STK11/KEAP1 co-mutations in SMARCA4-mutant advanced non-small cell lung cancer: genetic characteristics and impact on immunotherapy efficacy.

Background: The impact of STK11/KEAP1 co-mutations on the efficacy of immunotherapy in patients with SMARCA4-mutant advanced non-small cell lung cancer (NSCLC) remains incompletely understood. Our aim was to investigate the effects of STK11/KEAP1 co-mutations on the clinical prognosis of patients with SMARCA4-mutant advanced NSCLC receiving immunotherapy.

Methods: We obtained 2,098 patients with stage IIIB-IV NSCLC from the cBioPortal database. Patients harboring EGFR, ALK, ROS1 and RET mutations were excluded. The impacts of SMARCA4 and STK11/KEAP1 co-mutations on the efficacy of chemoimmunotherapy were analyzed, along with their associations with tumor mutational burden (TMB), programmed cell death ligand 1 (PD-L1) expression, and patient prognosis.

Results: Among 2,098 patients with NSCLC, SMARCA4-mutant patients accounted for 7.7% (162/2,098), and wild-type patients accounted for 92.3% (1,936/2,098). SMARCA4 mutations are more common in elderly patients, smokers, and patients with adrenal metastasis. Compared with SMARCA4 wild-type patients, SMARCA4-mutant patients had significantly greater TMB (P<0.001) and poorer median overall survival (mOS) (10.6 vs. 17.5 months, P<0.001). Further analysis revealed that patients with SMARCA4 class I alterations had significantly shorter mOS (8.7 vs. 14.1 months, P=0.008) and median first-line treatment progression-free survival (mPFS1) (3.7 vs. 6.6 months, P=0.003) than those with class II alterations. Multivariate regression analysis confirmed that SMARCA4 mutations significantly increased the risk of death [hazard ratio (HR) =1.329, 95% confidence interval (CI): 1.106-1.596, P=0.002]. Compared with chemotherapy, chemoimmunotherapy significantly prolonged mPFS1 (5.6 vs. 3.9 months, P=0.01) but not mOS (10.8 vs. 9.5 months, P=0.91) in patients with SMARCA4 mutations. Among patients receiving first-line chemoimmunotherapy, TMB levels had no significant effect on mPFS1 (5.6 vs. 6.6 months, P=0.83) or mOS (8.5 vs. 10.8 months, P=0.38), but PD-L1-positive patients had significantly longer mPFS1 (8.3 vs. 5.1 months, P=0.02) and mOS (18.9 vs. 9.3 months, P=0.03). SMARCA4 and STK11/KEAP1 co-mutations were not significantly correlated with TMB (P=0.85) or PD-L1 expression (P=0.08). However, the patients with SMARCA4 and STK11/KEAP1 co-mutations had significantly shorter mPFS1 (4.5 vs. 13.3 months, P<0.001) and mOS (8.7 vs. 20.1 months, P=0.005) in the chemoimmunotherapy group. Among SMARCA4-mutant patients, those without STK11/KEAP1 co-mutations derived longer mPFS1 (13.3 vs. 5.6 months, P=0.01) benefits from immunotherapy. In contrast, this benefit markedly reduced mPFS1 (4.5 vs. 2.9 months, P=0.16) in patients with STK11/KEAP1 co-mutations, suggesting that STK11/KEAP1 may affect the immunological efficacy in patients with SMARCA4 mutations.

Conclusions: Patients with SMARCA4-mutant NSCLC can benefit from chemoimmunotherapy. However, STK11/KEAP1 co-mutations were associated with poorer prognosis and reduced immunotherapy efficacy in SMARCA4-mutant advanced NSCLC. Moreover, STK11/KEAP1 co-mutations may serve as key stratification markers for predicting the potential benefit of immunotherapy in SMARCA4-mutant NSCLC.