Abstract
Background: Although clinical practice guidelines for the management of Immune Checkpoint Inhibitor (ICI)-related adverse events have recently been published, precise and nuanced toxicity data for combination ICI therapy are lacking. Therefore, herein we have conducted a systematic review and meta-analysis of published clinical trials on combination ICI to synthesize the treatment-related adverse event (TRAE) profile of combination ICI therapy.Methods: PUBMED, EMBASE, and the Cochrane Database/EBM were searched for eligible studies. Clinical trials evaluating combination immune checkpoint inhibitor therapy in advanced unresectable cancer were included in the analysis based on prespecified criteria. Risk of bias across studies was evaluated using Begg's funnel plot and Egger's regression test. The summary outcomes were pooled risk ratios (RR) and the logit-transformed proportion for incidence data.Results: A total of 18 studies comprising 2,767 patients across 10 cancer types were included in the final analysis. Combination ICI was associated with a slightly higher risk of all-grade adverse events (RR 1.07 [95% CI 1.03–1.11]) and markedly greater risk of grade 3 or higher adverse events (RR 2.21 [95% CI 1.57–3.10]) compared to monotherapy ICI. Subgroup analyses showed significant differences in risk of grade 3 or higher adverse events between treatment types (PD-1 + CTLA-4 and PD-L1 + CTLA-4), among cancer types, and among dosing regimens (N1I3, N3I1, and D20T1). The incidence of all-grade adverse events was 0.905 [95% CI 0.842–0.945], and the ratio of grade 3 or higher events to all-grade adverse events was 0.396 [95% CI 0.315–0.483]. The most common all-grade TRAEs were diarrhea/colitis, fatigue/asthenia, nausea/vomiting, rash, and pruritis.Conclusion: Combination ICI therapy has a significantly different treatment-related adverse event profile compared to monotherapy.
Highlights
Within a short span of time, with increasingly frequent use of immune checkpoint inhibitors across different types of cancer, knowledge and experience with immune checkpoint inhibitor (ICI)-related adverse events has been increasingly accumulating [1,2,3,4,5,6]
Combination ICI was associated with a slightly higher risk of all-grade adverse events (RR 1.07 [95% confidence intervals (CI) 1.03–1.11]) and markedly greater risk of grade 3 or higher adverse events (RR 2.21 [95% CI 1.57–3.10]) compared to monotherapy ICI
Combination ICI therapy has a significantly different treatment-related adverse event profile compared to monotherapy
Summary
Within a short span of time, with increasingly frequent use of immune checkpoint inhibitors across different types of cancer, knowledge and experience with immune checkpoint inhibitor (ICI)-related adverse events has been increasingly accumulating [1,2,3,4,5,6] Based on these accumulated data, clinical practice guidelines have been published to improve the management of these adverse events [7]. There is a general consensus that combination ICI therapy results in higher risk of TRAEs compared to ICI monotherapy, data are unclear on whether this risk differs with different ICI combinations or across different cancer types and whether there are notable associations with certain ICI combinations and specific TRAEs [7, 8] It is unclear whether the severity and frequency of adverse events are synergistic or just additive. We have conducted a systematic review and meta-analysis of published clinical trials on combination ICI to synthesize the treatment-related adverse event (TRAE) profile of combination ICI therapy
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