SUN-356 Unprecedented High-Dose Levothyroxine Requirement for Overt Hypothyroidism During Pembrolizumab and Lenvatinib Therapy: A Case Report

Abstract Disclosure: R. Karov: None. E. Osher: None. Y. Greenman: None. Title: Unprecedented High-Dose Levothyroxine Requirement for Overt Hypothyroidism During Pembrolizumab and Lenvatinib Therapy: A Case Report Background: Pembrolizumab, an immune checkpoint inhibitor (ICI), and lenvatinib, a tyrosine kinase inhibitor (TKI), are approved for the treatment of several solid malignancies, including renal cell carcinoma (RCC), endometrial cancer, and hepatocellular carcinoma. While combination therapy significantly improves survival outcomes, it is associated with a higher incidence of thyroid dysfunction compared to ICI or TKI monotherapy. This case highlights the need for unprecedented high-dose levothyroxine to manage severe hypothyroidism in a patient undergoing combination therapy. Case Description: A 63-year-old male with a history of atrial fibrillation, abdominal aortic aneurysm, and three malignancies (plasmacytoma, prostate cancer, and RCC) initiated pembrolizumab and lenvatinib therapy in December 2022. Baseline thyroid function tests were normal. By January 2023, he developed subclinical hypothyroidism (TSH 12 mU/L, free T4 1.04 ng/dL) and began levothyroxine at 0.51 mcg/kg/day. Despite regular dose increases, TSH levels remained persistently elevated, peaking at 135 mU/L (free T4 0.68 ng/dL) in March 2024, necessitating a final dose of 5.67 mcg/kg/day to achieve thyroid balance. No clinical or biochemical evidence of malabsorbtion was evident. Following pembrolizumab discontinuation in July 2024, TSH normalized further, allowing dose tapering to 4.1 mcg/kg/day by November 2024. Discussion: The case emphasizes the challenges of managing thyroid dysfunction during combination pembrolizumab and lenvatinib therapy. Recent data have shown that thyroid dysfunction occurs more rapidly and frequently when using combination therapy, with hypothyroidism reported in up to 40% of cases. Moreover, levothyroxine dosing requirements in combination therapy are higher than in monotherapy, reflecting potentially greater thyroid tissue destruction or altered hormone metabolism. This case demonstrates the need for multidisciplinary management, including close endocrinology follow-up, to address these unique challenges effectively. Conclusion: This case highlights a novel and severe presentation of hypothyroidism requiring unprecedented thyroid hormone doses in a patient receiving pembrolizumab and lenvatinib without prior immune therapy. These findings emphasize the vital role of endo-oncology teams in optimizing care for complex cases.Keywords: hypothyroidism, high-dose levothyroxine, pembrolizumab, lenvatinib, immune-related adverse events. Table 1: Course of Thyroid Function and Levothyroxine Dose Adjustments Presentation: Sunday, July 13, 2025