Analysing the impact of size of NGS panel in defining first line therapeutic strategies in NSCLC.

Abstract

3070 Background: NCCN recommends the analysis of 8 genes (EGFR, ALK, ROS1, BRAF, KRAS, MET, RET, ERBB2, and NTRK1/2/3) for NSCLC patients to identify efficacious target therapies. Concerned with the rising incidence of sub-optimal response to first-line therapy and rather early progression of disease we performed retrospective analysis in a subset of patients treated at our hospital in order to streamline molecular evaluation strategies. Methods: In this study, we retrospectively evaluated the impact of NGS panel sizes in therapy-naïve NSCLC patients. 242 therapy naïve patients evaluated for molecular genetic profiling were stratified into three groups based on gene panel size: a) Small panel (<20 genes): Focused on NCCN-recommended genes, b) Medium panel (50–100 genes): Included organ agnostic genes, c) Comprehensive panel (>100 genes): Included genomic signatures like TMB, MSI & HRD scores. Results: Of 242 therapy-naïve NSCLC patients, 60% (145/242) were evaluated using a small panel of which 13% (19/145) had no detectable genetic alterations while 37% (54/145) had 1 st line targetable mutations, 31% (45/145) exhibited both targetable and resistance causing mutations, and 19% (28/145) showed only resistance causing mutations. In the 50–100 genes Panel, comprising 29% (70/242) of patients, 10% (7/70) had no genetic alterations, while 26% (18/70) had 1 st line targetable mutations, 30% (21/70) demonstrated both targetable and resistance mutations, and 34% (24/70) harboured only resistance causing mutations. Finally, in the comprehensive NGS group (>100 genes), which accounted for 11% (25/242) of cases, only 4% (1/25) lacked detectable genetic alterations; while, 12% (3/25) had 1 st line targetable mutations, 32% (8/25) exhibited both targetable and resistance causing mutations, and 52% (13/25) showed only resistance causing mutations. Conclusions: a. Increase in gene panel size results in reduction of true negatives. Hence smaller panels may not necessarily capture resistance causing mutations. b. As the gene panel size increases, the detection of actionable driver mutations (e.g., EGFR, ALK) remains consistent; however, there is a notable shift in the mutation profile, with a decrease in cases harbouring only targetable mutations and an increase in those exhibiting both actionable and resistance causing mutations. Hence opting for comprehensive NGS profiling at baseline may increase diagnostic costs marginally, but will have significant impact in designing more effective 1 st line therapeutic strategies.