ENDOCRINE ADVERSE EVENTS WITH IMMUNOTHERAPY

In a systematic review and meta-analysis reported in JAMA Oncology, Barroso-Sousa et al evaluated the incidence of endocrine dysfunction in patients receiving currently approved immune checkpoint inhibitors for various advanced solid tumors. Patients who received combination therapy were found to have an increased risk of thyroid dysfunction and hypophysitis.

Study Details

A PubMed search through July 2016 identified 38 randomized clinical trials of ipilimumab (Yervoy; cytotoxic T-lymphocyte–associated protein 4 [CTLA-4] inhibitor), nivolumab (Opdivo; programmed cell death protein 1 [PD-1] inhibitor), pembrolizumab (Keytruda; PD-1 inhibitor), and atezolizumab (Tecentriq; programmed cell death protein ligand [PD-L1] inhibitor), involving a total of 7,551 patients. Regimens were categorized into monotherapy with a PD-1 inhibitor, a CTLA-4 inhibitor, or a PD-L1 inhibitor, and combination therapy with a PD-1 plus CTLA-4 inhibitor. Outcomes of interest were the incidence of all-grade hypothyroidism, hyperthyroidism, hypophysitis, primary adrenal insufficiency, and insulin-deficient diabetes.

Risk of Endocrine Dysfunction

The overall incidence of hyperthyroidism of any grade was estimated at 2.9%, ranging from 0.6% with PD-L1–inhibitor monotherapy to 8.0% with combination therapy. The overall incidence of hypothyroidism was estimated at 6.6%, ranging from 3.8% with ipilimumab to 13.2% with combination therapy. Patients treated with combination therapy had a higher risk of hyperthyroidism (odds ratio [OR] = 4.27, P = .001) and hypothyroidism (OR = 3.81, P < .001) than those receiving ipilimumab monotherapy. Compared with patients treated with ipilimumab, those treated with PD-1 inhibitors had a higher risk of hypothyroidism (OR = 1.89, P = .03), and the risk of hyperthyroidism—but not hypothyroidism—was significantly greater with PD-1 inhibitors than with PD-L1 inhibitors (OR = 5.36, P = .002).

Overall, the incidence of any-grade hypophysitis was 6.4% with combination therapy, 3.2% with CTLA-4–inhibitor monotherapy, 0.4% with PD-1–inhibitor monotherapy, and < 0.1% with PD-L1–inhibitor monotherapy. Compared with patients receiving ipilimumab monotherapy, the risk of hypophysitis was significantly lower in those receiving a PD-1 inhibitor (OR = 0.29, P < .001) and significantly higher in those receiving combination therapy (OR = 2.2, P = .001).

No statistical inferences were made for the risk of primary adrenal insufficiency or insulin-deficient diabetes due to the smaller number of events.

The investigators concluded: “Our study provides more precise data on the incidence of endocrine dysfunctions among patients receiving [immune checkpoint inhibitor] regimens. Patients on combination therapy are at increased risk of thyroid dysfunction and hypophysitis.”