Characterization of Non-Small-Cell Lung Cancers With MET Exon 14 Skipping Alterations Detected in Tissue or Liquid: Clinicogenomics and Real-World Treatment Patterns.

Abstract

<i>MET</i> exon 14 (<i>MET</i>ex14) skipping alterations are oncogenic drivers in non-small-cell lung cancer (NSCLC). We present a comprehensive overview of <i>MET</i>ex14 samples from 1,592 patients with NSCLC, associated clinicogenomic characteristics, potential mechanisms of acquired resistance, treatment patterns, and outcomes to MET inhibitors. Hybrid capture-based comprehensive genomic profiling (CGP) was performed on samples from 69,219 patients with NSCLC. For treatment patterns and outcomes analysis, patients with advanced <i>MET</i>ex14-altered NSCLC were selected from the Flatiron Health-Foundation Medicine clinicogenomic database, a nationwide deidentified electronic health record-derived database linked to Foundation Medicine CGP for patients treated between January 2011 and March 2020. A total of 1,592 patients with NSCLC (2.3%) were identified with 1,599 <i>MET</i>ex14 alterations spanning multiple functional sites (1,458 of 60,244 tissue samples and 134 of 8,975 liquid samples). Low tumor mutational burden and high programmed death ligand 1 expression were enriched in <i>MET</i>ex14-altered samples. <i>MDM2</i>, <i>CDK4</i>, and <i>MET</i> coamplifications and <i>TP53</i> mutations were present in 34%, 19%, 11%, and 42% of tissue samples, respectively. Comparing tissue and liquid cohorts, coalteration frequency and acquired resistance mechanisms, including multiple <i>MET</i> mutations, <i>EGFR</i>, <i>ERBB2</i>, <i>KRAS</i>, and PI3K pathway alterations, were generally similar. Positive percent agreement with the tissue was 100% for <i>MET</i>ex14 pairs collected within 1 year (n = 7). Treatment patterns showed increasing adoption of MET inhibitors in <i>MET</i>ex14-altered NSCLC after receipt of CGP results; the real-world response rate to MET inhibitors was 45%, and time to treatment discontinuation was 4.4 months. Diverse <i>MET</i>ex14 alterations were present in 2%-3% of NSCLC cases. Tissue and liquid comparisons showed high concordance and similar coalteration profiles. Characterizing common co-occurring alterations and immunotherapy biomarkers, including those present before or acquired after treatment, may be critical for predicting responses to MET inhibitors and informing rational combination strategies.