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Updated: Jul 16, 2026
Ultra-Fast Amplicon-Based Next-Generation Sequencing in Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Targeting MET in 2025: From Exon 14 Skipping to MET-Amplified Acquired Resistance in Non-Small Cell Lung Cancer
Aliya Khan1, Michael Imeh1, Priyanka Barad2
1Hematology-Oncology Fellowship Program, Memorial Cancer Institute, Memorial Healthcare System, Hollywood, FL 33021, USA.
Abstract:
MET pathway alterations have evolved from a niche translational interest into one of the most clinically actionable axes in non-small cell lung cancer (NSCLC). Three biologically distinct lesions-MET exon 14 (METex14) skipping mutations, focal high-level MET amplification, and c-Met protein overexpression-are now individually targetable, each with its own diagnostic prerequisites and therapeutic class. Selective type Ib MET tyrosine kinase inhibitors (capmatinib, tepotinib) anchor first-line therapy for METex14, while next-generation agents and type II inhibitors are being developed to address on-target D1228 and Y1230 resistance mutations. In parallel, MET amplification has emerged as a leading mechanism of acquired resistance to osimertinib in EGFR-mutated NSCLC, with the SAVANNAH, SACHI, and INSIGHT 2 trials providing biomarker-guided combination strategies. The 2025 accelerated approval of telisotuzumab vedotin for c-Met-overexpressing tumors expanded the therapeutic armamentarium beyond kinase inhibition. Despite these advances, lineage plasticity, polyclonal bypass signaling, and inconsistent diagnostic thresholds for MET amplification continue to limit durable benefit. This review integrates the molecular biology, current clinical evidence, resistance mechanisms, and a proposed 2025 treatment algorithm for MET-altered NSCLC, with emphasis on the translational interface between mutation class, drug class, and emerging combinatorial approaches. As a narrative review, it synthesizes peer-reviewed literature and pivotal trial and regulatory data through early 2026, identified by structured searches of PubMed and major oncology congress proceedings, and prioritizes sources that link mutation class to drug class and resistance mechanism.
Insights
MET pathway alterations are now clinically actionable in non-small cell lung cancer (NSCLC). This review integrates molecular biology, clinical evidence, and resistance mechanisms for a proposed 2025 treatment algorithm for MET-altered NSCLC.
Area of Science:
- Oncology
- Molecular Biology
- Translational Research
Background:
- MET pathway alterations, including MET exon 14 skipping, MET amplification, and c-Met overexpression, are key drivers in non-small cell lung cancer (NSCLC).
- These alterations represent actionable targets with distinct diagnostic and therapeutic implications.
- MET pathway dysregulation is also a significant mechanism of acquired resistance to other targeted therapies in NSCLC.
Purpose of the Study:
- To review the current landscape of MET-targeted therapies in NSCLC.
- To integrate molecular biology, clinical evidence, and resistance mechanisms.
- To propose a 2025 treatment algorithm for MET-altered NSCLC, emphasizing the interplay between mutation class, drug class, and combination strategies.
Main Methods:
- Narrative review synthesizing peer-reviewed literature and pivotal trial data through early 2026.
- Structured searches of PubMed and major oncology congress proceedings.
- Prioritization of sources linking mutation class to drug class and resistance mechanisms.
Main Results:
- Three distinct MET lesions (METex14 skipping, MET amplification, c-Met overexpression) are individually targetable with approved or investigational agents.
- Selective MET inhibitors (capmatinib, tepotinib) are first-line for METex14, with next-generation inhibitors addressing resistance.
- MET amplification is a resistance mechanism to EGFR inhibitors, addressed by combination strategies; telisotuzumab vedotin is approved for c-Met overexpression.
- Challenges remain, including lineage plasticity, bypass signaling, and diagnostic inconsistencies for MET amplification.
Conclusions:
- Significant progress has been made in targeting MET alterations in NSCLC, expanding therapeutic options.
- Despite advances, durable benefit is limited by resistance mechanisms and diagnostic challenges.
- A comprehensive understanding of MET biology, resistance, and emerging combinations is crucial for optimizing treatment strategies in MET-altered NSCLC.
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