The Safety of Immunosuppressants Used in the Treatment of Immune-Related Adverse Events due to Immune Checkpoint Inhibitors: a Systematic Review

Abstract

Purpose: 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 recommend systemic steroids and immunosuppressants such as infliximab and vedolizumab for the treatment of refractory cases. Limited information is available about the safety profile and potential adverse effects of these immunosuppressants. We have investigated the safety profile of multiple immunosuppressants which are used in the treatment of ICI-related irAEs. Methods: We performed a systematic review of studies reporting irAEs, from ICI use, 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 1024 (98.8%) patients had their irAEs treated with systemic steroids with majority having colitis and hepatobiliary irAEs; 335 patients (32.3%) were also treated with infliximab (mainly for colitis). Our review found 22.3% of patients treated for irAEs developed 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. Conclusions: 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, future prospective studies should further investigate the safety of immunosuppressants in treating irAEs.

Sargramostim for Prophylactic Management of Gastrointestinal Immune-Related Adverse Events of Immune Checkpoint Inhibitor Therapy for Cancer

“…Currently, the treatment for GI irAEs begins after the onset of symptoms using broad immune suppression; while generally effective, this approach runs the risk of inhibiting optimal anti-tumor responses. In particular, systemic glucocorticoids and TNF inhibitors may reduce the full benefit of immunotherapy [109,110]. A number of investigators have recognized the similarities between GI irAEs and IBD.…”

Outcomes of Budesonide as a Treatment Option for Immune Checkpoint Inhibitor-Related Colitis in Patients with Cancer

“…Our group has previously shown that the length of systemic steroid exposure can independently increase the risk of infection in a cancer patient population with a significantly higher risk when used for >30 days [8,22]. Furthermore, a recent systematic review assessing the safety profile of immunosuppressants in the management of irAEs which included 11 studies (1036 patients) showed that adverse events from irAE therapy occurred in about one-third of patients that received either systemic steroids or a combination of the same and other immunosuppressants [5]. Burdett et al [23] showed that patients receiving steroids to treat irAEs had heterogeneous results regarding their cancer outcomes.…”

“…Immune-mediated colitis (IMC) has been reported in up to 40% of patients treated with ICIs, varies widely in severity [2,3], and can be a cause for discontinuation of ICI therapy [4]. Failure in early recognition and delayed or suboptimal treatment can lead to an increased risk of complications such as bowel perforation [5].…”