Comprehensive Meta-analysis of Key Immune-Related Adverse Events from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients

Abstract

Immune-related adverse events (irAEs) have been described with immune checkpoint inhibitors (ICIs), but the incidence and relative risk (RR) of irAEs associated with these drugs remains unclear. We selected five key irAEs from treatments with approved cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors (ipilimumab, nivolumab or pembrolizumab, and atezolizumab, respectively) to better characterize their safety profile. We performed a meta-analysis of randomized phase II/III immunotherapy trials, with non-ICI control arms, conducted between 1996 and 2016. We calculated the incidence and RR of selected all-grade and high-grade gastrointestinal, liver, skin, endocrine, and pulmonary irAEs across the trials using random-effect models. Twenty-one trials were included, totaling 11,454 patients, of whom 6528 received an ICI (nivolumab, 1534; pembrolizumab, 1522; atezolizumab, 751; and ipilimumab, 2721) and 4926 had not. Compared to non-ICI arms, ICIs were associated with more all-grade colitis (RR 7.66, P < 0.001), aspartate aminotransferase (AST) elevation (RR 1.80; P = 0.020), rash (RR 2.50; P = 0.001), hypothyroidism (RR 6.81; P < 0.001), and pneumonitis (RR 4.14; P = 0.012). Rates of high-grade colitis (RR 5.85; P < 0.001) and AST elevation (RR 2.79; P = 0.014) were higher in the ICI arms. Ipilimumab was associated with a higher risk of all-grade rash (P = 0.006) and high-grade colitis (P = 0.021) compared to PD-1/PD-L1 ICIs. Incidence of fatal irAE was < 1%. This meta-analysis offers substantial evidence that ICIs are associated with a small but significant increase in risk of selected all-grade irAEs and high-grade gastrointestinal and liver toxicities. Although fatal irAEs remain rare, AEs should be recognized promptly as early interventions may alleviate future complications.

Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials

“…The incidence of TRAEs associated with ICIs ranged from 9% to 31%, with a pooled rate of 16% (95% confidence interval, 12%‐21%) 30. Treatment with ICIs was associated with a higher incidence of any‐grade and grade 3 to 4 irAEs (ie, rash, aspartate aminotransferase increase, hypothyroidism, colitis, and pneumonitis) compared with non‐ICI regimens 31. The incidence of IRRs and hypersensitivity reactions occurring with avelumab and other ICIs was similar to or less than the incidence reported with other systemic and targeted treatments, including commonly used taxane‐based chemotherapy 32.…”

Characterization of Thyroid Disorders in Patients Receiving Immune Checkpoint Inhibition Therapy

“…Hypophysitis is more commonly associated with CTLA-4 inhibition, whereas thyroid disorders are more common in patients receiving anti–PD-1 therapy (2, 7, 12, 13). Although the clinical manifestations of immune checkpoint inhibition-related hypophysitis have been well described in several large case series (9–11, 14), few studies have characterized the nature and progression of immune checkpoint inhibition-related thyroid disorders.…”

Requirement of Treg-intrinsic CTLA4/PKCη signaling pathway for suppressing tumor immunity

“…Despite the clinical success of anti-CTLA4 mAb, treatment with anti-CTLA4 mAbs often leads to the development of autoimmune-related adverse events that predominantly affect the skin and the gastrointestinal tract (14). Hence, identifying more specific and efficient strategies aimed at neutralizing the protumor…”