Gastrointestinal, pancreatic, and hepatic toxicity profile of CTLA-4 immune checkpoint inhibitors alone and in combination with PD-1/PD-L1 inhibitors: A meta-analysis of clinical trials.

Abstract

e14117 Background: Cytotoxic T-lymphocyte activator-4 immune checkpoint inhibitors (CTLA-4-ICPI) is believed to cause more toxicity than programmed cell death/Ligand-1 (PD-1/PD-L1) ICPIs. We conducted a meta-analysis to outline the gastrointestinal (GI), pancreatic, and hepatic toxicity of CTLA-4 ICPIs when used alone and in combination with PD-1/PD-L1 ICPIs (C-ICPI). Methods: Ovid MEDLINE, EMBASE, Cochrane Library, SCOPUS, Web of Science, ClinicalTrials.gov, and WHO ICTRP were queried from January 2007-October 2018. Clinical trials reporting ICPI associated adverse events (AEs) were included. Colitis was defined as the development of diarrhea or documented colitis of any grade. Pancreatitis was defined as an elevation of amylase or lipase. Hepatitis was defined as elevation of ALT, AST, or transaminitis of any grade. A meta-analysis of proportions was conducted to report pooled AEs rate with 95% confidence intervals (CI) using a random effects model. Results: Overall, 30 study arms (20 CTLA-4, 10 C-ICPI) enrolling 3721 patients were included. There were a total of 3944 and 3317 AEs with CTLA-4 and C-ICPI use, respectively, with a pooled incidence of high grade AEs (grade 3-5; HAEs) of 23% (95% CI 16-33%) with CTLA-4 use and 52% (95% CI 37-67%) with C-ICPI use ( Table). The incidence of high-grade colitis was higher among patients treated with CTLA-4 ICPI. The proportion of high-grade pancreatitis was higher among patient who received C-ICPI. Two GI perforations were reported with CTLA-4 use. Pooled incidence of treatment related mortality was 1% in both groups. Conclusions: Though the overall GI, hepatic and pancreatic safety profile of CTLA-4 is comparable to C-ICPI, a higher incidence of high-grade colitis was found with CTLA-4. Two GI perforations were reported with CTLA-4 and warrant further investigation. No difference in treatment related mortality was found among the two groups. [Table: see text]

Checkpoint Inhibitor-Induced Colitis—A Clinical Overview of Incidence, Prognostic Implications and Extension of Current Treatment Options

“…A meta-analysis of clinical trial data consisting of 3721 patients from 30 study arms showed a 27% rate of colitis (95% CI 19–34%) when anti-CTLA-4 ICIs were used (20 CTLA-4 therapy study arms, 10 combined PD-1/PD-L1 and CTLA-4 therapy study arms), and 58% (95% CI 41–76%) of these had colitis of grade 3–5 in severity. In contrast, only 11% (95% CI 7–15%) had colitis when receiving combination therapy with PD-1/PD-L1 and CTLA-4, of which only 15% (95% CI 8–22%) were of a more severe grade (grade 3–5) [ 53 ].…”

Bacterial Metabolism-Initiated Nanocatalytic Tumor Immunotherapy

“…The advances in cancer immunotherapy have brought new opportunities to the field of oncology [ 1 – 3 ]. Although therapies that block T-cell immunosuppressive pathways, such as PD-1/PD-L1 and CTLA-4 inhibitors, can activate the adaptive immune system and have achieved unprecedented clinical advances, overall response rates in the treated patients remain low at the current stage [ 4 – 6 ]. Crafty malignant cells can easily evade the surveillance, recognition, and attack of the immune system by leveraging various strategies, resulting in the failure of antitumor immunotherapies [ 7 – 9 ].…”