Clinical characteristics and association with immunotherapy outcomes in SMARCA4-deficient NSCLC

Abstract Introduction: SMARCA4, also known as transcription activator, is an ATP-dependent catalytic subunit of SWI/SNF chromatin-remodeling complexes that participates in the regulation of chromatin structure and gene expression by supplying energy. SMARCA4-deficient lung cancer has been recognized as a distinct subtype based on subtle differences in its clinical, morphological, and immunophenotypic attributes compared to other NSCLC. Chemotherapy combined with immune checkpoint inhibitors are currently most commonly used in clinical practice, the effect of immunotherapy in SMARCA4-deficient lung cancer is now contradictory. We designed this study to characterize the clinicopathological features and immunotherapy outcomes of SMARCA4-deficient NSCLC patients. Methods: 8827 patients who underwent SMARCA4 detection by immunohistochemistry between January 2018 to January 2022 were enrolled in this retrospective study. 33 patients diagnosed with advanced SMARCA4-deficient NSCLC and 59 operable SMARCA4-deficient NSCLC were selected, and propensity score matching(PSM) was utilized to match the SMARCA4-deficient group. Clinical characteristics were collected and clinical outcomes to treatment were evaluted. Results: Among 8827 patients, 300 patients were advanced stage and 8527 patients were after operation. Of all advanced stage patients, 33(11%) were SMARCA4-deficient. Compared with SMARCA4-intact patients, SMARCA4-deficient NSCLC was significantly associated with smoking history, decreased PD-L1 expression and less squamous carcinoma. 57(0.6%) patients were resectable SMARCA4-deficient NSCLC. Among them, the majority(38.6%) was stage III patients and 15(26.3%) patients had relapsed. Majority patients were negative for markers including p40 and CK5/6. SMARCA4-deficient patients had worse PFS than SMARCA4-intact patients(p = 0.04). Totally 15 patients received immunotherapy, these patients showed better PFS than those without immunotherapy (8.05 months vs 3.8 months), due to the small sample size, the data were not statistically significant(p = 0.26). Conclusion: The current results showed that SMARCA4-deficient NSCLC has unique clinical features and are more aggressive, often diagnosed at advanced stage, tend to relapse after surgery. The efficacy of immunotherapy might bring survival benefits but need to be observed for longer periods.