm A, erlotinib was given weekly on days 2, 9, and 16 (800–1400 mg). In arm B, erlotinib was given on days 2 to 16 (150–250 mg). Patients continued therapy until disease progression or unacceptable toxicity.Results:Forty-two patients with advanced solid tumors, including 16 NSCLC, were treated. Patient characteristics included median age of 63 (range, 29–77), 19 males, and Karnofsky performance status ≥90/