Targeting MET in NSCLC: An Ever-Expanding Territory

Abstract

MET protooncogene (MET) alterations are known driver oncogenes in NSCLC. Since the identification of MET as a potential therapeutic target, extensive clinical trials have been performed. As a result, MET-targeted therapies, including MET tyrosine kinase inhibitors, monoclonal antibodies, and MET antibody-drug conjugates now play important roles in the standard treatment of MET-altered NSCLC; they have considerably improved the outcomes of patients with tumors that harbor MET oncogenic drivers. Although clinical agents are currently available and numerous other options are in development, particular challenges in the field require attention. For example, the therapeutic efficacy of each drug remains unsatisfactory, and concomitantly, the resistance mechanisms are not fully understood. Thus, there is an urgent need for optimal drug sequencing and combinations, along with a thorough understanding of treatment resistance. In this review, we describe the current landscape of pertinent clinical trials focusing on MET-targeted strategies and discuss future developmental directions in this rapidly expanding field.

Keywords: Antibody-drug conjugate; MET; Monoclonal antibodies; Non–small cell lung cancer; Tyrosine kinase inhibitor.

Figure 1

Targeting MET alterations in NSCLC. MET alterations in NSCLC mainly include METex14 skipping mutations (2%–4%), MET amplification (1%–6%), MET fusion (0.2%–0.3%), and MET overexpression (20%–25%). MET-targeted regimens can be divided into three categories: MET TKIs, monoclonal antibodies, and ADCs. In the future, increased therapeutic efficacy remains a focus in the MET field, and combined strategies provide potentially feasible approaches. n% represents the prevalence and n% represents the objective response rate. /, not applicable; 1L, previously untreated patients; 2L+, previously treated patients; ADC, antibody-drug conjugate; METex14, MET exon 14; TKI, tyrosine kinase inhibitor.