Discontinuation Risk from Adverse Events: Immunotherapy Alone vs. Combined with Chemotherapy: A Systematic Review and Network Meta-analysis

Abstract

Abstract Background While immunotherapy combined with chemotherapy (Chemo-IO) is generally recognized for providing superior outcomes compared to monotherapy (mono-IO), it is associated with a higher incidence of treatment-related adverse events (TRAEs). However, there have been few direct comparisons of treatment discontinuation rates between these two treatments. In this study, we compared the rates of treatment discontinuation between mono-IO and Chemo-IO as first-line treatments for various solid tumors. Methods We systematically reviewed clinical trials from databases (PubMed, Embase, Cochrane Library, and an additional source) published from January 1, 2018, to July 10, 2023. We included phase III randomized controlled trials (RCTs) that utilized immunotherapy agents in at least one arm as first-line treatments for a variety of solid tumors. Data extraction followed the Preferred Reporting Items for Systematic Reviews (PRISMA) extension statement for network meta-analysis. A random effects model was used for the network meta-analysis, with the risk of bias assessed using the Cochrane risk-of-bias tool II. The primary outcomes encompassed treatment discontinuation rates due to TRAEs among patients who underwent immunotherapy, either alone or combined with chemotherapy, for various solid tumors. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated to compare between treatment groups. Results From 29 RCTs, a total of 21,677 patients and 5 types of treatment were analyzed. Compared to mono-IO, Chemo-IO showed a significantly higher rate of discontinuation due to TRAEs (RR 2.68, 95% CI 1.98–3.63). Subgroup analysis for non-small cell lung cancer (NSCLC) patients also exhibited a greater risk of discontinuation due to TRAEs with Chemo-IO compared to mono-IO (RR 2.93, 95% CI 1.67–5.14). Additional analyses evaluating discontinuation rates due to either treatment emergent adverse events (TEAEs) or AEs regardless of causality (any AEs) consistently revealed an elevated risk associated with Chemo-IO. Conclusions Chemo-IO was associated with an elevated risk of treatment discontinuation not only due to TRAEs but also any AEs or TEAEs. Given that the treatment duration can impact clinical outcomes, a subset of patients might benefit more from mono-IO than combination therapy. Further research is imperative to identify and characterize this subset.