Yanlin Li, Xiaohui Jia, Mengjie Liu, Zehui Zhu, Hui Qiao, Jun Jiang, Miao Li, Weihu Xia, Longwen Xu, Enyong Zhang, Wenjuan Wang, Juan Liu, Rui Xu, Yujuan Qi, Guoqing Jing, Yixue Bai, Min Jiao, Senyi Hu, Zhiyan Silvia Liu, Hui Guo, Lili Jiang
BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used medications in non-small cell lung cancer (NSCLC). We comprehensively evaluated the effect of NSAID exposure patterns on immunotherapy outcomes, prostaglandin E2 (PGE2) and immune cells. METHODS: This multicenter study employed both prospective and retrospective approaches for patient enrollment. Patients were included if they had advanced NSCLC, and were first-time users of immune checkpoint inhibitor (ICI). Endpoints included progression-free survival (PFS) and overall survival (OS). Serum and tumor tissue were collected in the prospective subset for PGE2 and immune cell assay. RESULTS: A total of 1,748 patients were included, with 232 patients prospectively enrolled. After multivariable adjustment, NSAID use was independently associated with improved PFS (HR 0.72, 95% CI 0.58 to 0.91, p=0.0053) and OS (HR=0.76, 95% CI 0.58 to 0.98, p=0.0364). Benefit was observed for both before-ICI (HR 0.75, 95 % CI 0.57 to 0.99, p=0.0383) and after-ICI initiation (HR 0.63, 95% CI 0.43 to 0.92, p=0.0159). For aspirin, low-dose aspirin users had better PFS than non-users (HR 0.69, 95% CI 0.51 to 0.94, p=0.0191), especially when used at least 30 days (HR=0.69, 95% CI 0.48 to 0.99, p=0.0464). Among non-selective NSAIDs, only after-ICI initiation improved OS (HR=0.49, 95% CI 0.24 to 0.99, p=0.0458). Any-grade (57.8% vs 53.4%) and grade ≥3 adverse events (9.2% vs 9.8%) were comparable among NSAID users and non-users. Serum sample indicated that aspirin was associated with less PGE2, which was related to better outcomes. On immune cells, RNA-seq revealed a correlation between the cyclooxygenase-2 pathway and neutrophils. Biosample analysis further demonstrated that aspirin use was associated with decreased neutrophils in both circulation and tumor. CONCLUSIONS: Long-term low-dose aspirin enhanced immunotherapy efficacy in patients with advanced NSCLC. PGE2 and neutrophils represented potential biomarkers guiding NSAID-immunotherapy integration. TRIAL REGISTRATION NUMBER: NCT05754983.