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Randomized Phase II Trial of Three Schedules of Pemetrexed and Gemcitabine As Front-Line Therapy for Advanced Non–Small-Cell Lung Cancer

From the Department of Oncology and Medicine, Mayo Clinic and Foundation, Rochester; Duluth Community Clinical Oncology Program (CCOP), Duluth; CentraCare Clinic, St Cloud, MN; Geisinger Medical Center, Danville, PA; Illinois Oncology Research Association CCOP, Peoria; Carle Cancer Center CCOP, Urbana, IL; Scottsdale CCOP, Scottsdale, AZ; and Eli Lilly & Company, Indianapolis, IN

Address reprint requests to Alex A. Adjei, MD, PhD, Division of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: adjei.alex{at}mayo.edu

PURPOSE: A randomized three-arm phase II study was undertaken to evaluate the optimum administration schedule of pemetrexed and gemcitabine in chemotherapy-naïve patients with non–small-cell lung cancer.

PATIENTS AND METHODS: Patients were randomly assigned to three schedules of pemetrexed 500 mg/m² plus gemcitabine 1,250 mg/m², separated by a 90-minute interval, on a 21-day cycle as follows: schedule A, pemetrexed followed by gemcitabine on day 1 and gemcitabine on day 8; schedule B, gemcitabine followed by pemetrexed on day 1 and gemcitabine on day 8; and schedule C, gemcitabine on day 1 and pemetrexed followed by gemcitabine on day 8.

RESULTS: One hundred fifty-two eligible patients (schedule A, n = 59; schedule B, n = 31, and schedule C, n = 62) received a median of five (schedule A), two (schedule B), and four (schedule C) treatment cycles. Overall, 66% of patients experienced grade 3 or 4 neutropenia. Common grade 3 and 4 nonhematologic toxicities were dyspnea (11%), fatigue (16%), and transaminase elevation (9%). Schedule A seemed less toxic compared with schedule C (grade 3 or 4 events: 86% v 94%, respectively; P = .19; grade 4 events: 39% v 48%, respectively; P = .30). Schedule B was closed at interim analysis for inferior efficacy. Schedule A, with a confirmed response rate of 31% (95% CI, 20% to 45%), met the protocol-defined efficacy criteria, whereas schedule C, with a confirmed response rate of 16.1% (95% CI, 11% to 34%), did not. Median survival time and time to progression were 11.4 and 4.4 months, respectively, with no observable difference between the arms.

CONCLUSION: Pemetrexed and gemcitabine administered as outlined for schedule A met the protocol-defined efficacy criteria, was less toxic compared with the other treatment schedules, and should be further evaluated.

Supported in part by Public Health Service grant Nos. CA-25224, CA-37404, CA-15083, CA-35448, CA-35113, CA-35269, CA-35195, and CA-60276 from the National Institutes of Health and conducted as a collaborative trial of the North Central Cancer Treatment Group, Mayo Clinic, and Eli Lilly & Company, Indianapolis, IN.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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