Targeted therapies in combination with chemotherapy in non-small cell lung cancer.

Abstract

With rare exceptions, attempts to combine so-called targeted agents with standard cytotoxic chemotherapy in advanced non-small cell lung cancer have yielded disappointing results. The reasons underlying these spectacular failures are not always fully understood, but certainly the lack of careful patient selection is a major contributing factor. In addition, recent preclinical and clinical studies indicate that antagonism may exist between the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy primarily in tumor cells with wild-type EGFR. By contrast, tumor cells harboring somatic mutations in EGFR experience massive apoptosis when exposed to the EGFR tyrosine kinase inhibitors. Therefore, in theory, mutant tumor cells should exhibit enhanced cell kill when treated with concomitant chemotherapy and EGFR tyrosine kinase inhibitors akin to what is observed with chemotherapy and trastuzumab in breast cancer. Clinical data from the recently completed TRIBUTE trial support the latter possibility. Ideally, future studies of EGFR tyrosine kinase inhibitors and other targeted drugs will use careful patient selection criteria based on well-characterized and validated predictive markers. However, in the absence of such biomarkers, clinical judgment, common sense, and innovative clinical trial design are necessary to avoid undue delay in drug development.