The role of pemetrexed combined with targeted agents for non-small cell lung cancer

Pemetrexed is a novel third-generation multitargeted antifolate agent used in the first- and second-line treatment of unresectable pleural mesothelioma and advanced non-small cell lung cancer (NSCLC). Owing to its mild toxicity, this compound is a preferred partner in the multidrug regimens. In the last few decades, better understanding of molecular oncology and genetics has allowed for the development of an array of molecular targeted agents, many of which have been found active in NSCLC. It has been hoped that these compounds will disrupt tumor signaling pathways complementary to those targeted by chemotherapy. This review outlines the current preclinical and clinical studies using pemetrexed in combination with targeted agents in advanced NSCLC. Clinical experience with the use of these combinations is still limited and mostly includes phase I and II trials. These investigations have mainly focused on compounds previously shown to be active in NSCLC: anti-angiogenic agents (bevacizumab and small molecule tyrosine kinase inhibitors) and inhibitors of epidermal growth factor receptor (cetuximab and erlotinib). Preliminary results have shown the feasibility of these combinations and their promising activity but large phase III studies are warranted to verify the real value of this strategy. Combinations of pemetrexed with other targeted agents, such as mTOR inhibitors and compounds targeting proteasome are still at early stages of development.