Capmatinib and gefitinib combination therapy: will EGFR-mutated MET-dysregulated NSCLC "capitulate"?

Abstract

The mesenchymal-epithelial transition factor (MET)/hepatocyte growth factor (HGF) axis is a key pathway in acquired resistance against epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in EGFR-mutated non-small cell lung cancer (NSCLC). The binding of the cognate HGF ligand to MET induces receptor activation, promoting cell proliferation, cell invasion, and cell survival in multiple preclinical cancer models (1). Evidence of MET dysregulation conferring resistance to EGFR TKI therapy was identified as early as 2007 when Engelman and colleagues demonstrated that focal MET amplification drives ERBB3-dependent activation of PI3K and subsequent resistance to gefitinib. Crucially, MET inhibitor monotherapy was not sufficient to overcome gefitinib resistance; combined treatment with a MET inhibitor and gefitinib was required, suggesting that selective pressure exerted by gefitinib causes cancer cells to adapt so that sustained downstream signaling of either the EGFR pathway or MET pathway is sufficient for survival (2), necessitating the concurrent use of both an EGFR inhibitor and a MET inhibitor. These early observations would herald the paramount importance of carefully selecting EGFR-mutated NSCLC patients with documented acquired resistance to primary EGFR TKI therapy in the clinical development of MET inhibitors, as earlier disappointingly negative clinical studies investigating MET inhibitors largely featured unselected NSCLC patient populations.