Edatrexate studies in non-small cell lung cancer

Edatrexate (10-ethyl-10-deaza-aminopterin, or 10-EDAM) is a water-soluble antifolate which is under study in a variety of malignancies. Edatrexate demonstrated greater antitumor activity than methotrexate in several solid tumor models and xenografts, which may be due to a more extensive formation of polyglutaminates within tumor cells by edatrexate metabolites. Phase I studies have recommended a dose of 80 mg/m2 i.v. weekly for tumor specific trials. When used with leucovorin, edatrexate doses more than 10 times as high have been found to be well-tolerated. Dose-limiting toxicity is mucositis, with leukopenia and thrombocytopenia being less prominent. In three Phase II trials without leucovorin in non-small cell lung cancer, edatrexate has shown an overall objective major response rate of 17% in 66 previously untreated patients (95% C.I.: 9-28%), making it one of the more active single agents in this malignancy. With its relatively low degree of myelosuppression, edatrexate has been an attractive agent for use in combination. To date, trials combining this drug with mitomycin plus vinblastine, cisplatin plus cyclophosphamide, paclitaxel, and carboplatin have been initiated. The encouraging response rates and low degree of toxicity make this agent interesting for further investigation in non-small cell lung cancer.