Lenvatinib plus Pembrolizumab-Associated Delayed-Onset Hypothyroidism

Lenvatinib and pembrolizumab are emerging agents being used for various malignant tumors with antitumor activity and an acceptable safety profile. However, monotherapy with these immunotherapies can lead to various endocrinopathies, which raises an important question-whether the combination increases the risk of endocrinopathy even further and even after discontinuation. The objective of this report is to describe a case of development of hypothyroidism 13 weeks following discontinuation of the combined immunotherapy lenvatinib and pembrolizumab.

A 75-year-old man was started on lenvatinib and pembrolizumab after he was found to have metastatic renal cell carcinoma. He was diagnosed with subclinical hypothyroidism following 1 month of treatment, which resolved spontaneously with normalization of thyroid-stimulating hormone level. The immunotherapies were discontinued after 8 months. He presented with generalized weakness, failure to thrive, and poor oral intake 3 months following discontinuation of immunotherapies and was diagnosed with hypothyroidism as laboratory workup revealed a thyroid-stimulating hormone level of >150 mIU/mL (normal range, 0.5-5.0 mIU/mL) and free thyroxine level of 0.17 ng/dL (normal range, 0.9-1.7 ng/dL).

Both lenvatinib and pembrolizumab can cause hypothyroidism and should be considered even after discontinuation of the immunotherapies. Keeping a broad differential is key to early diagnosis and treatment initiation and to reduce mortality and morbidity associated with hypothyroidism.

Although adverse endocrine toxicities are common with immunotherapy with lenvatinib-pembrolizumab, development of such adverse reactions following discontinuation of the combined chemotherapy is rare. Our case represents hypothyroidism as late as 3 months after the discontinuation of immunotherapies.