Impact of NSAID type, initiation timing, duration and dose on clinical outcomes of immunotherapy in NSCLC: a multicenter two-cohort study

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.