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Pemetrexed

A Review of its Use in Malignant Pleural Mesothelioma and Non-Small-Cell Lung Cancer

  • Adis Drug Evaluation
  • Published:
American Journal of Cancer

Summary

Abstract

Pemetrexed is a multi-targeted antifolate that inhibits DNA and RNA synthesis. It is approved in the US and Europe for use with cisplatin in the treatment of malignant pleural mesothelioma (MPM) in patients who are not candidates for surgery. It is also approved in Europe, and has received accelerated approval from the US FDA, for the second-line treatment of locally advanced or metastatic NSCLC.

Pemetrexed has shown clinical activity against MPM and NSCLC, and has favorable tolerability when patients are supplemented with folic acid and cyanocobalamin (vitamin B12). In patients with refractory or recurrent NSCLC, it has similar activity to docetaxel, with better tolerability and lower treatment costs. In the treatment of unresectable MPM, pemetrexed plus cisplatin has superior efficacy to single-agent cisplatin and is the only chemotherapeutic regimen to significantly prolong survival.

Pharmacologica Properties

Pemetrexed is a pyrimidine-derived antifolate that primarily targets thymidylate synthase (TS), but also inhibits dihydrofolate reductase, and, to a lesser extent, glycinamide ribonucleotide formyl transferase (GARFT), and 5-aminoimidazole-4-carboxamide ribonucleotide formyl transferase (AICARFT). This limits the formation of both thymidylate and purines, thereby inhibiting DNA and RNA synthesis.

Pemetrexed enters the cell through both the reduced folate transporter and the higher affinity, but lower capacity, α-folate receptor. It is rapidly polyglutamated, increasing retention and enhancing the affinity of pemetrexed for, and inhibition of, TS, AICARFT, and GARFT. The multi-enzyme activity of pemetrexed may explain its cytotoxicity against cell lines that are resistant to other single-target antifolates and may underlie its activity against some chemotherapy-resistant cancers, such as MPM. Pemetrexed induces synchronization of the cell cycle in the S phase, which may generate synergistic cytotoxicity by sensitizing cells to radiotherapy and other chemotherapeutic agents.

Following a 10-minute infusion of pemetrexed 500 mg/m2, the mean peak plasma concentration was 78 μg/mL, the terminal elimination half-life was 3.2 hours, and the mean clearance was 63 mL/min/m2 in patients with advanced solid tumors. Pemetrexed is ≈81% bound to human plasma proteins, not metabolized significantly in humans, and primarily eliminated through renal excretion. The amount of drug eliminated in the first 24 hours following pemetrexed infusion is significantly higher in women than in men. The use of pemetrexed in patients with a creatinine clearance <45 mL/min is not recommended.

Therapeutic Efficacy

Pemetrexed demonstrated clinical activity in patients with MPM, and those who had previously received treatment for NSCLC in two well designed trials. In patients with MPM, the use of pemetrexed in combination with cisplatin significantly improved median survival time (primary endpoint) by 2.8 months and the 1-year survival rate by 12% compared with cisplatin monotherapy. Pemetrexed plus cisplatin recipients also experienced a longer median time to disease progression, a greater objective response rate, superior overall health-related quality of life, and greater symptomatic relief (pain, dyspnea, fatigue, anorexia, and cough) than recipients of cisplatin alone.

In patients with NSCLC who had received prior treatment, no significant differences in median survival time, 1-year survival rate, objective response rate, or symptom palliation were observed between pemetrexed and docetaxel monotherapy. Non-inferiority analysis indicated at least 52% of the survival benefit of docetaxel over best supportive care was maintained with pemetrexed.

Tolerability

Pemetrexed monotherapy, when supplemented with folic acid and cyanocobalamin, is generally well tolerated. In patients with NSCLC, the tolerability profile of pemetrexed is favorable in comparison with that of docetaxel,with a significantly lower incidence of neutropenia and febrile neutropenia and a similar frequency of nonhematologic adverse events. Pemetrexed recipients also had a lower rate of hospitalization for neutropenic fever than docetaxel recipients and a reduced requirement for supportive care that, in a UK analysis, resulted in a lower cost per patient.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Authors and Affiliations

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    Dean M. Robinson, Gillian M. Keating & Antona J. Wagstaff

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Additional information

Various sections of the manuscript reviewed by: H.A. Burris, The Sarah Cannon Research Institute, Nashville, Tennessee, USA; M. Del Tacca, Department of Oncology, Transplants and Advanced Technologies in Medicine, Division of Pharmacology and Chemotherapy, University of Pisa, Pisa, Italy; I.D. Goldman, Albert Einstein College of Medicine Cancer Center, New York, New York, USA; A.R. Hanauske, Department of Medicine, Division of Medical Oncology, General Hospital St Georg, Hamburg, Germany; M. Karthaus, Med. Klinik II, Ev. Johannes Krankenhaus, Bielefeld, Germany; D.A. Rinaldi, Louisiana Oncology Associates, Lafayette, Louisiana, USA; D. Von Hoff, Arizona Cancer Center, Tuscon, Arizona, USA; A. Wozniak, Hudson-Webber Cancer Research Center, Detroit, Michigan, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on pemetrexed, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘pemetrexed’ or ‘LY-231514’ and (‘non small cell lung cancer’ or ‘mesothelioma’). EMBASE search terms were ‘pemetrexed’ or ‘LY-231514’ and (‘non small cell lung cancer’ or ‘mesothelioma’). AdisBase search terms were ‘pemetrexed’ or ‘LY231514’ and (‘non-small-cell-lung-cancer’ or ‘*mesothelioma’ ). Searches were last updated 18 Nov 2004.

Selection: Studies in patients with mesothelioma or non-small-cell lung cancer who received pemetrexed. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Pemetrexed, mesothelioma, non-small-cell lung cancer, pharmacodynamics, pharmacokinetics, therapeutic use.

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Robinson, D.M., Keating, G.M. & Wagstaff, A.J. Pemetrexed. Am J Cancer 3, 387–399 (2004). https://doi.org/10.2165/00024669-200403060-00006

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