Whole exome sequencing (WES) of non-small cell lung cancer (NSCLC) for tumor mutational burden (TMB) analysis and long-term benefit to immune checkpoint inhibitors (ICIs).

Abstract

9071 Background: ICIs have significantly changed the therapeutic landscape of advanced NSCLC. As such, characterizing predictive markers of long-term clinical benefit is a critical objective. TMB quantification using targeted gene panels associates with long-term response to ICIs in NSCLC patients (Rizvi H ASCO 18). Although TMB quantified by targeted NGS correlates with that of WES, caution may be needed when using smaller panels. Methods: Here we analyzed WES of tumors and matched normal tissue from 67 NSCLC patients including 42 treated with ICIs. We correlated TMB with clinico-pathological features and outcomes. TMB was categorized as high vs. low according to the upper quartile of cohort distribution. Results: The median TMB was 2.68 non-synonymous variants (nSNVs)/Mb, ranging from 0 to 15.6 nSNVs/Mb, with upper quartile at 5.42 nSNVs/Mb. TMB was higher for smoker/current smoker (median 3.51) compared to never smokers (median 0.94, p = 0.0048) but no differences were seen in elderly ( > 70 years) vs. young patients or across histologies (squamous, adeno and other) and stages at diagnosis. In patients treated with ICIs, median TMB was 5.44 for those achieving complete response, 3.87 for patients with partial response and 2.42 for patients with progressive disease (PD) (p = 0.04). Moreover, improved clinical outcomes were associated with higher TMB (Table). In patients treated with ICIs, TMB as continuous variable had an impact on progression free survival (PFS) (p = 0.03). Median PFS was 22.3 months (mo) (14-not reached) for those with high TMB and 6.4 mo (3-16) for those with low TMB (HR 0.34, 0.13-0.9, p = 0.03). Median overall survival was not reached for those patients with high TMB and 32 mo (22-43) for those with low TMB (HR 0.29, 0.1-0.86, p = 0.02). Conclusions: High TMB correlates with long-term ICI benefit in NSCLC patients. Mutations in individual genes potentially linked to long-term benefit or resistance to ICIs will be presented. [Table: see text]