P85.05 MET Exon 14 Skipping Mutation Positive Non-Small Cell Lung Cancer: A Population-Based Cohort

Abstract

MET exon 14 skipping is a potentially targetable molecular alteration. The goals of this study were to identify patients with MET exon 14 skipping to understand prevalence, biology and response to treatment, and to identify molecular signatures that may predict for response or resistance to targeted MET therapy. British Columbia Cancer provides care for a population of 5.1 million. A laboratory-developed focused DNA-based next generation sequencing (NGS) panel was performed on advanced non-squamous non-small cell lung cancer (NSCLC) and selected never-smoking squamous patients. Patients with advanced NSCLC found to have MET exon 14 skipping alterations between January 2016-September 2019 were identified. Retrospective chart review was completed to collect baseline characteristics, response to systemic treatments, and outcomes. Median overall survival (OS) was calculated using the Kaplan Meier method. Forty-three patients out of 1,934 tested were identified with MET exon 14 skipping (2.2%). Forty-one patients had metastatic disease: median age 77 years, female 46%, non-squamous/squamous/mixed adenosquamous 85/12/2%, current or former/never smoking status 61/39%, median number of pack years 30. Thirty-three patients received systemic therapy; 24 patients treated with crizotinib in the first/second line setting 87/13%. Response rate was PR/SD/PD/NE 21/33/25/21% for a disease control rate (DCR) of 54.2% in the evaluable patients. Median time to treatment discontinuation (TTD) for crizotinib was 2.2 months with 5 patients still on therapy and 3 stopping due to toxicity. Eleven patients received platinum-based chemotherapy with PR/SD/PD/NE 9/64/18/9% and DCR of 73% in the evaluable patients. Median time to platinum discontinuation of 2.8 months. Fourteen patients received immunotherapy (IO) with PR/SD/PD/NE 7/43/21/29% and DCR of 50% in the evaluable patients. Median time to IO treatment discontinuation 2.4 months. Median OS for metastatic patients treated with any systemic therapy was 14.6 months. Molecular details of 41 patients: PDL1<1%/PDL1 1-49%/PDL1≥50%/unknown status was 7/17/63/12%. MET variant frequency <50/≥50% 76/24%. MET alteration type: 2% CBL binding domain mutation, 34% poly- pyrimidine tract deletion, 63% splice donor mutation or deletion. Co-mutations: 20% TP53 alterations, 22% other, 59% none. In this small cohort there were no clear correlations between molecular aberrations and response, TTD or OS. The prevalence of MET exon 14 skipping in a North American population was 2.2%. Unlike other targeted mutations, patients were older and more commonly current or former smokers. Patients with MET exon 14 skipping alteration demonstrate disease control with crizotinib, platinum-based chemotherapy and immunotherapy. Co-mutations with p53 were commonly noted. Correlation between co-mutations and efficacy of therapy were not identified in this cohort.