Immune checkpoint inhibitor‐associated pituitary‐adrenal dysfunction: A systematic review and meta‐analysis

Abstract

With the growing use of immune checkpoint inhibitors (ICIs), case reports of rare yet life‐threatening pituitary‐adrenal dysfunctions, particularly for hypopituitarism, are increasingly being published. In this analysis, we focus on these events by including the most recent publications and reports from early phase I/II and phase III clinical trials and comparing the incidence and risks across different ICI regimens. PubMed, Embase, and the Cochrane Library were systematically searched from inception to April 2019 for clinical trials that reported on pituitary‐adrenal dysfunction. The rates of events, odds ratios (ORs), and 95% confidence intervals (CIs) were obtained using random effects meta‐analysis. The analyses included data from 160 trials involving 40 432 participants. The rate was 2.43% (95% CI, 1.73%‐3.22%) for all‐grade adrenal insufficiency and 3.25% (95% CI, 2.15%‐4.51%) for hypophysitis. Compared with the placebo or other therapeutic regimens, ICI agents were associated with a higher incidence of serious‐grade adrenal insufficiency (OR 3.19, 95% CI, 1.84 to 5.54) and hypophysitis (OR 4.77, 95% CI, 2.60 to 8.78). Among 71 serious‐grade hypopituitarism instances in 12 336 patients, there was a significant association between ICIs and hypopituitarism (OR 3.62, 95% CI, 1.86 to 7.03). Substantial heterogeneity was noted across the studies for the rates of these events, which in part was attributable to the different types of ICIs and varied phases of the clinical trials. Although the rates of these events were low, the risk was increased following ICI‐based treatment, particularly for CTLA‐4 inhibitors, which were associated with a higher incidence of pituitary‐adrenal dysfunction than PD‐1/PD‐L1 inhibitors.

Management of endocrine immune-related adverse events of immune checkpoint inhibitors: an updated review

“…Several authors have reported high IH frequencies (11–13%) ( 15 , 16 ) and relative risk for all-grade IH as high as 22.03 ( 17 ). However, according to the latest reviews and meta-analyses IH incidences are lower but they notably depend on the type of ICI used and the treatment regimen ( 1 , 18 , 19 , 20 , 21 , 22 , 23 ). Combination therapy has been associated with the highest estimated incidence of IH, ranging from 7.7 to 10.5%, remarkably higher than monotherapy with anti-CTLA-4 (1.8–5.6%) or anti-PD-1 drugs (0.3–1.1%) ( 1 , 18 , 19 , 20 , 21 , 22 , 23 ).…”

Endocrine Adverse Events Caused by Different Types and Different Doses of Immune Checkpoint Inhibitors in the Treatment of Solid Tumors: A Meta‐Analysis and Systematic Review

“…In this study, among the three types of ICIs, only patients treated with CTLA‐4 inhibitors were at higher risk of primary adrenal insufficiency. The reason might be that the PD‐1/PD‐L1 axis activated restricted subsets of T cells in the tumor microenvironment and circulation 44 . However, the CTLA‐4 immune checkpoint participated in the early phase of the immune response during T‐cell priming and activation and enhanced the immunosuppressive activity of Treg cells, thus having a broad impact on the immune system 45 .…”

“…The reason might be that the PD-1/PD-L1 axis activated restricted subsets of T cells in the tumor microenvironment and circulation. 44 However, the CTLA-4 immune checkpoint participated in the early phase of the immune response during T-cell priming and activation and enhanced the immunosuppressive activity of Treg cells, thus having a broad impact on the immune system. 45 Therefore, plasma cortisol rhythm and blood electrolyte levels should be monitored in patients with tumors treated with ICIs, especially CTLA-4 inhibitors.…”

Systemic adverse effects and toxicities associated with immunotherapy: A review

“…Pituitary dysfunction and adrenal insufficiency have also been well documented irAEs of ICI therapy. In a meta-analysis conducted by Lu et al [ 28 ], the incidence of adrenal insufficiency was found to be 2.43% (95%CI: 1.73%-3.22%), while the rate of hypophysitis was reported to be 3.25% (95%CI: 2.15%-4.51%). Hypophysitis most frequently occurs secondary to CTLA-4 inhibitor therapy[ 28 ].…”

“…In a meta-analysis conducted by Lu et al [ 28 ], the incidence of adrenal insufficiency was found to be 2.43% (95%CI: 1.73%-3.22%), while the rate of hypophysitis was reported to be 3.25% (95%CI: 2.15%-4.51%). Hypophysitis most frequently occurs secondary to CTLA-4 inhibitor therapy[ 28 ]. The specific mechanism is not well understood; however, multiple theories are currently being investigated.…”