Updated clinical information on multitargeted antifolates in lung cancer

Pemetrexed, a third-generation antifolate already indicated in combination with cisplatin for the systemic treatment of malignant pleural mesothelioma and, as a single agent, for the second-line treatment of non-small-cell lung cancer was in 2008 granted approval for histologically based first-line treatment by both the EMEA and FDA. Thymidylate synthase, the main molecular target of pemetrexed, has higher mRNA and protein expression in squamous- and small-cell lung cancer compared with adenocarcinoma. This differential expression might well molecularly explain the differential clinical activity of pemetrexed in the various histotypes of lung cancer, including the marginal activity in small-cell lung cancer. These hypothesis-generating findings are currently validated in prospective studies.