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 allgrade 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.
Background: Given the inconclusive evidence behind the safety and efficacy of immune checkpoint inhibitors re-challenge, herein, we have conducted a systematic review and meta-analysis to synthesize available data. Results/methodology: PubMed, Embase, Cochrane Database, and ASCO and ESMO were searched for studies published from conception to March 2020. Pooled incidence of recurrent immune-related adverse events (irAEs), objective response rates, and odds ratios for irAEs at initial versus re-treatment were calculated. Overall, 437 patients (ten studies) were included. Incidence of any grade, grade 3/4, and steroid-requiring recurrent irAEs were 47%, 13.2%, and 26% respectively. Objective response rate in previous non-responders was 12.5% (5.8–24.8%). Odds ratio for severe irAEs was 0.28 (0.11–0.72) and steroid-requiring irAEs 0.19 (0.06–0.56). Discussion/conclusion: This analysis suggests that immune checkpoint inhibitors re-challenge is safe and potentially efficacious.
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