Immune-Related Endocrine Events Associated With Immune Checkpoint Inhibitor Therapy Linked to Prognosis, Response

Hospitalized patient, female, doctor
Hospitalized patient, female, doctor
Investigators sought to identify risk factors associated with the development of immune-related endocrine events in patients with cancer undergoing treatment with immune checkpoint inhibitors.

In adults with metastatic cancer who are receiving immune checkpoint inhibitor (ICI) therapies, immune-related endocrine events (irEEs) are common, but their development may be predictive of tumor response to immunotherapy and a favorable cancer prognosis, according to research results published in the Journal of the Endocrine Society.

Severe irEEs associated with the use of ICIs have been reported in the literature, calling into question their safety, the study authors explained. Endocrine toxicities resulting from ICI therapy are frequently encountered, ranging from thyroiditis to adrenal insufficiency to hypothyroidism, they noted further.

The researchers sought to identify risk factors associated with the development of irEEs — which may be clinical or subclinical in presentation, making early diagnosis a challenge — as well as timelines for the development of these events and the prognosis of patients who develop conditions resulting from irEEs.

A retrospective observational study of sites within the Cleveland Clinic health system was conducted from 2014 to 2017. Adults with a confirmed cancer diagnosis who received treatment with the ICIs nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, or ipilimumab were eligible for inclusion.

The cohort included 570 eligible patients; 19 demonstrated irEEs of unclear etiology and were excluded from the study. The final analysis cohort included 551 patients (median age, 67.4 years; 90% White; 65.2% men). Among the patients in the final analysis cohort, the most common underlying malignancies were non-small cell lung cancer (44.6%), melanoma (17.4%), renal cell carcinoma (12.3%), and bladder cancer (8.5%).

ICI agents administered included nivolumab (n=276), pembrolizumab (n=117), atezolizumab (n=54), and ipilimumab (n=17); 63 patients received 2 or more agents including ipilimumab, and 24 patients received 2 or more agents without ipilimumab.

Endocrine-related adverse events due to ICIs were observed among 17.7% of patients. The overall median timeline for the development of irEEs was 9 weeks, regardless of treatment regimen. The median timeline for irEEs observed with nivolumab and atezolizumab was 10 weeks, pembrolizumab was 8 weeks, and ipilimumab monotherapy was 15.5 weeks. The timeline for the development of irEEs with combination therapy with ipilimumab was 9 weeks and without ipilimumab was 23.5 weeks.

Symptoms were reported in 57.1% of patients. Most symptoms were nonspecific and included fatigue, nausea, vomiting, and changes in weight, all of which are common among many patients with cancer. Most patients who were symptomatic, however, reported symptom improvement after receiving treatment for their endocrinopathies.

Across all cancer types, melanoma was associated with the highest risk of irEE development; 31.3% of patients with melanoma experienced these events compared with 14.9% of patients with nonmelanoma cancer types.

Most endocrine toxicities were grade 1 or 2 (33.7% each); grade 3 toxicity was experienced among 21.4% of the patients, and 11.2% had life-threatening grade 4 toxicities. Grade 4 toxicity was most common among patients who received ipilimumab monotherapy or combination therapy.

Despite their prevalence, irEEs were “fairly well tolerated” by most study patients, and only 9 patients discontinued their ICI therapy because of endocrine toxicity. The most common reasons for treatment discontinuation were disease progression, nonendocrine toxicity, treatment completion, and transition to hospice.

The thyroid gland was the most commonly involved organ, with toxicities manifesting as primary hypothyroidism (45.9%), thyroiditis (29.6%), secondary hypothyroidism (11.2%), and thyrotoxicosis (5.1%) of an undetermined mechanism. Hypothyroidism was most commonly associated with nivolumab and pembrolizumab monotherapy.

Primary hypothyroidism was the most common irEE, with an overall incidence of 8.2%, and it was associated with all ICI therapies excluding ipilimumab monotherapy. Ipilimumab was associated with the highest rate of irEEs (29.4% monotherapy, 30.2% combination therapy).

Patients who developed irEEs demonstrated a better tumor response to ICIs compared with patients who did not develop endocrine toxicity. Those patients also demonstrated a “significantly better overall survival” (hazard ratio [HR], 1.86; 95% CI, 1.39-2.49; P <.001)), as did patients treated with nivolumab and 2 or more agents including ipilimumab.

After adjusting for age, gender, race, body mass index, and cancer type, patients without endocrine toxicity had a higher risk for mortality (HR, 1.77; 95% CI, 1.31-2.38; P <.001).

Among patients who discontinued their immunotherapy regimen for any cause and developed an immune-related endocrine toxicity requiring treatment, 82% required long-term treatment for their endocrine disorder.

Study limitations included those inherent to retrospective analyses, a lack of generalizability to other non-White races, possible overestimation of the severity of some toxicities, and the potential that a portion of the primary hypothyroidism cohort may have had destructive thyroiditis with an undocumented or missed thyrotoxic phase. Longer follow-up is needed to better understand the long-term outcomes for this patient population, the study authors commented.

“[Immune-related endocrine event] development may predict better cancer response to immunotherapy and better overall survival,” the researchers suggested. “Stopping [immune checkpoint inhibitors] will not reverse endocrine toxicity most of the time. Thus, the development of non-life-threatening irEEs may be a reason to continue treatment…if tolerated, rather than discontinue,” they added.

“Further prospective studies are needed to confirm our findings regarding the impact on overall survival,” the study authors concluded.


Al Ashi SI, Thapa B, Flores M, et al. Endocrine toxicity and outcomes in patients with metastatic malignancies treated with immune checkpoint inhibitors. J Endocr Soc. 2021;5(8):bvab100. doi:10.1210/jendso/bvab100