Targeting non-small cell lung cancer with epidermal growth factor tyrosine kinase inhibitors: Where do we stand, where do we go

Cytotoxic chemotherapy has only yielded modest gains in survival in lung cancer in the past decade. However, the development of agents targeting specific signaling pathways that drive carcinogenesis has heralded a major paradigm shift in the approach to treatment of cancer. In non-small cell lung cancer (NSCLC), many researchers have focused on the epidermal growth factor receptor (EGFR) because this protein is present on a relatively high proportion of non-small cell lung cancers and its intracellular tyrosine kinase activates a signaling cascade that drives tumor growth. Blockade of the EGFR by small molecule inhibitors of the tyrosine kinase, such as gefitinib and erlotinib, causes tumor regressions in NSCLC. Phase II monotherapy trials of EGFR tyrosine kinase inhibitors in patients with previously treated advanced NSCLC demonstrated anti-tumor activity with objective response rates of 10-19% with acceptable toxicities and an associated improvement in lung cancer symptomatology. Gefitinib is now an FDA approved treatment for advanced NSCLC previously treated with platinum and docetaxel-based therapies. However, phase III trials of gefitinib and erlotinib in combination with chemotherapy doublets have failed to demonstrate a survival advantage when compared with chemotherapy alone. It remains unclear why these drugs work so effectively in certain patients and so poorly in combination with chemotherapy. The goal of ongoing and future investigation is to identify which patients may benefit from this new therapeutic approach.