The safety and tolerability of combined immune checkpoint inhibitors (anti-PD-1/PD-L1 plus anti-CTLA-4): a systematic review and meta-analysis

Background: The future of combined immunotherapy (a PD-1/PD-L1 plus a CTLA-4 antagonist) is very bright. However, besides improving efficacy, combined therapy increases treatment-related adverse events (TRAEs). Also, the clinical application is limited in some solid tumors. Methods: This paper purports to investigate the TRAEs for the combined immunotherapy aiming for a more appropriate utilization of immune checkpoint inhibitors (ICIs) in clinical practice through a meta-analysis. Results: A total of 17 eligible studies covering 2626 patients were selected for a meta-analysis based on specified inclusion and exclusion criteria. The incidence rates of any grade and grade 3 or higher TRAEs were 88% (95%CI, 84-92%) and 41% (95%CI, 35-47%), respectively. The overall incidence of any grade TRAEs leading to discontinuation of treatment was 20% (95%CI, 16-24%). The incidence rate of treatment related deaths was 4.3 (95%CI, 1.4 parts per thousand-8.4 parts per thousand). Analysis showed that NIVO1+IPI3 cohort had higher incidences of grade 3 or higher TRAEs (RR=1.77, 95%CI, 1.34-2.34, p<0.0001) and any grade TRAEs leading to discontinuation of treatment (RR=1.81, 95%CI, 1.08-3.04, P=0.02), compared with NIVO3+IPI1 regimen. Conclusions: The combined therapy had high TRAEs. The TRAEs, especially grade 3 or higher, led to discontinuation of the treatment. Furthermore, the incidence of treatment-related deaths was rare. Moreover, the NIVO3+IPI1 regimen, regardless of efficacy, is more recommended because of better tolerance and lower adverse events.