A meta-analysis of 38 randomized clinical trials including 7,551 patients treated with immune checkpoint inhibitors provides more precise data on the incidence of endocrine dysfunctions that were significantly higher among those treated with combination therapy compared with ipilimumab alone. Regarding monotherapy, the incidence of thyroid dysfunction and hypophysitis was highest with PD-1 inhibitors and with ipilimumab according to data published in the JAMA Oncology.

The authors put an emphasis on the fact that endocrine dysfunction can be life-threatening if not promptly recognized. They performed an analysis with aim to compare the incidence and risk of endocrine adverse events following treatment with immune checkpoint inhibitor regimens approved by US Food and Drug Administration. The study team searched in PubMed relevant publications using such keywords as ipilimumab, MDX-010, nivolumab, BMS-963558, pembrolizumab, MK-3475, atezolizumab, MPDL3280A, and phase.

Identified regimens for the treatment of advanced solid tumors were categorized by class into monotherapy with a PD-1 inhibitor, a CTLA-4 inhibitor, or a PD-L1 inhibitor, and combination therapy with PD-1 plus CTLA-4 inhibitors.

Main outcomes and measures were incidence of all-grade hypothyroidism, hyperthyroidism, hypophysitis, primary adrenal insufficiency, and insulin-deficient diabetes. Patients on the combination regimen were significantly more likely to experience hypothyroidism (OR, 3.81; p < 0.001) and hyperthyroidism (OR, 4.27; p = 0.001) than patients on ipilimumab. Compared with patients on ipilimumab, those on PD-1 inhibitors had a higher risk of developing hypothyroidism (OR, 1.89; p = 0.03). The risk of hyperthyroidism, but not hypothyroidism, was significantly greater with PD-1 than with PD-L1 inhibitors (OR, 5.36; p = 0.002). While patients who received PD-1 inhibitors were significantly less likely to experience hypophysitis than those receiving ipilimumab (OR, 0.29; p < 0.001), those who received combination therapy were significantly more likely to develop it (OR, 2.2; p = 0.001). For primary adrenal insufficiency and insulin-deficient diabetes, no statistical inferences were made due to the smaller number of events.

The authors concluded that their study provides more precise data on the incidence of endocrine dysfunctions among patients receiving immune checkpoint inhibitors. Patients on combination therapy are at increased risk of thyroid dysfunction and hypophysitis.