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Updated: Nov 16, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Current and future treatment options for MET exon 14 skipping alterations in non-small cell lung cancer
Lingzhi Hong1, Jianjun Zhang1, John V Heymach1
1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract:
It has been over three decades since the hepatocyte growth factor (HGF) ligand and its receptor MET proto-oncogene (MET) pathway was established as promoting cancer growth and metastasis. MET exon 14 skipping (METex14) alterations occur in 3-4% of all non-small cell lung cancer (NSCLC) patients, typically in elderly patients (older than 70 years), and result in constitutive activation of the MET receptor by altering a region required for receptor degradation. Multi-kinase inhibitor of MET, such as crizotinib, and more recently selective MET inhibitors, such as capmatinib and tepotinib, have demonstrated clinical efficacy and safety in METex14 NSCLC patients in clinical trials. These results have led to the approval of MET inhibitors by regulatory agencies across the globe. The success also fueled the excitement of further development of therapeutic strategies to target METex14 in lung cancers. This article provides an overview of the clinical development program targeting METex14 in NSCLC, including small molecular tyrosine kinase inhibitors and anti-MET antibodies. Furthermore, combination therapy immune checkpoint inhibitors or other targeted therapies are also under development in various patient populations, with acquired resistance immune or targeted therapy. Clinical trials in different development stages are ongoing and more drugs targeted to c-MET will be available for NSCLC patients with METex14 skipping mutations in the future.
Insights
MET exon 14 skipping alterations drive non-small cell lung cancer (NSCLC) growth. MET inhibitors show efficacy, with ongoing trials for targeted therapies and combination treatments in NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The MET signaling pathway, involving hepatocyte growth factor (HGF) and its receptor MET, has been implicated in cancer progression for over 30 years.
- MET exon 14 skipping (METex14) alterations are found in 3-4% of non-small cell lung cancer (NSCLC) patients, often older individuals, leading to constitutive MET receptor activation.
- This alteration affects a critical region for receptor degradation, promoting uncontrolled signaling.
Purpose of the Study:
- To provide an overview of the clinical development of therapies targeting METex14 in NSCLC.
- To discuss the efficacy and safety of existing and emerging therapeutic strategies.
- To highlight ongoing research into combination therapies and overcoming resistance mechanisms.
Main Methods:
- Review of clinical trial data for MET inhibitors in NSCLC patients with METex14 alterations.
- Analysis of small molecular tyrosine kinase inhibitors and anti-MET antibodies.
- Examination of combination therapy approaches, including immune checkpoint inhibitors.
Main Results:
- Multi-kinase and selective MET inhibitors (e.g., crizotinib, capmatinib, tepotinib) have demonstrated clinical efficacy and safety in METex14 NSCLC.
- Regulatory agencies have approved MET inhibitors based on trial results.
- Ongoing trials are exploring novel targeted therapies and combinations.
Conclusions:
- MET inhibitors represent a significant advancement in treating NSCLC with METex14 alterations.
- Further development of targeted therapies, including antibodies and combination strategies, holds promise for improved patient outcomes.
- Continued clinical trials are essential to expand treatment options for NSCLC patients with METex14 mutations.
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