Clinical and Pathological Characteristics of Stage IV SMARCA4-Deficient Lung Cancer and the Efficacy of Immune Checkpoint Inhibitors.

[AIMS] The aim of this study was to investigate clinicopathological characteristics and immune checkpoint inhibitor (ICI) efficacy in stage IV SMARCA4-deficient lung cancer.

[MATERIALS AND METHODS] We retrospectively analysed the medical records of 286 patients with stage IV lung cancer treated between 2021 and 2025, including 70 (24.5%) with SMARCA4 deficiency and 216 (75.5%) with SMARCA4 proficiency. Patients who completed two or more cycles of systemic therapy were stratified into non-ICI and ICI groups according to the first-line treatment regimen. SMARCA4 loss was defined by immunohistochemistry (IHC) as the complete absence or marked reduction of SMARCA4 expression. Overall survival (OS) and progression-free survival (PFS) were analysed by the Kaplan-Meier method and compared using log-rank test.

[RESULTS] SMARCA4-deficient patients had a median age of 66 years (interquartile range [IQR]: 57-71), were predominantly male (100.0%), and had a documented smoking history in 87.1% of cases. IHC analysis revealed that the SMARCA4-deficient patients showed significantly higher negative expression rates for thyroid transcription factor-1 (TTF-1) (79.4% vs. 60.3%, P = 0.004) and Napsin A (95.3% vs. 68.3%, P < 0.001), P40 (89.4% vs. 70.9%, P = 0.002), and programmed death ligand-1 (PD-L1) tumour proportion score (TPS) (52.3% vs. 28.1%, P < 0.001), than the SMARCA4-proficient patients. Survival analysis revealed that the SMARCA4-deficient group had a significantly shorter median OS than the SMARCA4-proficient group (10.4 vs. 19.3 months, P = 0.021). Among SMARCA4-deficient patients, the ICI group demonstrated significantly improved survival outcomes compared to the non-ICI group, with a median OS of 14.4 versus 8.6 months (P = 0.044) and a median PFS of 8.0 versus 4.1 months (P < 0.001). Among patients treated with ICI-based regimens, no statistically significant differences in OS or PFS were observed between the SMARCA4-deficient and SMARCA4-proficient groups, with a median OS of 14.4 versus 34.6 months (P = 0.303) and a median PFS of 8.0 versus 9.4 months (P = 0.870), respectively.

[CONCLUSION] SMARCA4 deficiency defined an aggressive subset of lung cancer characterised by distinct clinicopathological features and was associated with significantly shorter median OS than SMARCA4-proficient tumours. ICI-based therapy may significantly improve survival outcomes in SMARCA4-deficient patients, supporting its prioritisation in this high-risk population.