The Safety of Immunosuppressants Used in the Treatment of Immune-Related Adverse Events of Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

Introduction: Immune checkpoint inhibitor (ICI) use can lead to immune-related adverse events (irAEs) that require treatment with immunosuppressive medications in moderate to severe cases. Oncology society guidelines typically recommend systemic steroids and other potent immunosuppressants such as infliximab and vedolizumab for refractory cases. Scarce information is available about the safety and prospective harms of using these immunosuppressants. Hence, we investigated the safety of different immunosuppressants used in treating ICI-related irAEs. Methods: We performed a systematic review of studies reporting irAEs and their medical management with immunosuppressants in adult cancer patients. We searched MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov from inception through September 1, 2022, using the following keywords or their equivalents: ICI, immunosuppressant, and irAE. We extracted observational studies and clinical trials that matched our criteria. A random effects model was used to estimate the overall incidence of infections associated with the treatment of irAEs. Results: Among the 11 studies included in this review (1036 total patients), melanoma (548 patients, 52.9%) was the most common primary cancer, followed by lung cancer (139 patients, 13.4%) and genitourinary cancers (131 patients, 12.6%). PD-1/PD-L1 monotherapy (460 patients, 44.4%) was used most, followed by a combination of PD-1/PD-L1 and CTLA-4 therapy (350 patients, 33.8%) and CTLA-4 monotherapy (226 patients, 22%). A total of 1044 (101%) patients had their irAEs (mainly colitis and hepatobiliary toxic effects) treated with systemic steroids; 335 patients (32.3%) were also treated with infliximab (mainly for colitis). Our review found 22.3% of patients treated for irAEs had infectious adverse events (95% CI: 15.6%–29.1%, P< 0.001). Among the 3 studies reporting the types of infections (41 total patients), bacterial (80.5%), followed by fungal (36.6%), infections were most common (Figure 1). Conclusion: Adverse events from irAE treatment occurred in about one-third of patients that received either steroids or a combination of steroids and other immunosuppressants. Clinicians should be aware of these immunosuppressant-related adverse effects, which can negatively impact cancer treatment and patient outcomes, when treating irAEs and consider shortening treatment duration or using alternative strategies when possible to mitigate these complications.Figure 1.: A. PRISMA flow diagram of study selection. B. Forest plot of the pooled infections adverse events from treatment of irAE.