Targeting MET in advanced and metastatic non-small cell lung cancer: a literature review of the current landscape.

Background and Objective: MET alterations have been identified as both primary oncogenic drivers and drivers of acquired resistance in non-small cell lung cancer (NSCLC). There are several mechanisms by which the MET axis can become altered, and an evolving understanding of these pathways provides insight into unique therapeutic targets. Despite considerable research and numerous strategies under investigation, challenges remain, and approved therapies are limited. The purpose of this review is to provide an updated summary of the current evidence, key challenges, and future directions for the diagnosis, classification, and management of advanced and metastatic NSCLC harboring MET alterations. Methods: A broad literature review was conducted using key terms related to MET-alterations and targeted therapy in advanced and metastatic NSCLC. While no definitive inclusion or exclusion criteria were applied, articles were selected based on their relevance and rigor, with an emphasis on primary and secondary literature published within the last 10 years. Key Content and Findings: We review here the pathophysiology and epidemiology of MET alterations that have been identified in NSCLC, including MET exon 14 skipping mutation (METex14), MET amplification (MET AMP), MET overexpression (MET OE), and MET fusion (MET FUS). We review data supporting established treatment strategies as well as areas of active investigation, with a focus on MET tyrosine kinase inhibitors (TKIs), anti-MET and anti-hepatocyte growth factor (HGF) antibodies, bispecific antibodies (B-Abs), antibody-drug conjugates (ADCs), and immunotherapy (IO). We identify key challenges to progress in this space, including standardization of biomarker-driven patient selection, identification of novel therapeutic mechanisms, and management of emerging treatment resistance. Finally, we discuss future directions and areas of promising development, including multi-omics diagnostic approaches, ADCs, and B-Abs. Conclusions: MET-altered NSCLC is a challenging and heterogeneous molecular subset, and our knowledge is rapidly evolving. Work is ongoing to define the spectrum of actionable mutations, to develop standardized and clinically meaningful biomarker-driven identification of these alterations, and to determine the most effective treatment approaches, with the goal of expanding the treatment landscape and improving outcomes for a subset of patients with limited treatment options.