Immunotherapy plus chemotherapy improves survival in SMARCA4-deficient NSCLC: a real-world cohort study

SMARCA4‑deficient non‑small‑cell lung cancer (SMARCA4‑dNSCLC) is a rare, aggressive NSCLC subtype driven by SWI/SNF complex dysfunction with no standardized therapeutic strategies. Although chemoimmunotherapy represents standard first‑line therapy for driver‑negative advanced NSCLC, its real‑world efficacy in SMARCA4‑dNSCLC remains controversial. SMARCA4 loss frequently generates an immune‑desert tumor microenvironment with low PD‑L1 and sparse CD8⁺ T‑cell infiltration, potentially conferring intrinsic resistance to immune checkpoint inhibitors (ICIs). Pre‑clinical data suggest synergism between anti‑angiogenic agents and chemoimmunotherapy; however, real‑world evidence comparing chemoimmunotherapy alone versus chemoimmunotherapy plus anti‑angiogenics for SMARCA4‑dNSCLC is limited.

This single‑center retrospective cohort enrolled 22 patients with immunohistochemically‑confirmed advanced SMARCA4‑dNSCLC treated from January 2021 to September 2024. Clinicopathological characteristics, treatment regimens, survival outcomes and safety data were collected. The Kaplan‑Meier method was applied to estimate progression‑free survival (PFS) and overall survival (OS). Given the small sample size, only univariate survival analysis was performed. Objective response rate (ORR) and disease control rate (DCR) were evaluated per RECIST 1.1, and treatment‑related adverse events were graded using CTCAE v4.0. This study obtained local ethics‑committee approval with informed consent waived. The last follow‑up date was September 1, 2025.

Most patients were elderly male smokers with high Ki‑67, frequent adrenal metastasis and low‑to‑negative PD‑L1 expression. Compared with non‑ICI‑based therapy, ICI‑containing regimens achieved significantly superior survival: median OS not reached versus 8.7 months (HR = 0.28, 95%CI:0.08‑0.98, P = 0.047), accompanied by improved PFS, ORR and DCR. Addition of anti‑angiogenic agents brought no extra survival benefit. Elevated CYFRA21‑1 and poor ECOG‑PS predicted unfavorable prognosis. Treatment‑related adverse events were generally tolerable across groups.

Despite an immune‑suppressed tumor microenvironment, real‑world ICI‑containing chemoimmunotherapy delivers meaningful survival benefits for advanced SMARCA4‑dNSCLC, whereas additional anti‑angiogenic combination yields no further clinical advantage. Our findings should be interpreted cautiously given retrospective design and small sample size. Large‑scale multi‑center prospective studies incorporating multivariable prognostic analyses are required to validate these results and optimize individualized treatment for this rare molecular NSCLC subtype.