Pemetrexed: a multitargeted antifolate

The US Food and Drug Administration approved pemetrexed in February 2004 for the treatment of malignant pleural mesothelioma (MPM) in combination with cisplatin in patients with unresectable disease or for whom curative surgery is not an option. Pemetrexed is the first agent approved for the treatment of MPM. In August 2004, pemetrexed was approved as a second-line, single-agent treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC).

The goals of this article were to summarize the pharmacology, pharmacokinetics, efficacy, and safety of pemetrexed, and to review its current and potential roles in therapy for MPM, NSCLC, and other oncologic conditions.

Relevant English-language literature was identified through searches of PubMed (1966-December 2004), International Pharmaceutical Abstracts, and the Proceedings of the American Society of Clinical Oncology (January 1995-December 2004). Search terms included pemetrexed, Alimta, MTA, multitargeted antifolate, LY231514, mesothelioma, MPM, non-small cell lung cancer, NSCLC, breast cancer, and pancreatic cancer. In addition to published literature, abstracts and posters presented at national and international scientific meetings were reviewed.

Myelosuppression was the predominant dose-limiting toxicity of pemetrexed reported in Phase I studies. Identification of the correlation between poor folate status and increased pemetrexed toxicity in a multivariate analysis led to the requirement of folic acid and vitamin B12 supplementation for patients in all pemetrexed studies, with a resulting noted decrease in pemetrexed toxicity. A single, multicenter, randomized Phase III trial compared the efficacy of pemetrexed in combination with cisplatin versus cisplatin alone in the treatment of MPM. Response rates were 41.3% in the pemetrexed/cisplatin combination and 16.7% with single-agent cisplatin (P < 0.001). The median survival time for the pemetrexed/cisplatin combination was significantly longer at 12.1 months versus 9.3 months for cisplatin alone (P = 0.02). One international, multicenter, randomized Phase III trial in patients with NSCLC compared single-agent pemetrexed versus docetaxel in patients previously treated with chemotherapy. Overall response rates (9.1% and 8.8%) and median survival (8.3 months and 7.9 months) did not differ between pemetrexed and docetaxel (P = 0.105 and P = 0.226, respectively). Hematologic adverse effects-grade 3/4 neutropenia (40.2% vs 5.3%; P < 0.001), febrile neutropenia (12.7% vs 1.9%; P < 0.001), and neutropenic infections (3.3% vs 0%; P = 0.004)-were significantly greater in the docetaxel-treated patients than in the pemetrexed-treated patients, as was alopecia (37.7% vs 6.4%; P < 0.001). Results of an international, multicenter Phase III trial of pemetrexed in combination with gemcitabine conducted in patients with pancreatic cancer indicate that the combination is no more efficacious than single-agent gemcitabine. Results in other disease states are still preliminary.

Pemetrexed is a multitargeted antifolate that has demonstrated antitumor activity in various tumor types as a single agent and in combination with other chemotherapeutic agents. Efficacy for the treatment of MPM in combination with cisplatin has been demonstrated, and approval as a second-line agent in NSCLC was based on response rate as a surrogate end point for survival. The addition of folic acid and vitamin B12 supplementation markedly reduced.