Dose erlotinib add beneficial effect on cytotoxic agent for patients with pretreated advanced non-small cell lung cancer?

Combination of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) with platinumcontaining standard chemotherapy failed to provide better outcomes in the first-line setting for advanced nonsmall cell lung cancer (NSCLC) in several phase III trials. The approved monotherapy of erlotinib, pemetrexed or docetaxel as the second-line regimen still remains unsatisfactory in anti-tumor effects for recurrent NSCLC. Combination of EGFR-TKI with cytotoxic drug seemed a promising strategy to improve therapeutic outcome for pretreated advanced NSCLC, because preclinical studies indicated schedule-dependent administration of EGFR-TKI with a specific cytotoxic drug had synergistic anti-tumor effects against NSCLC cells. Several clinical pharmacokinetic analyses in dose-finding phase I studies revealed that intermittent erlotinib with pemetrexed or docetaxel did not induce any potential antagonism between two drugs when erlotinib and its metabolites were almost completely swept away from plasma at the subsequent pemetrexed or docetaxel dosing. Recently, four phase II studies of combination of erlotinib with pemetrexed or docetaxel in the second-line setting for patients with NSCLC were reported. As a result, additional anti-tumor effects of erlotinib on cytotoxic drug still remain controversial. Three phase II studies showed favorable results and supported combination strategy of erlotinib, but our study failed to demonstrate the benefits from combination of intermittent erlotinib with tri-weekly pemetrexed. Herein, we review whether combination of erlotinib with cytotoxic drug is a promising therapeutic approach as the second-line treatment for advanced NSCLC.