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

• Published in: JCO precision oncology Vol. 5
• Main Authors: Lee, Jessica K, Madison, Russell, Classon, Anthony, Gjoerup, Ole, Rosenzweig, Mark, Frampton, Garrett M, Alexander, Brian M, Oxnard, Geoffrey R, Venstrom, Jeffrey M, Awad, Mark M, Schrock, Alexa B
• Format: Journal Article
• Language: English
• Published: United States 2021
• ISSN: 2473-4284
• DOI: 10.1200/PO.21.00122

exon 14 ( ex14) skipping alterations are oncogenic drivers in non-small-cell lung cancer (NSCLC). We present a comprehensive overview of 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 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 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 ex14-altered samples. , , and coamplifications and 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 mutations, , , , and PI3K pathway alterations, were generally similar. Positive percent agreement with the tissue was 100% for ex14 pairs collected within 1 year (n = 7). Treatment patterns showed increasing adoption of MET inhibitors in 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 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.