Treatment-related adverse events, including fatal toxicities, in patients with solid tumours receiving neoadjuvant and adjuvant immune checkpoint blockade: a systematic review and meta-analysis of randomised controlled trials

Background Incorporating immune checkpoint blockade into perioperative cancer therapy has improved clinical outcomes. However, the safety of immune checkpoint blockade needs better evaluation, given the chances of more prolonged disease-free survival. We aimed to assess how adding immune checkpoint blockade to perioperative therapy affects treatment-related adverse events. Methods For this systematic review and meta-analysis, we searched PubMed/MEDLINE, Embase, Web of Science, and the Cochrane Library from database inception until Aug 8, 2023, for randomised controlled trials that assessed the addition of immune checkpoint blockade to neoadjuvant or adjuvant therapy for cancer, reported treatmentrelated deaths, and had a design in which the experimental group assessed immune checkpoint blockade in combination with the therapy used in the control group. Meta-analysis was done to pool odds ratios (ORs) of treatment-related deaths, any grade and grade 3-4 treatment-related adverse events, serious adverse events, and adverse events leading to treatment discontinuation. The protocol is registered with PROSPERO, CRD42022343741. Findings 28 randomised controlled trials with 16 976 patients were included. The addition of immune checkpoint blockade was not significantly associated with increased treatment-related deaths (OR 1 center dot 76, 95% CI 0 center dot 95-3 center dot 25; p=0 center dot 073), consistent across immune checkpoint blockade subtype (I2=0%). 40 fatal toxicities were identified across 9864 patients treated with immune checkpoint blockade, with pneumonitis being the most common (six [15 center dot 0%]); 13 fatal toxicities occurred among 7112 patients who were not treated with immune checkpoint blockade. The addition of immune checkpoint blockade increased the incidence of grade 3-4 treatment-related adverse events (OR 2 center dot 73, 95% CI 1 center dot 98-3 center dot 76; p<0 center dot 0001), adverse events leading to treatment discontinuation (3 center dot 67, 2 center dot 45-5 center dot 51; p<0 center dot 0001), and treatment-related adverse events of any grade (2 center dot 60 [1 center dot 88-3 center dot 61], p<0 center dot 0001). The immune checkpoint blockade versus placebo design primarily used as adjuvant therapy was associated with increased incidence of treatment-related deaths (4 center dot 02, 1 center dot 04-15 center dot 63; p=0 center dot 044) and grade 3-4 adverse events (5 center dot 31, 3 center dot 08-9 center dot 15; p<0 center dot 0001), whereas the addition of immune checkpoint blockade in the neoadjuvant setting was not associated with increased incidence of treatmentrelated death (1 center dot 11, 95% CI 0 center dot 38-3 center dot 29; p=0 center dot 84) or grade 3-4 adverse events (1 center dot 17, 0 center dot 90-1 center dot 51; p=0 center dot 23). Interpretation The addition of immune checkpoint blockade to perioperative therapy was associated with an increase in grade 3-4 treatment-related adverse events and adverse events leading to treatment discontinuation. These findings provide safety insights for further clinical trials assessing neoadjuvant or adjuvant immune checkpoint blockade therapy. Clinicians should closely monitor patients for treatment-related adverse events to prevent treatment discontinuations and morbidity from these therapies in earlier-stage settings. Copyright (c) 2023 Elsevier Ltd. All rights reserved.