Clonal MET Amplification and Tyrosine Kinase Inhibitor Treatment Outcome in EGFR-Mutant NSCLC
In a Singaporean study reported in the Journal of Clinical Oncology, Lai et al found that tyrosine kinase inhibitor treatment outcome did not differ according to mesenchymal epithelial transition factor (MET)-high vs MET-low status in treatment-naive, EGFR-mutant non–small cell lung cancer (NSCLC), although outcome was poorer in patients classified as MET-amplified. As noted by the authors, MET activation has been implicated as an oncogenic driver in EGFR-mutant disease that can mediate primary and secondary resistance to EGFR tyrosine kinase inhibitors.
Study Details
The study involved retrospective identification of 200 consecutive patients from the National Cancer Center Singapore database with metastatic adenocarcinoma and known MET fluorescence in situ hybridization (FISH) status diagnosed between September 2014 and September 2016. MET-high was defied as copy number gain (CNG) ≥ 5, with the additional criterion of MET/centromeric portion of chromosome 7 ratio ≥ 2 for MET amplification. Time-to-treatment failure on EGFR tyrosine kinase inhibitor treatment in patients identified as MET-high vs MET-low was estimated by Kaplan-Meier analysis and compared using a log-rank test.
Association With Outcome
Overall, 52 (26%) of 200 patients in the cohort were MET-high at diagnosis, with 46 (23%) having polysomy and 6 (3%) having amplification. Median time to treatment failure was 12.2 months among MET-high patients vs 13.1 months among MET-low patients (P = .566). No significant differences in response were observed, irrespective of copy number thresholds used in analysis. Loss of MET was observed in three of six patients identified as MET-high who underwent postprogression biopsies, a finding consistent with marked intratumoral heterogeneity in MET CNG in early stage tumors. Suboptimal responses, with time to treatment failure of 1.0 to 6.4 months, on EGFR tyrosine kinase inhibitor treatment was observed in 5 patients with coexisting MET amplification.
The investigators concluded, “Although up to 26% of tyrosine kinase inhibitor–naive, EGFR-mutant-positive NSCLC harbor high MET CNG by fluorescence in situ hybridization, this did not significantly affect response to tyrosine kinase inhibitor[s], except in patients identified as MET-amplified. Our data underscore the limitations of adopting arbitrary copy number thresholds and the need for cross-assay validation to define therapeutically tractable MET pathway dysregulation in EGFR-mutant–positive NSCLC.”
Daniel S.W. Tan, MD, PhD, of the Division of Medical Oncology, National Cancer Centre Singapore, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was funded by the National Medical Research Council-Singapore. The study authors' full disclosures can be found at jco.ascopubs.org.
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