Pemetrexed and its emerging role in the treatment of thoracic malignancies

Abstract

Pemetrexed (Alimta); Eli Lilly and Co., Indianapolis, IN, USA) is a unique multitargeted antifolate that inhibits at least three enzymes, thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase. This novel drug is being evaluated in a comprehensive clinical programme for use in both front-line and second-line therapies. It has shown broad activity in a number of solid tumours, including colon cancer, breast cancer, lung cancer, head and neck, cervical cancer and others. While a number of antifolates have been evaluated in clinical trials, further development has been stopped or delayed by the occurrence of life-threatening toxicities. Similar trends were also initially observed with pemetrexed as well, but investigators later showed that these toxicities could be minimised with folic acid and vitamin B(12) supplementation included in the treatment regimen. Preliminary data indicate that this supplementation does not hamper drug efficacy in most tumour types and in many cases, supplemented patients exhibit improved clinical outcome. Here, the current data for pemetrexed in treating thoracic malignancies are reviewed, with special focus on malignant pleural mesothelioma and non-small cell lung cancer.

Recent Clinical Trials in Non-Small Cell Lung Cancer

“…This agent acts by inhibiting at least three intracellular enzymes (thymidine synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase) that are essential for DNA and RNA synthesis [84]. Following phase II studies of pemetrexed that demonstrated promising activity in advanced NSCLC [85], a phase III trial was conducted to compare the efficacy of pemetrexed to docetaxel for advanced NSCLC patients who progressed with one prior chemotherapy regimen [86]. The trial was designed to show non-inferiority for pemetrexed.…”