Immune checkpoint inhibitor–induced arthralgia is tightly associated with improved overall survival in cancer patients

Abstract Objectives With the increased use of immune checkpoint inhibitors (ICIs) in cancer patients, arthralgia has been the most commonly reported musculoskeletal immune-related adverse event (irAE). We aimed to characterize arthralgia and its association with overall survival (OS). Material and methods Randomized controlled trials (RCTs) reporting on data for ICI-induced arthralgia from four online databases were comprehensively investigated. Odds ratios (ORs) with 95% CIs were calculated for arthralgia using a random-effects model meta-analysis. Individual patient data were reconstructed from RCTs assessing OS in patients with or without ICI-induced arthralgia. We also retrospectively collected data on the clinical features and outcomes of ICI-induced arthralgia in the Yokohama City University (YCU) registry. Results We analysed 14 377 patients from 24 RCTs. The OR of ICI-induced arthralgia was 1.37 (95% CI 1.20, 1.56). Of the 369 patients in the YCU registry, 50 (13.6%) developed ICI-induced arthralgia. Among them, 30 had other grade ≥2 irAEs, which was noticeably more frequent than in those without arthralgia (OR 1.92, 95% CI 1.04, 3.52). By irAE types, a significant difference was found for relative adrenal insufficiency (OR 3.88, 95% CI 1.80, 8.39). In the YCU registry, patients with (vs without) ICI-induced arthralgia had better OS (log-rank, P < 0.001). OS results were validated from RCT patients with matched cancer types, drugs, and time to arthralgia onset (hazard ratio 0.34, 95% CI 0.17, 0.65, P < 0.001). Conclusions If arthralgia develops after ICIs, another irAE, such as relative adrenal insufficiency, may have developed. The incidence of arthralgia was associated with better OS, and the condition of patients with irAEs must be carefully evaluated to determine optimal management.