Total mutation burden (TMB) in lung cancer (LC) and relationship with response to PD-1/PD-L1 targeted therapies.

Abstract

9017 Background: Immune checkpoint inhibitor (ICPI) therapies, including nivolumab and pembrolizumab, have been FDA-approved in squamous and non-squamous non-small cell (LC). Current IHC based diagnostics are challenged by assay and slide scoring issues, and more robust and comprehensive biomarkers of ICPI efficacy are needed. Methods: Comprehensive genomic profiling (CGP) was performed on FFPE specimens during the course of clinical care. TMB (mutations/Mb) was assessed as the number of somatic, coding, base substitution and indel alterations per Mb of genome. The top quartile of LC was classified as TMB high. Microsatellite instable (MSI-H) or stable (MSS) status was determined using a proprietary computational algorithm. Results: TMB was similar across all LC histologies, but elevated compared to an average TMB of 7.3 for all 60,000+ samples in the database. TMB was consistently low in LC harboring known drivers, with the exception of BRAF or KRAS mutant tumors. (See Table.) 22/5,895 LC cases (0.4%) assessed were MSI-H and 5,849 (99%) were MSS. 21/22 MSI-H cases had high TMB, and represented 9 Adeno, 7 NSCLC NOS, 5 SCC, and 1 SCLC. Alterations in BRCA1, BRCA2, and POLE were significantly enriched in LC with high TMB. 85 (0.7%) of 11,662 LC had PD-L1amplification. Responses to PD-1/PD-L1 targeted therapies and dependence on TMB will be presented. Conclusions: TMB was consistent across LC histologies and was significantly reduced in most LC with confirmed druggable oncogenic drivers, but not in KRAS or BRAF mutated cases. MSI-H status strongly correlated with high TMB. CGP of LC to simultaneously determine TMB, MSI status, PD-L1 amplification, and the presence of driver alterations may provide clinically useful predictors of response to ICPI and other targeted therapies. Adeno (n=7,925) SCC (n=1,324) NSCLC NOS (n=1,773) SCLC (n=640) EGFR mutation (n=1,775) ALK or ROS1 fusion (n=489) METex14 alteration (n=286) BRAF mutation (n=493) KRAS mutation (n=3,155) Mean 9.1 11.3 11.0 10.3 4.5 3.1 6.2 9.7 10.3 TMB > 10 (%) 2350 (30) 541 (41) 711 (40) 269 (42) 129 (7) 17 (3) 27 (9) 153 (31) 1,238 (39) TMB > 20 (%) 760 (10) 113 (9) 233 (13) 42 (7) 21 (1) 4 (1) 4 (1) 51 (10) 298 (9) Wilcoxon signed-rank test vs KRAS P<0.001 P<0.001 P<0.001 P<0.001