Effective treatment strategies and key factors influencing therapeutic efficacy in advanced SMARCA4-deficient non-small cell lung cancer

Highlights•First-line local treatment combined with immunotherapy is associated with a lower risk of disease progression in locally advanced SMARCA4-deficient NSCLC.•First-line immunotherapy improves survival in metastatic SMARCA4-deficient NSCLC.•STK11/KEAP1 mutations are linked to reduced immunotherapy efficacy in SMARCA4-deficient NSCLC.AbstractIntroductionSMARCA4/BRG1-deficient non-small cell lung cancer (SD-NSCLC) with high invasiveness and poor prognosis is associated with primary resistance to standard treatment, especially in late-stage patients. This study aimed to explore effective treatments and identify critical factors impacting therapeutic efficacy to enhance outcomes for SD-NSCLC patients.Methods103 SD-NSCLC patients in stage III/IV diagnosed by immunohistochemistry from May 2019 to March 2024 were included in this study. We assessed the patients' clinical and genetic features, analyzed the clinical outcomes of local treatment and immunotherapy according to the TNM stage, and further evaluated the factors impacting therapeutic efficacy.ResultsIn stage III patients, no significant differences in the median progression-free survival (mPFS) and median overall survival (mOS) were observed between patients receiving local treatment at the primary site and those who did not (p > 0.05), while adding ICIs (immune checkpoint inhibitors) to local treatment significantly improved mPFS compared with non-ICIs (15.0 vs. 7.7 months, p = 0.033), though not mOS (p > 0.05). For stage IV patients, ICIs significantly improved mPFS (8.9 vs. 4.2 months, p = 0.006) and mOS (19.7 vs. 13.1 months, p = 0.007) compared to non-ICIs treatments. However, among ICIs-treated patients, the addition of local treatment to the primary lesion did not significantly affect mPFS and mOS (p > 0.05). Patients with STK11/KEAP1 mutations had significantly shorter mPFS (3.6 vs. 16.2 months, p = 0.001) and mOS (17.7 vs. 31.3 months, p = 0.002), while no significant difference was observed in mPFS and mOS in patients with different tumor mutation burden (TMB) and PD-L1 expression levels.ConclusionICIs to local treatment shows promising results for locally advanced patients with SD-NSCLC, and first-line ICIs are associated with improved survival in metastatic SD-NSCLC. STK11/KEAP1 mutations may be linked to reduced efficacy of immunotherapy.