e15206 Background: SMARCA4-deficient tumors represent a newly defined category of malignancies in recent years, characterized by high aggressiveness, rapid progression, and a lack of established treatment guidelines. Previous studies on SMARCA4-deficient thoracic tumors have suggested immune checkpoint inhibitor (ICI) therapy as a potential treatment strategy. However, the clinicopathological features and treatment approaches for SMARCA4-deficient tumors of other pathological types remain understudied. Tumor-agnostic therapy is a novel treatment approach that involves using the same molecularly targeted drug across different tumor types sharing a common molecular alteration. Whether this therapeutic strategy can be applied to SMARCA4-deficient tumors warrants investigation. Methods: We retrospectively analyzed the clinicopathological features, prognostic factors, treatment patterns, and clinical outcomes of 66 patients diagnosed with SMARCA4-deficient tumors at Xijing Hospital. Results: Tumors primarily occurred in the thoracic cavity, digestive system, nasal and paranasal sinuses, uterus, ovary, and other sites. Intermediate PD-L1 expression was observed in 42.9% (9/21) of patients. Over half of the tumors expressed Syn, CgA, CD56, and INSM1 (60%, 24/40). Genetic testing (n = 10) identified TP53 and KRAS as the predominant co-mutated genes, with other co-mutated genes including APC, CDKN2B, LRP1B, and PREX2. Thoracic tumors, two or more metastases, and stage IV disease were associated with poor prognosis, whereas surgical intervention was correlated with improved survival. First-line ICI-based combination therapy (n = 6) achieved an objective response rate (ORR) of 33.3%, a disease control rate (DCR) of 66.7%, and a median progression-free survival (mPFS) of 11.8 months. In contrast, later-line therapy (n = 8) resulted in an ORR of 0%, a DCR of 25.0%, and an mPFS of 2.4 months. First-line chemotherapy (n = 9) yielded an ORR of 22.2%, a DCR of 33.3%, and an mPFS of 1.8 months. First-line anti-angiogenic treatments (n = 5) showed an ORR of 0%, a DCR of 40%, and an mPFS of 3.2 months. Conclusions: SMARCA4-deficient tumors exhibit moderate PD-L1 expression and neuroendocrine differentiation features. Surgery can improve patient survival. For patients ineligible for surgery, first-line ICI-based combination therapy across different pathological types is associated with improved survival outcomes. This suggests that ICI-based combination therapy holds potential as a tumor-agnostic treatment strategy for SMARCA4-deficient tumors to overcome the histological and anatomical constraints.
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