Genetic profiling and the response to RET inhibitors in RET fusion positive non-small cell lung cancer (NSCLC) identified by international genomic screening project (LC-SCRUM-Asia).

Abstract

9557 Background: RET fusions are targetable oncogenic drivers in 1 – 2 % of NSCLC, yet no RET inhibitors are approved. Selective RET inhibitors, such as LOXO-292 and BLU-667, are currently in development. The impact of co-occurring mutation on outcome in RET-TKI therapy remains largely unknown. Methods: In an international genome screening project in Asia (LC-SCRUM-Asia), 161 cancer-related genes have been analyzed by a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay. The therapeutic efficacy and survival of RET fusion+ NSCLC were evaluated using a large-scale clinicogenomic database in the LC-SCRUM-Japan. Results: From Feb 2013 to Dec 2019, a total of 7177 patients with non-squamous NSCLC were enrolled. RET fusion were detected in 167 patients (2.3 %). Median age was 61 years (range: 29 - 85), 60 % were female, 61 % were never-smokers, 99 % had adenocarcinoma, and 78 % had stage IIIB/IV disease. Based on our database, the median overall survival was 37 months. 62 patients received RET inhibitor therapy. RET fusions was identified by NGS assay (KIF5B-RET: 75, CCDC6-RET: 30, Others: 2) in 107 patients. Co-occurring genomic alterations were detected in 62 (58 %) patients, the median number of co-mutations was 1 (range 0 - 4). The most common co-occurring mutations in tumor involved TP53 (31; 29 %), STK11 (6; 6 %), CDKN2A (5; 5 %) and TSC2 (5; 5 %). In 23 patients treated with RET inhibitor (unapproved drugs), there was a strong association between co-occurring mutation and time to treatment discontinuation (TTD) in RET inhibitor therapy; HR 2.75 (95%CI 1.71 - 15.6, P = 0.0096). Conclusions: RET rearrangements continue to represent a rare but high unmet need disease. Co-occurring mutation was significantly associated with shorter TTD. Our data is the largest cohort of advanced-stage RET fusion+ NSCLC profiled by NGS to date. Co-occurring mutation should be evaluated in the development of novel targeted therapies for RET fusion+ NSCLC.