Mild Primary Adrenal Insufficiency During Treatment With Lenvatinib and Pembrolizumab: A Report of 3 Patients

Multi-kinase inhibitors (MKIs), such as lenvatinib, have been approved for the treatment of various malignancies. Although hypertension and hypothyroidism are well-recognized adverse events, primary adrenal insufficiency (PAI) remains underrecognized. Herein, we present a case series of 3 patients who developed mild PAI during treatment with lenvatinib and pembrolizumab for advanced cancer. Several months after treatment initiation, plasma ACTH levels increased and remained elevated despite normal serum cortisol levels. In 1 patient, plasma ACTH levels improved during treatment interruption but increased again after resumption. All patients were suggested to have mild or subclinical PAI based on a reduced cortisol response to a 250 μg ACTH stimulation test. Based on clinical features, PAI is likely attributed to lenvatinib, although a potential contribution from pembrolizumab cannot be ruled out. All patients were asymptomatic but were initiated on hydrocortisone. To date, detailed reports on MKI-related PAI are limited to a few studies with small sample sizes. Consequently, many cases of MKI-related PAI may remain undiagnosed because of a lack of awareness of the disease. Therefore, it is essential to recognize the potential for MKI-related PAI and closely monitor adrenal function during MKI treatment for early diagnosis and appropriate management.