OBJECTIVES: Combination immune checkpoint inhibitors (cICPi) are widely used despite limited understanding of its benefits over single-agent immunotherapy. cICPi can produce debilitating and life-threatening immune-related adverse events. We performed a systematic review and meta-analysis to examine the safety of nivolumab and ipilimumab versus nivolumab alone among cancer patients.

METHODS: A systematic literature review was conducted using Medline-Ovid, PubMed, The Cochrane Library, to identify original articles published in English until June 2018. We also searched the conference abstracts presented at the conferences at National Comprehensive Cancer Network and American Society of Clinical Oncology, for studies on nivolumab and ipilimumab in cancer. RevMan was used to perform meta-analysis to evaluate the pooled risk ratio (RR) and its 95% confidence interval (CI) of adverse events. I² statistics was examined to evaluate heterogeneity between the studies. The Cochrane Risk of Bias tool was used to assess the study quality of the randomized controlled trials (RCT).

RESULTS: Three RCTs were identified and included in the meta-analysis. Compared to nivolumab monotherapy, concomitant use of nivolumab with ipilimumab showed an increased risk of adverse events of any grade (RR=1.17, 95% CI=1.11-1.23, I²=78%), colitis, diarrhea, hypothyroidism, and pneumonitis. In addition, use of combination therapy showed increased risk of grade III/IV adverse events (RR=2.10, 95% CI=1.79-2.46, I²=78%), grade III/IV colitis (RR=7.75, 95% CI=2.78-21.62, I²=0%), and grade III/IV diarrhea (RR=3.69, 95% CI=1.89-7.23, I²=0%) compared to nivolumab monotherapy.

CONCLUSIONS: cICPi increase the risk of grade III/IV adverse events including colitis and diarrhea. Our findings will help guide oncology providers in identifying candidates for cICPi versus single-agent therapy.