BIOMARKER-DRIVEN TREATMENT STRATEGIES FOR NON-SMALL-CELL LUNG CANCER

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Abstract

Lung cancer is the leading cause of cancer deaths worldwide. Given that the efficacy of conventional chemotherapeutic agents with regard to improving clinical outcome in lung cancer patients is limited, target-based therapies are being pursued as potential treatment alternatives. Small-molecule tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) were the first molecularly targeted agents to become clinically available for the treatment of NSCLC. The discovery of somatic mutations in EGFR and of the association of such mutations with a high response rate to EGFR-TKIs had remodeled our approach for clinical development of EGFR-TKIs. Asian landmark phase III trials have now led to the new paradigm of using EGFR-TKIs for first-line treatment of EGFR-mutation positive advanced NSCLC. Another excitement in NSCLC is EML4-ALK, which results in dominant oncogenic activity providing very specific therapeutic target. The first ALK-targeted therapy tested in the clinic is crizotinib, a small molecule tyrosine kinase inhibitor, which demonstrated marked activity in phase I study for EML4-ALK-positive NSCLC. Although the overall frequency of EML4-ALK in the general NSCLC population is pretty low (∼5%), the clinical development of crizotinib occurred over a remarkably short period of time, from the initial identification of the EML4-ALK translocation as an oncogene in 2007, with validation of the fusion protein as a clinical target for NSCLC in 2010, to the approval of crizotinib by the FDA in 2011. The important lesson is that the diligent use of molecular targeted agents for molecularly selected patients could dramatically improve the clinical outcome in advanced NSCLC. The promise of molecular targeted drugs against these driver gene alterations brings us closer to personalized lung cancer therapy.

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