Impact of KRAS allele subtypes and concurrent genomic alterations on clinical outcomes to programmed death 1 axis blockade in non-small cell lung cancer.

Abstract

9082 Background: Immune checkpoint inhibitors (ICI) treatment can result in durable responses for KRAS-mutant (mut) non-small cell lung cancer (NSCLC). The impact of KRAS allele subtypes and concurrent genomic alterations on ICIs efficacy is unknown. Methods: We collected clinicopathologic and genomic data from patients (pts) with advanced NSCLC treated with programmed death (PD)-1 axis inhibition at the Dana-Farber Cancer Institute. We evaluated outcomes to ICIs according to KRAS mut alleles and concurrent STK11 and KEAP1 mut. Results: Of 617 ICI-treated NSCLCs, 181 (29.3%) had KRAS mut. Median TMB (mTMB) and median PD-L1 tumor proportion score (TPS) were similar between KRAS mut and KRAS wild type (wt) tumors. Among tumors with KRAS codon 12 mut, mTMB was higher in G12V (n = 37, 12.2 mut/Mb) compared to G12C (n = 84, 11.4 mut/Mb), G12D (n = 20, 9.4 mut/Mb) and G12A (n = 13, 10.1 mut/Mb), P = 0.05. Tumors with KRAS transversions (Tv) (n = 156) had higher mTMB compared to those with KRAS transitions (Ti) (n = 25) (10.9 vs 7.6 mut/Mb, P = 0.03). Median PD-L1 TPS was similar across KRAS mut alleles. Pts with KRAS G12V had longer median progression-free survival (mPFS) (5.5 vs 2.7 months, HR:0.62 [95%CI:0.40-0.96], P = 0.03) and overall survival (mOS) (17.5 vs 9.7 months, HR:0.62 [95%CI:0.36-0.99], P = 0.05), compared to non-G12V. Pts with KRAS Tv had longer mPFS and mOS compared to pts with Ti (mPFS: 3.4 vs 2.0 months, HR: 0.58 [95%CI:0.37-0.92], P = 0.02; mOS: 10.9 vs 5.4 months, HR:0.59 [95%CI:0.35-0.99], P = 0.048). Clinicopathologic features and STK11/KEAP1 mut were balanced across all KRAS mut alleles. Among KRAS mut pts, those with KEAP1 (n:52) and STK11 (n:50) concurrent mut had shorter mPFS (KEAP1 mut 1.8 vs. KEAP1 wt 4.1 months, HR: 0.55 [95%CI:0.38-0.80], P = 0.002; STK11 mut 1.8 vs STK11 wt 4.6 months, HR:0.46 [95%CI:0.32-0.67], P < 0.0001) and mOS (KEAP1 mut 4.8 vs KEAP1 wt 15.1 months, HR: 0.51 [95%CI:0.34-0.76], P = 0.001; STK11 mut 4.8 vs STK11 wt 13.6 months, HR:0.51 [95%CI:0.34-0.76], P = 0.001). KEAP1 and STK11 mut did not impact outcome in KRAS wt pts. Conclusions: KRAS allele subtypes and concurrent genomic alterations impact ICI efficacy in NSCLC.