Patients Receiving PD-1/PD-L1 Inhibitor Therapy More Frequently Experience Secondary Adrenal Insufficiency

A study analyzing the long-term adrenal insufficiency outcomes of patients receiving immune checkpoint inhibition therapy found that secondary insufficiency was more common than primary in this patient population.

Patients receiving PD-1/PD-L1 immune checkpoint inhibition therapy who experience adrenal insufficiency are more likely to develop secondary insufficiency than primary insufficiency, according to a retrospective chart review presented at the 2022 ASCO Annual Meeting. Investigators noted that most patients will require long-term replacement steroids to manage low cortisol and adrenocorticotropic hormone (ACTH) levels.

Overall, 6 patients (15%)experienced primary adrenal insufficiency and 34 patients (85%) experienced secondary insufficiency following immunotherapy. Twenty-one patients experienced new primary hypothyroidism. In addition, 10 patients (25%) experienced arthritis, 8 patients (20%) experienced colitis, 4 patients (10%) developed rash, 4 patients (10%) experienced nephritis and 3 patients (8%) experienced pneumonitis.

Although infrequent, endocrine immune-related adverse events (irAES) secondary to anti–PD-1/PD-L1, such as hypophysis, insulin-dependent diabetes mellites, and adrenal insufficiency, are often associated with long term morbidity, the study authors wrote in a poster of the findings. Moreover, adrenal insufficiency is not well characterized in available literature, and the long-term outcomes for patients who develop this irAE are not well known.

Therefore, investigators conducted a retrospective chart analysis of 40 patients treated with nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), or cemiplimab (Libtayo), and who experienced consequent adrenal insufficiency as diagnosed by a board-certified endocrinologist. Patients who received CTLA-4-inhibitors were excluded.

Laboratory values for serum cortisol, and ACTH were collected at time of adrenal insufficiency diagnosis and at last follow-up. Primary adrenal insufficiency was defined as low AM serum cortisol with high AM serum ACTH levels and secondary adrenal insufficiency was defined as low AM serum cortisol with inappropriately low AM serum ACTH levels.

The median age of the study participants (n = 40) was 65 years (range, 38-84). Twenty-six patients were male (65%) and 14 (35%) were female. Genitourinary malignancies accounted for 38% of patient malignancies. Other malignancies included gastrointestinal (20%), skin (18%), lung (5%), breast (5%), head and neck (5%), hematologic (5%), gynecologic (2%), and adrenal (2%). Nine patients (22%) had clinical stage I-III disease and 31 (78%) had stage IV disease.

Nineteen patients (48%) of patients were receiving a PD-1 inhibitor, 11 patients (28%) were taking a PD-1 inhibitor plus chemotherapy, 8 patients (20%) were receiving a PD-1 inhibitor plus a tyrosine kinase inhibitor, 1 patient (2%) was receiving a PD-L1 inhibitor plus chemotherapy, and 1 patient was receiving a PD-L1 inhibitor plus an unspecified additional therapy. Four patients (10%) had history of prior hypothyroidism, and 1 patient (2%) had diabetes mellitus type 2.

Oncologic Outcomes

Ultimately, 19 patients out of 40 (48%) discontinued immunotherapy following adrenal insufficiency onset. Among these patients, 9 (47%) discontinued because of unmanageable adrenal insufficiency symptoms, 4 had completed their treatment regimen (21%), 3 experienced another toxicity (16%), and 3 (16%) had disease progression.

Further, among patients with stage IV disease, 5 (16%) achieved a complete response, 20 achieved a partial response (6%), and 6 (19%). None of these patients experienced disease progression.

Steroid Treatment

In the initial steroid treatment for patients experiencing with adrenal insufficiency, 33 patients (82%) received low-dose treatment and 7 patients (18%) received high-dose treatment. At last follow-up, 2 patients (5%) had stopped steroid use, 37 (93%) were receiving low-dose steroids treatment, and 1 patient (2%) was receiving high dose treatment. The 2 patients who stopped use did so after 7 and 10.4 months, respectively. Median follow-up time for the patients who remained on steroid treatment was 9.8 months (range, 0.7-59).

High-dose steroids were defined as daily steroid intake greater than 30 mg of hydrocortisone, 7.5 mg of prednisone, for 2 months. By 5 months, only 1 patient remained on high-dose treatment.

The most common symptom of adrenal insufficiency was fatigue, which affected 88% of patients. Other common symptoms included nausea and vomiting (33%), hyponatremia (30%), dizziness (18%), arthralgia (15%), headache (15%), hypotension (13%), and visual symptom problems (5%).


Nguyen B, Shah NJ, Knezevic A, et al. Long-term outcomes of adrenal insufficiency (AI) due to anti-PD-(L)-1 immune checkpoint inhibitors among cancer patients. J Clin Oncol. 2022;40(suppl 16):12084. doi:10.1200/JCO.2022.40.16_suppl.12084

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