Treatment-related adverse events, immune-related adverse events and discontinuation in patients with solid tumors adding adjuvant immune checkpoint blockade: a meta-analysis of 38 randomized controlled trials.

Background: The safety profile of immune checkpoint blockade (ICB) in the adjuvant setting has not been well characterized. This study aims to summarize the incidences of adverse events (AEs) in patients with solid tumors receiving ICB in adjuvant setting, and evaluate the effect of ICB addition on incidences of these adverse events.

Methods: We searched public databases and relevant international conference proceedings up to 20 September 2024, to identify eligible randomized controlled trials evaluating the ICB-based treatments in adjuvant setting for patients with solid tumors. The primary outcomes included treatment-related death, treatment-related adverse events (TrAEs), immune-related adverse events (IrAEs), serious AEs, and discontinuation due to AEs. The GRADE approach was used to evaluate the certainty of evidence for primary outcomes.

Results: Thirty-eight trials with 25 852 participants were included. Single-arm meta-analysis showed that combination therapies had higher grade 3-4 TrAEs than PD-1/PD-L1 monotherapy, while anti-CTLA-4-based therapies exhibited greater discontinuation rates (49.7% [39.4-60.0] for anti-CTLA-4 monotherapy) versus other ICB strategies. Treatment-related death was rare, occurring in 63 of 16 272 participants receiving adjuvant ICB-based treatments. The pairwise meta-analysis revealed that the addition of ICB was associated with increased treatment-related deaths (OR [95% CI]: 1.713 [1.117-2.628]), although this association was observed only in the CTLA-4 blockade and not in the PD-1 or PD-L1 blockade. ICB addition also increased incidences of TrAEs, IrAEs, serious AEs, and discontinuations, with consistent results across blockade types. Additionally, ICB addition was associated with higher incidences of 37 types of AEs, including 20 grade 3-4 events. Most results had moderate evidence quality.

Conclusion: Adding ICB in adjuvant setting was associated with increased AEs, but the toxicity profile was largely similar to that in the advanced setting.