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Updated: Sep 10, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
First-Line MET Tyrosine Kinase Inhibitors versus Immunotherapy ± Chemotherapy for Patients with MET Exon 14 Skipping
Federica Pecci1,2, Hui Li3,4, Alessandro Di Federico5,6
1Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Purpose:
First-line treatment options for MET exon 14 skipping-mutant metastatic non-small cell lung cancer vary because of differences in drug approvals and clinical experience. This study investigates factors influencing outcomes with first-line MET tyrosine kinase inhibitors (TKI) versus immune checkpoint inhibitors (ICI) ± chemotherapy.
Experimental Design:
Clinicopathologic data were collected from patients with metastatic MET exon 14 skipping-mutant non-small cell lung cancer treated with first-line MET TKI or ICI ± chemotherapy at five centers. Primary endpoints were real-world progression-free survival (rwPFS) and overall survival (OS) to first-line MET TKI versus ICI ± chemotherapy. Subgroup analyses by clinical and tumor characteristics were performed.
Results:
Among 158 patients, 80 received MET TKI and 78 received ICI ± chemotherapy as first-line treatment. Baseline clinicopathologic features were balanced except for a higher proportion of patients with a history of smoking in the ICI ± chemotherapy group (P = 0.03). With a median follow-up of 37.9 months, no difference was observed in rwPFS (HR, 0.85; P = 0.4) or OS (HR, 0.97; P = 0.9) with first-line MET TKI versus ICI ± chemotherapy. In subgroup analyses, first-line ICI ± chemotherapy improved rwPFS in PD-L1 ≥80% (HR, 0.50; P = 0.03), whereas MET TKI improved rwPFS (HR, 0.40; P = 0.005) and OS (HR, 0.49; P = 0.03) in PD-L1 <50%, as well as rwPFS (HR, 0.39; P = 0.02) and OS (HR, 0.36; P = 0.03) in brain metastases and rwPFS (HR, 0.55; P = 0.01) in bone metastases. No significant differences were observed in the incidence of high-grade toxicity (P = 0.9) or rates of permanent treatment discontinuation (P = 0.2) between first-line MET TKI and ICI ± chemotherapy.
Conclusions:
First-line MET TKI improved outcomes in PD-L1 <50% and brain/bone metastases, whereas ICI ± chemotherapy prolonged PFS only in PD-L1 ≥80%, emphasizing the need for personalized treatment selection.
Insights
First-line MET tyrosine kinase inhibitors (TKI) showed improved outcomes in MET exon 14 skipping (METex14) non-small cell lung cancer (NSCLC) patients with low PD-L1 or brain/bone metastases. Immune checkpoint inhibitors (ICI)±chemotherapy were better for high PD-L1 expression.
Area of Science:
- Oncology
- Medical Genetics
- Pharmacology
Background:
- Metastatic non-small cell lung cancer (NSCLC) with MET exon 14 skipping (METex14) mutations presents unique treatment challenges.
- First-line treatment decisions for METex14 NSCLC involve balancing efficacy and toxicity of MET tyrosine kinase inhibitors (TKI) versus immune checkpoint inhibitors (ICI)±chemotherapy.
- Understanding real-world outcomes is crucial for optimizing personalized treatment strategies in this patient population.
Purpose of the Study:
- To compare the real-world effectiveness of first-line MET tyrosine kinase inhibitors (TKI) versus immune checkpoint inhibitors (ICI)±chemotherapy in metastatic METex14 non-small cell lung cancer (NSCLC).
- To identify patient subgroups who benefit most from either MET TKI or ICI±chemotherapy based on clinicopathological characteristics, including PD-L1 expression and metastatic site.
Main Methods:
- Retrospective analysis of clinicopathologic data from 158 patients with metastatic METex14 NSCLC across five institutions.
- Patients received either first-line MET TKI or ICI±chemotherapy.
- Primary endpoints included real-world progression-free survival (rwPFS) and overall survival (OS); subgroup analyses were performed.
Main Results:
- No significant difference in overall rwPFS or OS was observed between first-line MET TKI and ICI±chemotherapy groups.
- First-line ICI±chemotherapy demonstrated improved rwPFS in patients with PD-L1 expression ≥80%.
- First-line MET TKI improved rwPFS and OS in patients with PD-L1 <50%, and in those with brain or bone metastases. No significant differences in high-grade toxicity or discontinuation rates were noted.
Conclusions:
- Personalized treatment selection is essential for METex14 NSCLC, with MET TKI showing benefit in specific subgroups (PD-L1<50%, brain/bone metastases).
- ICI±chemotherapy is a viable first-line option, particularly for patients with high PD-L1 expression (≥80%).
- These findings underscore the importance of considering both molecular and clinical factors for optimizing first-line therapy in METex14 NSCLC.
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