Lung Cancer with MET exon 14 Skipping Mutation: Genetic Feature, Current Treatments, and Future Challenges

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• MET exon 14 skipping mutations (MET∆ex14) occur in ~3% of non-small cell lung cancers (NSCLCs).
• MET∆ex14-NSCLC patients are typically older, have smoking histories, and present with specific histological subtypes.
• Co-occurring alterations like EGFR, FGFR1, KRAS, BRAF, and PIK3CA are common in MET∆ex14-NSCLC.

Purpose of the Study:

• To review clinical and molecular features of NSCLCs with MET∆ex14.
• To summarize the efficacy and safety of MET-tyrosine kinase inhibitors (TKIs) capmatinib and tepotinib.
• To discuss inherent and acquired resistance mechanisms and future treatment strategies for MET∆ex14-NSCLC.

Main Methods:

• Literature review of clinical trials and research studies on MET∆ex14-NSCLC.
• Analysis of patient data regarding demographics, histology, and molecular alterations.
• Synthesis of information on MET-TKI efficacy, resistance mechanisms, and emerging therapies.

Main Results:

• MET-TKIs capmatinib and tepotinib offer progression-free survival of 5.4-12.4 months.
• Significant proportions of patients exhibit intrinsic resistance (33-50%) or develop acquired resistance to MET-TKIs.
• Co-driver alterations are frequently observed alongside MET∆ex14.

Conclusions:

• MET-targeted therapies have advanced NSCLC treatment but face challenges with resistance.
• Understanding resistance mechanisms is crucial for developing next-generation treatments.
• Future strategies will focus on overcoming resistance and improving outcomes for MET∆ex14-NSCLC patients.