Gene copy deletion of STK11, KEAP1, and SMARCA4: clinicopathologic features and association with outcomes to immunotherapy +/- chemotherapy in nonsquamous non-small cell lung cancer.

Abstract

Background: Mutations in STK11, KEAP1, and SMARCA4 predispose to inferior immune checkpoint inhibitor (ICI) efficacy in non-small cell lung cancer (NSCLC), particularly among KRAS-mutant cases. However, the frequency, clinicopathologic features, and clinical impact of deletions in these genes are poorly characterized.

Methods: Clinicopathologic correlates of STK11, KEAP1, and SMARCA4 deletion were analyzed in nonsquamous NSCLCs at Dana-Farber Cancer Institute (DFCI). mRNA and LKB1 protein levels were assessed via The Cancer Genome Atlas. Clinical outcomes were analyzed in patients who received ICI+/-chemotherapy at DFCI and Memorial Sloan Kettering Cancer Center (MSKCC). Analyses of each deletion excluded cases with mutations in that gene.

Results: Among 3,194 nonsquamous NSCLCs, 14.7% had STK11 deletion (STK11^DEL), 13.5% KEAP1 deletion (KEAP1^DEL), and 13.7% SMARCA4 deletion (SMARCA4^DEL). These deletions correlated with lower PD-L1 expression and higher disease stage, tumor mutational burden, and aneuploidy. STK11^DEL, KEAP1^DEL, and SMARCA4^DEL each correlated with lower corresponding mRNA expression, and STK11^DEL with lower LKB1 protein expression. Among 767 patients treated with chemoimmunotherapy, these deletions associated with worse objective response rates (STK11 31% vs. 45%, P=0.005; KEAP1 33% vs. 45%, P=0.03; SMARCA4 29% vs. 45%, P=0.0007), progression free survival (STK11 HR 1.5, P=0.0001; KEAP1 HR 1.4, P=0.002; SMARCA4 HR 1.6, P<0.0001), and overall survival (STK11 HR 1.7, P<0.0001; KEAP1 HR 1.5, P=0.003; SMARCA4 HR 1.7, P<0.0001). The effect of these deletions on chemoimmunotherapy outcomes was comparable to the effect of mutations in these genes. Among 1,267 patients treated with ICI alone, these deletions did not impact outcomes in the MSKCC cohort, but generally associated with worse outcomes in the DFCI cohort among KRAS-mutant cases.

Conclusions: STK11, KEAP1, and SMARCA4 deletions correlate with distinct clinicopathologic features, reduced PD-L1, and poor chemoimmunotherapy efficacy in NSCLC.