High MET copy number gain (CNG) as measured by fluorescence in situ hybridization (FISH) was not associated with response to tyrosine kinase inhibitor (TKI) therapy in TKI-naive patients with metastatic non-small cell lung cancer (NSCLC) characterized by an activating EGFR mutation unless MET amplification, defined as CNG greater than 5 and MET/centromeric portion of chromosome 7 (CEP7) ratios greater than 2, was present.

Preclinical and clinical evidence suggests a role for MET pathway activation as an oncogenic driver in advanced NSCLC as well as a mechanism of acquired resistance to TKI therapy targeted to other genomic alterations (eg, EGFR). Nevertheless, consensus definitions characterizing MET positivity and the optimal methods for its detection do not yet exist. 

This retrospective analysis, which was published in the Journal of Clinical Oncology, involved an assessment of the clinical characteristics of a cohort of 200 patients with metastatic EGFR-mutant NSCLC and known MET FISH status diagnosed between September 2014 and September 2016. The primary endpoint of time-to-treatment failure (TTF) was evaluated for the 154 patients treated with first-line EGFR TKI monotherapy. In addition, MET tumor intratumoral heterogeneity (ITH) was evaluated through multiregional assessments of MET CNG status by exome sequencing and MET FISH testing in newly diagnosed EGFR-mutant NSCLC tumors.

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FISH testing of biopsy specimens obtained prior to treatment revealed that 26% of patients in the metastatic cohort had disease characterized as high MET CNG. However, only 3% of this group were found to have MET-amplified tumors. Median TTF was not significantly different in the subgroups of patients with or without high MET CNG following treatment with a first-line EGFR TKI (12.2 months [95% confidence interval (CI), 5.7-22.6]) for MET-high and 13.1 months (95% CI, 10.6-15.0) for MET-low [P =.566]). However, TTF between 1.0 and 6.4 months were observed in patients with MET-amplified tumors. 

While MET CGH ITH was observed in all tumor specimens undergoing multiregional exome sequencing, MET FISH testing showed MET-amplified tumors with the highest MET/CEP7 ratios exhibited relatively less ITH, suggesting a greater degree of clonality for these alterations. A low level of concordance was observed when MET status was assessed by FISH and exome sequencing. 

The lack of association between TTF and MET CNG status “is likely attributable to ITH and the equivocal impact of threshold-based definitions of MET,” the authors concluded. They further wrote that “elucidating additional parameters to delineate MET addiction should be further investigated to identify patients who are most likely to benefit from MET inhibitors.”

Reference

  1. Lai GGY, Lim TH, Lim J, et al. Clonal MET amplification as a determinant of tyrosine kkinase inhibitor resistance in epidermal growth factor receptor-mutant non-small-cell lung cancer [published online January 24, 2019]. J Clin Oncol. doi: 10.1200/JCO.18.00177