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Multicenter Real-World Analysis of Combined MET and EGFR Inhibition in Patients With Non-Small Cell Lung Cancer and
Fabian Acker1, Alexandra Klein1, Anna Rasokat2
1Department of Medicine II, Hematology and Oncology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany.
Purpose:
MET amplification is a common resistance mechanism to EGFR inhibition in EGFR-mutant non-small cell lung cancer (NSCLC). Several trials showed encouraging results with combined EGFR and MET inhibition (EGFRi/METi). However, MET amplification has been inconsistently defined and frequently included both polysomy and true amplification.
Methods:
This is a multicenter, real-world analysis in patients with disease progression on EGFR inhibition and MET copy number gain (CNG), defined as either true amplification (MET to centromere of chromosome 7 ratio [MET-CEP7] ≥ 2) or polysomy (gene copy number ≥ 5, MET-CEP7 < 2).
Results:
A total of 43 patients with MET CNG were included, 42 of whom were detected by FISH. Twenty-three, 7, and 14 received EGFRi/METi, METi, and SoC, respectively. Patients in the EGFRi/METi cohort exhibited a superior real-world clinical benefit rate, defined as stable disease or better, of 82% (95% confidence interval [CI], 60-95) compared to METi (29%, 4-71) and SoC (50%, 23-77). Median real-world progression-free survival was longer with EGFRi/METi with 9.8 vs. 4.3 months with METi (hazard ratio [HR], 0.19, 95% CI, 0.06-0.57) and 3.7 months with SoC (0.41, 0.18-0.91), respectively. Overall survival was numerically improved. Interaction analysis with treatment and type of CNG (amplification vs. polysomy) suggests that differences were exclusively driven by MET-amplified patients receiving EGFRi/METi (HR for OS, 0.09, 0.01-0.54).
Conclusion:
In this real-world study, EGFRi/METi showed clinical benefit over METi and SoC. Future studies should focus on the differential impact of the type of MET CNG with a focus on true MET amplification as predictor of response.
Insights
Combined EGFR and MET inhibition (EGFRi/METi) demonstrated superior clinical benefit in non-small cell lung cancer (NSCLC) patients with MET copy number gain. True MET amplification, not polysomy, was the key driver of this improved response to EGFRi/METi therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- MET amplification is a key resistance mechanism to EGFR inhibitors in EGFR-mutant non-small cell lung cancer (NSCLC).
- Combined EGFR and MET inhibition (EGFRi/METi) shows promise, but definitions of MET amplification vary, often including both true amplification and polysomy.
- Understanding the distinct roles of MET amplification and polysomy is crucial for optimizing treatment strategies.
Purpose of the Study:
- To evaluate the real-world clinical effectiveness of combined EGFR and MET inhibition (EGFRi/METi) versus MET inhibition (METi) or standard of care (SoC) in NSCLC patients with MET copy number gain (CNG).
- To differentiate the clinical impact of true MET amplification versus polysomy in patients receiving EGFRi/METi therapy.
Main Methods:
- A multicenter, real-world analysis of 43 NSCLC patients with MET CNG (defined as true amplification or polysomy) who progressed on EGFR inhibition.
- Patients received either EGFRi/METi, METi, or SoC.
- Fluorescence in situ hybridization (FISH) was used to assess MET copy number gain.
Main Results:
- The EGFRi/METi cohort showed a significantly higher clinical benefit rate (82%) compared to METi (29%) and SoC (50%).
- Median real-world progression-free survival was longer for EGFRi/METi (9.8 months) versus METi (4.3 months) and SoC (3.7 months).
- Interaction analysis indicated that the superior outcomes with EGFRi/METi were driven exclusively by patients with true MET amplification.
Conclusions:
- Combined EGFR and MET inhibition (EGFRi/METi) offers significant clinical benefit in NSCLC patients with MET copy number gain.
- True MET amplification, rather than polysomy, appears to be a critical predictor of response to EGFRi/METi therapy.
- Future research should focus on stratifying patients based on the type of MET copy number gain to personalize treatment.
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