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

Abstract

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‰-8.4‰). 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. Electronic supplementary material The online version of this article (10.1186/s12885-019-5785-z) contains supplementary material, which is available to authorized users.

Autoimmune complications of immunotherapy: pathophysiology and management

“…Patients treated with anti-PD-1 or anti-PD-L1 (“anti-PD-(L)1”) antibodies have a similar total incidence of irAEs, 74% (69 to 79), but fewer high-grade irAEs, 14% (12 to 16) 9. Combination therapy with anti-CTLA-4 plus anti-PD-1 antibodies is associated with the highest incidence of irAEs overall, 88% (84 to 92), and of high grade irAEs, 41% (35 to 47) 10. A three arm clinical trial in 945 patients with advanced melanoma that directly compared anti-CTLA-4 monotherapy with anti-PD-1 monotherapy with the combination of anti-CTLA-4 monotherapy and anti-PD-1 monotherapy, showed treatment related adverse events in 85%, 82%, and 96%, and high grade adverse events in 27%, 16%, and 55%, respectively 11…”

Immunotherapy in Corticotroph and Lactotroph Aggressive Tumors and Carcinomas: Two Case Reports and a Review of the Literature

“…Here, we report two cases. First, we present the response of a functioning corticotroph carcinoma to a different dosing regimen of combined immunotherapy with ipilimumab and nivolumab than the one already reported in literature (chosen based on a better tolerance with comparable efficacy of this regimen in other cancers [ 9 , 10 , 11 ]). Second, we present the first reported case of an aggressive prolactinoma treated with immunotherapy.…”

Review A meta-analysis of the efficacy and safety of additional anti-HER2-targeting drugs in HER2-positive advanced breast cancers

“…The AEs and cardiotoxicity involved were also used by risk ratio (RR) and a 95%CI to represent. We used the Begg's and Egger's test to evaluate publication bias and the Stata 12.0 Software to perform the sensitivity bias [26]. Because this study included a variety of treatments, we used a random-effects model in order to increase credibility.…”