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 treatment-related 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 1·76, 95% CI 0·95–3·25; p=0·073), 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 [15·0%]); 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 2·73, 95% CI 1·98–3·76; p<0·0001), adverse events leading to treatment discontinuation (3·67, 2·45–5·51; p<0·0001), and treatment-related adverse events of any grade (2·60 [1·88–3·61], p<0·0001). The immune checkpoint blockade versus placebo design primarily used as adjuvant therapy was associated with increased incidence of treatment-related deaths (4·02, 1·04–15·63; p=0·044) and grade 3–4 adverse events (5·31, 3·08–9·15; p<0·0001), whereas the addition of immune checkpoint blockade in the neoadjuvant setting was not associated with increased incidence of treatment-related death (1·11, 95% CI 0·38–3·29; p=0·84) or grade 3–4 adverse events (1·17, 0·90–1·51; p=0·23). 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. Funding None.