A meta-analysis of immune-related adverse events (irAE) of immune checkpoint inhibitors (ICI) from cancer clinical trials

Abstract

Background: Targeting immune checkpoints is a novel and growing strategic approach in cancer therapy. This strategy may trigger irAE. We hypothesize that more patients ( pts) will develop irAE with ICI targeting only immune cells compared to ICI targeting tumor cells as well (PD-L1). In addition, we want to determine specific irAE profile and overall response rate (ORR) for each of the ICI by target(s). Methods:We reviewed all ICI cancer clinical trials (103; 201 arms) that reported irAE and were published on PubMed or presented at an ASCO meeting (only if not published on PubMed) during 2005-2015. 127 arms from 81 trials were eligible for this meta-analysis (11400 pts). We collected and compared arm-specific data including ICI target, number of pts with irAE any grade, grade 3+ and grade 5, specific irAE, and ORR. R package "meta" was used for the meta-analysis to calculate and compare % of pts with irAE and ORR. Results: 23 studies with 2392 pts from 34 arms treated with ICI reported the incidence (%) of patients with any grade irAE per immune checkpoint target inhibition. The majority of arms (91%) and pts (88%) studied were on phase 1/2 clinical trials. Pts were treated for solid malignancy on 33 arms (97%), mainly melanoma (44.1%). No arms included ICI combinations. Incidence (%) of pts with irAE any grade was higher with ICI targeting CTLA-4 (54%) than PD-1 (26%) and PD-L1 ICI (13.7%) (P <0.001). % pts with irAE grade 3+ was higher with ICI targeting CTLA-4 (19%) than ICI targeting PD-1 or PD-L1 (P <0.001). irAE grade 5 was not significantly different among different ICI (<1%). Conclusions: Our meta-analysis supported our mechanistic-driven hypothesis that ICI targeting only immune cells caused more pts to develop irAE. Most specific irAE % and ORR were highest with PD-1/CTLA-4 ICI combination. Our observation is important to guide designing future ICI combination clinical trials. We encourage investigators to report % pts with global irAE in ICI trials. (Table presented).