This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hazarika, M. Articles by Pazdur, R. Search for Related Content PubMed PubMed Citation Articles by Hazarika, M. Articles by Pazdur, R.

Pemetrexed in Malignant Pleural Mesothelioma

Division of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland

Requests for reprints: Maitreyee Hazarika, Division of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, HFD-150, WOC 2, Room 2080, 5600 Fishers Lane, Rockville, MD 20857. Phone: 301-594-2473; Fax: 301-594-0499; E-mail: HazarikaM{at}cder.fda.gov.

Purpose: This report describes the data and analysis leading to the approval of pemetrexed (LY 231514, MTA, Alimta, Eli Lilly and Co., Indianapolis, IN) by the U.S. Food and Drug Administration (FDA) of a New Drug Application for the treatment of malignant pleural mesothelioma (MPM).

Experimental Design: The FDA review of the efficacy and safety of pemetrexed assessed in a randomized clinical trial of 448 patients with unresectable MPM comparing pemetrexed plus cisplatin with cisplatin alone, as well as preclinical pharmacology and chemistry data, are described. The basis for marketing approval is discussed.

Results: In one randomized, single-blind, multicenter international trial, 226 patients were randomized to the pemetrexed and cisplatin arm and 222 patients were randomized to cisplatin alone. Median survival times were 12.1 months for pemetrexed and cisplatin and 9.3 months for cisplatin (P = 0.021; hazard ratio, 0.766; 95% confidence interval, 0.61-0.96). Myelosuppression, predominantly neutropenia, was the most common toxicity of pemetrexed plus cisplatin. Other common adverse events were fatigue, leucopenia, nausea, dyspnea, vomiting, chest pain, anemia, thrombocytopenia, and anorexia.

Conclusions: Pemetrexed in combination with cisplatin was approved by the FDA on February 4, 2004 for the treatment of patients with MPM whose disease is either unresectable or who are otherwise not candidates for curative surgery. The recommended dose of pemetrexed is 500 mg/m² intra venous infusion over 10 minutes on day 1 of each 21-day cycle in combination with 75 mg/m² cisplatin infused over 2 hours beginning 30 minutes after the pemetrexed infusion. Patients must receive oral folic acid and vitamin B₁₂ injections before the start and during therapy to reduce severe toxicities. Patients should also receive corticosteroids with the chemotherapy to decrease the incidence of skin rash. Approval was based on a demonstration of survival improvement in a single randomized trial. Response rates and time to tumor progression were not included in product labeling because of inconsistencies in assessments among the investigators, independent radiologic reviewers, and the FDA, reflecting the difficulty of radiographic assessments in malignant mesothelioma. Complete prescribing information is available on the FDA Web site at http://www.fda.gov/cder/approval/index.htm.

This article has been cited by other articles:

				C. K. Daugherty, M. J. Ratain, E. J. Emanuel, A. T. Farrell, and R. L. Schilsky Ethical, Scientific, and Regulatory Perspectives Regarding the Use of Placebos in Cancer Clinical Trials J. Clin. Oncol., March 10, 2008; 26(8): 1371 - 1378. [Abstract] [Full Text] [PDF]

				British Thoracic Society Standards of Care Committ BTS statement on malignant mesothelioma in the UK, 2007 Thorax, November 1, 2007; 62(Suppl_2): ii1 - ii19. [Full Text] [PDF]

				G. L. Ceresoli, A. Chiti, P. A. Zucali, M. Rodari, R. F. Lutman, S. Salamina, M. Incarbone, M. Alloisio, and A. Santoro Early Response Evaluation in Malignant Pleural Mesothelioma by Positron Emission Tomography With [18F]Fluorodeoxyglucose J. Clin. Oncol., October 1, 2006; 24(28): 4587 - 4593. [Abstract] [Full Text] [PDF]

				J. Francart, C. Legrand, R. Sylvester, M. Van Glabbeke, J. P. van Meerbeeck, and A. Robert Progression-Free Survival Rate As Primary End Point for Phase II Cancer Clinical Trials: Application to Mesothelioma--The EORTC Lung Cancer Group J. Clin. Oncol., July 1, 2006; 24(19): 3007 - 3012. [Abstract] [Full Text] [PDF]

				G. L. Ceresoli, P. A. Zucali, A. G. Favaretto, F. Grossi, P. Bidoli, G. Del Conte, A. Ceribelli, A. Bearz, E. Morenghi, R. Cavina, et al. Phase II Study of Pemetrexed Plus Carboplatin in Malignant Pleural Mesothelioma J. Clin. Oncol., March 20, 2006; 24(9): 1443 - 1448. [Abstract] [Full Text] [PDF]

				A. Rahman and R. M. White Cytotoxic Anticancer Agents and Renal Impairment Study: The Challenge Remains J. Clin. Oncol., February 1, 2006; 24(4): 533 - 536. [Full Text] [PDF]

				S. Chattopadhyay, R. Zhao, S. A. Krupenko, N. Krupenko, and I. D. Goldman The inverse relationship between reduced folate carrier function and Pemetrexed activity in a human colon cancer cell line. Mol. Cancer Ther., February 1, 2006; 5(2): 438 - 449. [Abstract] [Full Text] [PDF]

				L. Pantanowitz, C. N. Otis, A. Munoz, R. Barcelo, G. Lopez-Vivanco, F. Lopez-Rios, M. Ladanyi, B. W.S. Robinson, and R. A. Lake Malignant Mesothelioma N. Engl. J. Med., January 19, 2006; 354(3): 305 - 307. [Full Text] [PDF]

				J. P. van Meerbeeck, R. Gaafar, C. Manegold, R. J. Van Klaveren, E. A. Van Marck, M. Vincent, C. Legrand, A. Bottomley, C. Debruyne, and G. Giaccone Randomized Phase III Study of Cisplatin With or Without Raltitrexed in Patients With Malignant Pleural Mesothelioma: An Intergroup Study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada J. Clin. Oncol., October 1, 2005; 23(28): 6881 - 6889. [Abstract] [Full Text] [PDF]