The pattern of time to onset and resolution of immune-related adverse events caused by immune checkpoint inhibitors in cancer: A pooled analysis of 23 clinical trials and 8,436 patients.

Abstract

e15110 Background: Immune checkpoint inhibitors (ICIs) yield remarkable clinical efficacy in the treatment of cancer. With the increasing use of ICI therapies, the dissemination of immune-related adverse events (irAEs) data is essential. This study aimed to investigate the pattern of onset and resolution of ICI-induced irAEs in cancer. Methods: Phase II–III clinical trials with single or multiple arms studying ICI-based treatments in cancer published between January 2007 and December 2019 were included. The pooled median time to onset (PMT-O), resolution (PMT-R), and immune-modulation resolution (PMT-IMR) of irAEs were analyzed based on irAE categories and severity grades using the metamedian package of the R software. Subgroup analyses were performed based on different ICI drugs, ICI doses, and cancer types. Results: Twenty-two eligible studies involving 23 clinical trials and 8,436 patients were included. On average, irAEs occurred at 6.1 weeks (95% confidence interval [95% CI], 5.7–7.4) after the initial ICI-based treatment. The first four irAEs with the shortest PMT-O were hypersensitivity/infusion reaction (3.1 weeks), neurological (4.0 weeks), skin (4.1 weeks), and gastrointestinal (6.1 weeks) events. IrAEs were resolved within 4.5 weeks (95% CI, 4.0–6.1), with the shortest and longest PMT-R for hypersensitivity/infusion reaction (0.1 weeks) and endocrine events (28.7 weeks), respectively. The application of immune-modulation drugs prolonged the general resolution time to 5.9 weeks, with the shortest and longest PMT-IMR for hypersensitivity/infusion reaction (0.2 weeks) and endocrine events (56.6 weeks), respectively. Grade ≥ 3 irAEs showed a significantly longer PMT-O (7.9 vs. 6.1 weeks; P < 0.01) compared with all grade irAEs. Nivolumab + ipilimumab had a significantly shorter PMT-O than nivolumab alone (6.0 vs. 8.2 weeks; P < 0.01). A significantly shorter PMT-O was observed for lung cancer compared with that for melanoma (4.7 vs. 6.1 weeks; P = 0.02). Conclusions: This study revealed the pattern and kinetics of the time to onset and resolution of irAEs in pan-cancers, which will promote the comprehensive understanding, timely detection, and effective management of ICI-induced irAEs.