Risk of Pituitary Immune-Related Adverse Events Caused by Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis.

OBJECTIVES

Immune checkpoint inhibitor (ICI)-induced hypophysitis is one of the common endocrine immune-related adverse events (irAEs). Our goal is to evaluate the risk of pituitary irAEs caused by ICIs.

METHODS

The relevant literatures were retrieved from PubMed, Embase, and Cochrane Library from inception to October 31, 2024. References were screened according to inclusion and exclusion criteria, and study data were extracted. Meta-analysis was performed using Revman 5.3 and Stata 18.0 software.

RESULTS

A total of 21 prospective single-arm trials and 17 randomized controlled trials (RCTs) were included. In single-arm trials, the incidence of hypophysitis (4.00%) and hypopituitarism (3.84%) caused by cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors was the highest in monotherapy, and the incidence of hypophysitis caused by programmed cell death 1 (PD-1) inhibitors plus CTLA-4 inhibitors was the highest in ICI combination therapy (9.36%). In RCTs, the risk of pituitary irAEs caused by ICIs was higher than that of the control group (relative risk = 10.09, 95% CI: 6.90-14.75). Compared with monotherapy, ICI combination therapy has a higher risk of pituitary irAEs (relative risk = 5.42, 95% CI: 3.36-8.73). In monotherapy, CTLA-4 inhibitors caused the highest incidence of hypophysitis and hypopituitarism, reaching 16.17% and 1.75%, respectively. Furthermore, the severity of adverse pituitary irAEs caused by CTLA-4 inhibitors was also the highest (5.12% in single-arm trials, 16.35% in RCTs).

CONCLUSIONS

The results showed that ICIs are associated with a significantly higher risk of pituitary irAEs, and ICI combination may further increase the risk. In monotherapy, CTLA-4 inhibitors caused the highest incidence and severity of pituitary irAEs, while PD-L1 inhibitors caused the lowest. In combination therapy, PD-1 inhibitors combined with CTLA-4 inhibitors resulted in a higher incidence of hypophysitis.