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Therapeutic strategies in METex14 skipping mutated non-small cell lung cancer
Leylah M Drusbosky1, Richa Dawar2, Estelamari Rodriguez2
1Guardant 360, 505 Penobscot Drive, Redwood City, CA, 94063, USA.
Abstract:
METex14 skipping mutations occur in about 3-4% of lung adenocarcinoma patients and 1-2% of patients with other lung cancer histology. The MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) are established oncogenic drivers of NSCLC. A mutation that results in loss of exon 14 in the MET gene leads to dysregulation and inappropriate signaling that is associated with increased responsiveness to MET TKIs. Results from GEOMETRY mono-1 and VISION Phase I/II clinical trials demonstrated significant clinical activity in patients treated with the MET Exon 14 skipping mutation inhibitors capmatinib and tepotinib with tolerable toxicity profile. In the GEOMETRY mono-1 trial, capmatinib was especially active in treatment-naïve patients supporting the upfront testing of this oncogenic driver. Tepotinib demonstrated superior activity in the pretreated patients in the VISION trial. Savolitinib is another MET TKI that has shown efficacy in the first- and second-line settings, including patients with aggressive pulmonary sarcomatoid carcinoma. These studies have demonstrated that these TKIs can cross the blood brain barrier and demonstrated some activity toward CNS metastases. MET Exon 14 skipping mutation is detected by NGS-based testing of liquid or tissue biopsies, with preference for RNA-based NGS. The activity of capmatinib and tepotinib is limited by the development of acquired resistance. Current research is focused on strategies to overcome resistance and improve the effectiveness of these agents. Our aim is to review the current status of MET Exon 14 skipping mutation as it pertains NSCLC.
Insights
MET exon 14 skipping mutations drive non-small cell lung cancer (NSCLC). MET tyrosine kinase inhibitors (TKIs) like capmatinib and tepotinib show significant clinical activity, offering new treatment options for NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- MET exon 14 skipping mutations are oncogenic drivers in 3-4% of lung adenocarcinoma and 1-2% of other lung cancers.
- MET receptor tyrosine kinase and hepatocyte growth factor (HGF) signaling are implicated in non-small cell lung cancer (NSCLC) pathogenesis.
- MET exon 14 skipping mutations lead to dysregulated signaling, increasing sensitivity to MET tyrosine kinase inhibitors (TKIs).
Purpose of the Study:
- To review the current status of MET exon 14 skipping mutations in NSCLC.
- To summarize the efficacy and safety of MET TKIs targeting this mutation.
- To discuss diagnostic methods and challenges in overcoming resistance.
Main Methods:
- Review of clinical trial data (GEOMETRY mono-1, VISION) for MET TKIs.
- Analysis of Next-Generation Sequencing (NGS) based detection methods (liquid and tissue biopsies).
- Evaluation of TKI properties, including blood-brain barrier penetration and CNS metastasis activity.
Main Results:
- Capmatinib and tepotinib demonstrated significant clinical activity and tolerable toxicity in NSCLC patients with MET exon 14 skipping mutations.
- Capmatinib showed particular activity in treatment-naïve patients, while tepotinib was superior in pretreated patients.
- Savolitinib also demonstrated efficacy in various settings, including pulmonary sarcomatoid carcinoma.
- TKIs exhibited blood-brain barrier penetration and activity against CNS metastases.
- Resistance to capmatinib and tepotinib is a known limitation, prompting research into overcoming strategies.
Conclusions:
- MET exon 14 skipping mutations represent a targetable driver in NSCLC.
- MET TKIs offer effective treatment options with manageable toxicity.
- RNA-based NGS is preferred for detecting MET exon 14 skipping mutations.
- Further research is needed to address acquired resistance and enhance TKI effectiveness.
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