Gene Copy Deletion of STK11, KEAP1, and SMARCA4: Clinicopathologic Features and Association With the Outcomes of Immunotherapy With or Without Chemotherapy in Nonsquamous NSCLC

Abstract

Introduction

Mutations in STK11, KEAP1, and SMARCA4 predispose to inferior immune checkpoint inhibitor (ICI) efficacy in NSCLC, particularly among KRAS-mutant cases. Nevertheless, 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 cases of nonsquamous NSCLC at Dana-Farber Cancer Institute (DFCI). mRNA and LKB1 protein levels were assessed using The Cancer Genome Atlas. Clinical outcomes were analyzed in patients who received ICI with or without chemotherapy at DFCI and Memorial Sloan Kettering Cancer Center. Analyses of each deletion excluded cases with mutations in that gene.

Results

Among the 3194 cases of nonsquamous NSCLC, 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 programmed death-ligand 1 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 were associated with worse objective response rates (STK11 31% versus 45%, p = 0.005; KEAP1 33% versus 45%, p = 0.03; SMARCA4 29% versus 45%, p = 0.0007), progression-free survival (STK11 hazard ratio [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 1267 patients treated with ICI alone, these deletions did not impact outcomes in the Memorial Sloan Kettering Cancer Center cohort but were 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 programmed death-ligand 1 expression, and poor chemoimmunotherapy efficacy in NSCLC.