Prognostic impact of SMARCA4 deficiency and STK11 co-mutations on non-small cell lung cancer treated with immune checkpoint inhibitors.

Abstract

e20511 Background: SMARCA4/BRG1-deficient non-small cell lung cancer (SD-NSCLC) is highly aggressive and has a poor prognosis. The efficacy of immune checkpoint inhibitors in the context of highly aggressive SD-NSCLC remains unclear. Combined KRAS, STK11, KEAP1, and CDKN2A gene co-mutations may affect survival outcomes in SMARCA4-deficient patients. This study aims to investigate the potential differential responses of SD-NSCLC versus SMARCA4-intact NSCLC to immune checkpoint inhibitors, and the key factors influencing the prognosis of these two patient populations. Methods: A retrospective analysis was conducted on patients diagnosed with SMARCA4-deficient tumors at Tianjin Medical University Cancer Institute & Hospital from March 2019 to October 2024, with a particular focus on non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors. SMARCA4-intact NSCLC patients treated with immune checkpoint inhibitors during the same period were used as a control group. Prognostic differences were assessed by grouping patients in the SMARCA4-deficient NSCLC group according to the presence or absence of combined KRAS,STK11,KEAP1 and CDKN2A gene co-mutations. Progression-free survival (PFS) and overall response rate (ORR) were used as study endpoints to evaluate the prognosis. Results: In this study, the median Progression-Free Survival (mPFS) for the SMARCA4-intact group was 14.0 months (95% CI: 8.94–19.06), while for the SMARCA4-deficient group, it was 7.0 months (95% CI: 4.95–9.06)(P=0.0015).The two groups showed a significant difference in PFS. In the univariate and multivariate analyses, SMARCA4 status was identified as a significant prognostic factor for PFS. In the univariate analysis, SMARCA4 deficiency was associated with a hazard ratio (HR) of 2.335 (95% CI: 1.356–4.02, P = 0.002), and in the multivariate analysis, the HR increased to 2.613 (95% CI: 1.453–4.699, P = 0.001).In the SMARCA4-deficient NSCLC group, comparing STK11 wild-type and STK11-altered groups, the median survival time for the STK11-wild group was 7.5 months (95% CI: 3.71–11.29), while for the STK11-altered group, it was 1.0 month (95% CI: 0.25–1.75,P = 0.0013). STK11 mutation was identified as a significant prognostic factor, with an HR of 6.877 (95% CI: 1.706–27.668, P = 0.007) in univariate analysis and 7.860 (95% CI: 1.388–44.628, P = 0.020) in multivariate analysis. Conclusions: After treatment with immune checkpoint inhibitors, SMARCA4 deficiency remains an independent risk factor affecting prognosis, and the prognosis is even worse when accompanied by STK11 co-mutations.