MET in Non-Small-Cell Lung Cancer (NSCLC): Cross 'a Long and Winding Road' Looking for a Target

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Non-Small-Cell Lung Cancer (NSCLC) exhibits diverse MET alterations, including overexpression (MET OE), amplification (MET AMP), and mutations.
• Historically, identifying specific 'druggable' drivers in MET-dysregulated NSCLC proved challenging until the discovery of MET exon 14 skipping mutations (METex14).
• METex14 alterations are found in approximately 3% of NSCLC cases and are associated with modest efficacy when treated with immune checkpoint inhibitors (ICIs).

Purpose of the Study:

• To review the prognostic significance of MET alterations in NSCLC.
• To summarize pivotal clinical trials involving selective MET inhibitors (MET-Is).
• To explore resistance mechanisms and future directions in MET-targeted therapy for NSCLC.

Main Methods:

• Literature review of retrospective surgical series and clinical trials.
• Analysis of data on MET alterations (OE, AMP, mutations, METex14) in NSCLC.
• Synthesis of findings regarding MET inhibitor efficacy and resistance.

Main Results:

• MET dysregulation in NSCLC is linked to poorer clinical outcomes.
• Selective MET inhibitors demonstrate significant long-term clinical benefit in METex14 NSCLC.
• MET inhibitors show modest activity in MET AMP NSCLC, with ongoing research into novel therapies like ADCs.

Conclusions:

• MET alterations play a crucial prognostic role in NSCLC.
• Selective MET inhibitors represent a promising therapeutic strategy for specific MET-altered NSCLC subtypes.
• Further research is needed to overcome resistance mechanisms and optimize future MET-targeted treatments.