Randomized Phase II and Pharmacogenetic Study of Pemetrexed Compared With Pemetrexed Plus Carboplatin in Pretreated Patients With Advanced Non–Small-Cell Lung Cancer Egbert F. Smit, Sjaak A. Burgers, Bonne Biesma, Hans J.M. Smit, Pier Eppinga, Anne-Marie C. Dingemans, Markus Joerger, Jan H. Schellens, Andrew Vincent, Nico van Zandwijk, and Harry J.M. Groen From the Department of Pulmonary Diseases Vrije Universiteit Medical Centre; Department of Medical Oncol- ogy, Netherlands Cancer Institute; Nederlandse Vereniging Artsen voor Longziekten en Tuberculose Data Centre, Amsterdam; Jeroen Bosch Hospital, ’s-Hertogenbosch; Rijnstate Hospital, Arnhem; Nij Smellinghe, Drachten; Academisch Ziekenhuis Maastricht, Maastricht; University Medical Centre Groningen, Groningen, the Netherlands; Department of Oncology and Hematology, Cantonal Hospital, St Gallen, Switzerland; and Bernie Banton Centre, University of Sydney, Sydney, Australia. Submitted July 16, 2008; accepted October 2, 2008; published online ahead of print at www.jco.org on March 23, 2009. Written on behalf of the Nederlandse Vereniging Artsen voor Longziekten en Tuberculose Lung Cancer Group. Supported by an unrestricted educa- tional grant from Eli Lilly Co. The trans- lational part of this study was supported by a gift from the legacy of Liesbeth van Vuuren-Martens. Presented as a poster at the 44th Annual Meeting of the American Soci- ety of Clinical Oncology, May 30-June 3, 2008, Chicago, IL. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Clinical Trials repository link available on JCO.org. Corresponding author: Egbert F. Smit, MD, PhD, Department of Pulmonary Diseases, Vrije Universiteit Medical Centre, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands; e-mail: ef.smit@vumc.nl. © 2009 by American Society of Clinical Oncology 0732-183X/09/2712-2038/$20.00 DOI: 10.1200/JCO.2008.19.1650 A B S T R A C T Purpose We performed a randomized phase II trial comparing pemetrexed with pemetrexed plus carboplatin (PC) in patients experiencing relapse after platinum-based chemotherapy. Patients and Methods Main eligibility criteria were histologic or cytologic proof of advanced non–small-cell lung cancer (NSCLC), relapse more than 3 months after platinum-based chemotherapy, normal organ function, and Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned to pemetrexed 500 mg/m 2 (arm A) or carboplatin area under the curve 5 and pemetrexed 500 mg/m 2 (arm B), both administered intravenously every 3 weeks. Response assessment was performed every 6 weeks; toxicity assessment was performed every 3 weeks. Primary end point was time to progression (TTP); secondary end points were objective response rate (ORR), overall survival (OS), and toxicity. The study was designed to detect a 33% decrease in the hazard of disease progression in the combination arm ( = 0.05, two-sided log-rank test). Polymorphisms of thymidylate synthase, the reduced folate carrier, -glutamyl hydrolase, and methylenetetrahydrofolate reductase (MTHF) were investigated in peripheral WBCs of consenting patients. Results Two hundred forty patients were enrolled. Median TTP was 2.8 months for arm A versus 4.2 months for arm B (hazard ratio, 0.67; 95% CI, 0.51 to 0.89; P = .005). Median OS was 7.6 months and 8.0 months and ORR was 4% and 9% for arms A and B, respectively. Subgroup analyses found adenocarcinoma to be associated with favorable outcome. Toxicities in both arms was negligible, with one potential toxic death in arm A. Patients with MTHFR C677T homozygous mutation had increased progression-free survival compared with patients with wild-type or heterozygous mutations (P = .03). Conclusion PC as second-line treatment for relapsed NSCLC resulted in a significant 33% reduction of the hazard of disease progression as compared with pemetrexed alone. J Clin Oncol 27:2038-2045. © 2009 by American Society of Clinical Oncology INTRODUCTION Platinum-containing chemotherapy has become the cornerstone of treatment for patients that present with advanced non–small-cell lung can- cer (NSCLC), as it is associated with a modest pro- longation of life span and improvement of quality of life. However, these patients will inevitably experi- ence tumor progression and might qualify for second-line treatment. When compared with best supportive care, both docetaxel and erlotinib are associated with superior overall survival and signifi- cant improvement of quality of life. 1,2 Recently, a phase III study showed that therapeutic results with pemetrexed in these patients are comparable to those obtained with docetaxel, 3 with pemetrexed having a more favorable toxicity profile. Therapeu- tic results of these second-line treatments remain disappointing, with median survival times of ap- proximately 8 months and 1-year survival of 30%. One way to improve on these results is to investi- gate pemetrexed-based combination chemother- apy. The obvious candidate to combine with pemetrexed is cisplatin, because its combination has JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 27  NUMBER 12  APRIL 20 2009 2038 © 2009 by American Society of Clinical Oncology Downloaded from ascopubs.org by 34.239.46.140 on June 10, 2022 from 034.239.046.140 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.