Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors

Our plain-English summary of Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors, by A.R. Hanauske, V. Chen, P. Paoletti, et al (The Oncologist, 2001).

The study

• Authors: A.R. Hanauske, V. Chen, P. Paoletti, C. Niyikiza
• Journal: The Oncologist
• Published: 2001;6(4):363-73
• Type of article: Review
• Cited by: 183 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Pemetrexed disodium (ALIMTA), "pemetrexed") is a novel, multi-targeted antifolate that has demonstrated promising clinical activity in a wide variety of solid tumors, including non-small cell lung, breast, mesothelioma, colorectal, pancreatic, gastric, bladder, cervix, and head and neck. Pemetrexed inhibits multiple folate-dependent enzymes involved in both purine and pyrimidine synthesis including thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide ribonucleotide formyltransferase. As a single agent, pemetrexed exhibits a moderate toxicity profile at a dose of 500 mg/m(2) by 10-minute infusion once every 21 days with myelosuppression being the dose-limiting toxicity. Folic acid added to the diet in preclinical studies reduced toxicities while maintaining antitumor activity. Based on this observation and clinical toxicities, folic acid and vitamin B(12) dietary supplementation has been recently introduced into all ongoing trials. Studies combining pemetrexed with other active chemotherapeutic agents demonstrate that these combination therapies may become important treatment regimens in a variety of cancer types. Currently, pemetrexed phase III trials are ongoing in mesothelioma and non-small cell lung cancer with future trials planned to explore this unique multitargeted antifolate.

In plain English

This article was a review of laboratory and early clinical studies of pemetrexed, a cancer drug. All four authors were employees of Eli Lilly and Company, which supports the drug's development. The article did not study asbestos exposure. The authors described results from other researchers' trials in several cancers, including mesothelioma. In one study of pemetrexed with cisplatin, 5 partial responses were recorded among 11 assessable patients with pleural malignant mesothelioma. Based on that study, a randomized phase III trial comparing pemetrexed plus cisplatin with cisplatin alone had been started. A preliminary report of pemetrexed with carboplatin in malignant mesothelioma noted responses in 10 of 20 evaluable patients. Among 100 patients in early single-drug studies, six deaths were considered drug-related. Among 872 phase II patients given no vitamin supplements, grade 3 and grade 4 neutropenia, a drop in white blood cells, occurred in 23% and 27% respectively. The authors concluded that early, preliminary evidence suggested that folic acid and vitamin B12 reduced severe toxicities. They noted that final safety and efficacy data with these vitamins had yet to mature.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of preclinical and clinical studies of pemetrexed, written by employees of the company developing the drug
• Who was studied: Studies by other researchers: cell and animal experiments, and phase I and II trials in patients with non-small cell lung, breast, colorectal, pancreatic, gastric, cervical, bladder and head and neck cancers, and malignant mesothelioma
• Exposure: Pemetrexed given alone, usually 500 or 600 mg/m2 by 10-minute infusion every 21 days, or combined with cisplatin, carboplatin, gemcitabine or other drugs; with or without folic acid and vitamin B12. No asbestos exposure was studied.
• Main results:
  • In a cited phase I study of pemetrexed plus cisplatin (Thödtmann et al.), 5 partial responses were documented among 11 assessable patients with pleural malignant mesothelioma
  • Based on those data, a randomized phase III study of pemetrexed/cisplatin versus cisplatin had been initiated
  • In a preliminary report of pemetrexed plus carboplatin (Calvert et al.) in 27 enrolled patients with malignant mesothelioma, responses were noted in 10 of 20 evaluable patients
  • Of 100 patients evaluated in single-agent phase I studies, six deaths were considered drug-related
  • In 872 phase II patients treated without vitamin supplementation, grade 3 and grade 4 neutropenia occurred in 23% and 27% respectively
  • In a cited analysis of 246 phase II patients, higher baseline plasma homocysteine was statistically significantly correlated with febrile neutropenia (p less than 0.0001) and other severe toxicities
  • A table compared 246 nonsupplemented with 78 supplemented patients: toxic death 5 versus 0, and grade 4 neutropenia 32 versus 2.6 (the table does not state units)
• The authors' conclusion: The authors concluded that early and preliminary evidence suggested adding low-dose folic acid and vitamin B12 decreased the frequency of severe toxicities of pemetrexed
• Limitations the authors state:
  • Final safety and efficacy data with the lower doses of folic acid and vitamin B12 were not yet available
  • Combining pemetrexed with folic acid in patients was designed on an empirical basis
  • Final results of the pemetrexed/carboplatin mesothelioma trial were awaited

Topics

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Antifolate, Mesothelioma, Non-Small Cell Lung Cancer.

Related studies

• Clinical and pharmacokinetic phase I study of multitargeted antifolate (LY231514) in combination with cisplatin — R. Thödtmann, H. Depenbrock, et al. (1999)
• Thymidylate synthase and folyl-polyglutamate synthase are not clinically useful markers of response to pemetrexed in patients with malignant pleural mesothelioma — D.E. Lustgarten, C. Deshpande, et al. (2013)
• Phase I and pharmacologic study of sequences of gemcitabine and the multitargeted antifolate agent in patients with advanced solid tumors — A.A. Adjei, C. Erlichman, et al. (2000)
• New tricks for old biomarkers: thymidylate synthase expression as a predictor of pemetrexed activity in malignant mesothelioma — P.A. Zucali, E. Giovannetti, et al. (2010)
• Pharmacokinetic evaluation of pemetrexed — J.B. Sørensen (2011)
• The issue of studies evaluating biomarkers which predict outcome after pemetrexed-based chemotherapy in malignant pleural mesothelioma — F. Mairinger, C. Vollbrecht, et al. (2013)

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