Clinical outcomes of SMARCA4-deficient thoracic tumor patients and therapeutic value of immune checkpoint inhibitors in advanced stage patients

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Abstract Objectives SMARCA4-deficient thoracic tumor(SMARCA4-DT) is a relatively rare and highly aggressive tumors, typically associated with mutations or deletions of the SMARCA4 gene. This article aims to explore the clinical features of SMARCA4-DT patients, disease outcomes, effective prognostic indicators, and the therapeutic value of immune checkpoint inhibitors (ICIs) in advanced SMARCA4-DT patients. Methods A total of 98 cases of SMARCA4-DTs diagnosed at Shanghai Chest Hospital from May 2019 to September 2023 were selected and collected.The clinical features of all patients were analyzed, and disease-free survival (DFS) and overall survival (OS) were assessed for those with complete surgical resection. For advanced, non-resectable patients, treatment strategies were divided into a chemotherapy group and a combination therapy group, including ICIs. A statistical analysis of progression-free survival (PFS) and OS was performed to explore the therapeutic role of ICIs in advanced patients and to identify potential predictive markers. Results Among the 98 patients, 60 (61.2%) had SMARCA4-deficient non-small cell lung cancer, 32 (32.7%) had SMARCA4-dUT, and 6 (6.1%) had SMARCA4-deficient neuroendocrine carcinoma. In the resection cohort, 22 DFS events and 13 deaths occurred; stage I–II versus stage III (HR = 0.23, 95% CI: 0.08–0.63, P = 0.004) and dUT versus the carcinoma group (HR = 4.08, 95% CI: 1.67–9.98, P = 0.002) were independently associated with DFS, whereas stage I–II versus stage III (HR = 0.11, 95% CI: 0.02–0.53, P = 0.006) and NLR > 3.92 (HR = 4.20, 95% CI: 1.19–14.80, P = 0.025) were associated with OS. In the advanced-stage cohort, the ICI-containing and ICI-free chemotherapy groups each included 16 patients; the objective response rates were 50.0% and 12.5%, respectively ( P = 0.054). ICI-containing therapy was associated with longer unadjusted PFS (median, 8.6 vs. 4.5 months; HR = 0.36, 95% CI: 0.15–0.85, P = 0.020), but not OS (median, not reached vs. 15.3 months; HR = 0.41, 95% CI: 0.13–1.27, P = 0.122); after covariate adjustment and stratification by pathological group, neither PFS nor OS remained statistically significant. Among 19 unique ICI-treated patients, no statistically significant association was observed between PD-L1 expression and PFS or OS; the NLR cutoff and CDKN2A findings were exploratory and require independent validation. Conclusions Postoperative stage and pathological group were associated with DFS, whereas stage and preoperative NLR were associated with OS. In advanced disease, ICI-containing therapy was associated with longer unadjusted PFS, but the adjusted estimates were imprecise and not statistically significant; consequently, the treatment and biomarker findings should be regarded as hypothesis-generating rather than confirmatory, and prospective multicenter validation is warranted.