SMARCA4 and Other SWItch/Sucrose NonFermentable Family Genomic Alterations in NSCLC: Clinicopathologic Characteristics and Outcomes to Immune Checkpoint Inhibition

The SWItch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling complex acts as a regulatory component of transcription, and inactivating mutations (muts) within the complex are implicated in genomic instability, higher tumor mutational burden, and an aggressive cancer phenotype. Whether SMARCA4 and other SWI/SNF alterations are independent prognostic factors or associated with clinical outcomes to immune checkpoint inhibitors (ICIs) in NSCLC remains unclear.We collected clinicopathologic and genomic data from patients with NSCLC who underwent targeted next-generation sequencing at the Dana-Farber Cancer Institute. Tumors were characterized on the basis of the presence or absence of muts across a set of six SWI/SNF genes (ARID1A, ARID1B, ARID2, PBRM1, SMARCA4, and SMARCB1).Of 2689 patients with NSCLC, 20.6% (N = 555) had SWI/SNF genomic alterations. Compared with SWI/SNF wild-type (wt) NSCLC, patients with SWI/SNF-mutant NSCLCs had a lower prevalence of concurrent targetable driver muts (33.2% versus 22.2%; p < 0.001), a higher tumor mutational burden (median 8.5 versus 12.2 muts/megabase; p < 0.001), and a shorter median overall survival (mOS) from the time of advanced disease diagnosis (25.0 versus 19.3 mo, p = 0.01); the detrimental effect in OS seemed to be largely driven by SMARCA4 muts (mOS: 25.0 for SMARCA4 wt versus 15.6 mo for SMARCA4 mutant; p < 0.001). Among 532 patients who received ICIs, 25.5% (N = 136) harbored SWI/SNF muts. From the start of immunotherapy, there was no difference in objective response rate (ORR = 19.9% versus 25.0%, p = 0.2), median progression-free survival (mPFS = 3.0 versus 3.0 mo, hazard ratio [HR] = 0.96 [95% confidence interval [CI] = 0.77-1.18], p = 0.7), or mOS (13.1 versus 9.5 mo, HR = 0.81 [95% CI: 0.64-1.02], p = 0.07) in SWI/SNF-wt versus SWI/SNF-mutant NSCLC, respectively. Nevertheless, among KRAS-mutant NSCLCs treated with ICIs (N = 176), a concurrent SWI/SNF mut (N = 39) conferred a numerically lower ORR (21.9% versus 12.8%, p = 0.2), a significantly shorter mPFS (4.1 versus 1.8 mo, HR = 0.57 [95% CI: 0.38-0.84], p = 0.005), and a significantly shorter mOS (15.5 versus 8.2 mo, HR = 0.56 [95% CI: 0.36-0.86], p = 0.008). The deleterious effect on immunotherapy outcomes in KRAS-mutant NSCLC was most pronounced in the SMARCA4-mutant subset (N = 17), with a lower ORR (22% versus 0%, p = 0.03), a significantly shorter mPFS (4.1 versus 1.4 mo, HR = 0.25 [95% CI: 0.14-0.42], p < 0.001), and a significantly shorter mOS (15.1 versus 3.0 mo, HR = 0.29 [95% CI: 0.17-0.50], p < 0.001) compared with SMARCA4-wt KRAS-mutant NSCLCs.Although there were no associations between SWI/SNF mut status and immunotherapy efficacy in the overall NSCLC cohort, the presence of a SMARCA4 alteration may confer a worse outcome to immunotherapy among KRAS-mutant NSCLCs.