Prognostic and predictive value of non-steroidal anti-inflammatory drugs in the EORTC 1325/KEYNOTE-054 phase III trial of pembrolizumab versus placebo in resected high-risk stage III melanoma*

Background: Pain is common in patients with cancer. The World Health Organisation recommends paracetamol or non -steroidal anti-inflammatory drugs (NSAIDs) for mild pain and combined with other agents for moderate/ severe pain. This study estimated associations of NSAIDs with recurrence -free survival (RFS), distant metastasisfree survival (DMFS) and the incidence of immune -related adverse events (irAEs) in high -risk patients with resected melanoma in the EORTC 1325/KEYNOTE-054 phase III clinical trial. Patients and methods: Patients with AJCC7 stage IIIA, IIIB or IIIC resected melanoma were randomized to receive 200 mg of adjuvant pembrolizumab (N = 514) or placebo (N = 505) 3 -weekly for one year or until recurrence. As previously reported, pembrolizumab prolonged RFS and DMFS. NSAID use was defined as administration between 7 days pre -randomization and starting treatment. Multivariable Cox and Fine and Gray models were used to estimate hazard ratios (HRs) for associations of NSAIDs with RFS, DMFS and irAEs. Results: Of 1019 patients randomized, 59 and 44 patients in the pembrolizumab and placebo arms, respectively, used NSAIDs. NSAIDs were not associated with RFS (HR 0.91, 95% CI 0.58-1.43) or DMFS in the pembrolizumab (HR 1.03, 95% CI 0.65-1.66) or placebo arms (for RFS, HR 0.76, 95% CI 0.48-1.20; for DMFS, HR 0.80, 95% CI 0.49-1.31). NSAIDs were associated with the incidence of irAEs in the placebo arm (HR 3.06, 95% CI 1.45-6.45) but not in the pembrolizumab arm (HR 0.94, 95% CI 0.58-1.53). Conclusion: NSAIDs were not associated with efficacy outcomes nor the risk of irAEs in patients with resected high -risk stage III melanoma receiving adjuvant pembrolizumab.