SAT-295 - Selpercatinib Induced Regression of Bilateral Pheochromocytomas in A Patient with MEN2B and Metastatic Medullary Thyroid Carcinoma

Introduction
Medullary thyroid carcinoma (MTC) is a neuroendocrine thyroid malignancy frequently driven by activating RET variants in MEN2. The RET p.M918T variant is characteristic of MEN2B and is associated with early, aggressive MTC and an increased risk of pheochromocytoma. Selective RET inhibitors such as selpercatinib have demonstrated robust efficacy in advanced RET-driven MTC, including after multikinase inhibitors; however, their clinical activity against MEN2B-associated pheochromocytoma is not well established. We report a patient with MEN2B and metastatic MTC who developed bilateral pheochromocytomas with marked adrenal tumor regression after selpercatinib initiation.
Case
A 14-year-old girl with no significant past medical history presented with a progressively enlarging neck mass. She was diagnosed with multifocal MTC, staged pT4aN1b (AJCC stage IVa). Germline testing identified a heterozygous pathogenic RET p.M918T variant, consistent with MEN2B. One year later, persistent disease was documented by markedly elevated calcitonin (7,018 pg/mL; ref < 6) and CEA (13.4 ng/mL; ref < 2.5). PET/CT demonstrated an enhancing neck mass and focal uptake in the iliac crest. Over subsequent years, imaging showed progressive metastatic disease involving the brain, chest, bones, and liver. She was treated with vandetanib (2016–2020), then switched to cabozantinib due to disease progression. Cabozantinib was discontinued after two months and replaced with sorafenib due to side effects. A follow up PET/CT demonstrated disease in the neck, chest, liver, mediastinum, and bones (T6, T9, L4, left sacrum, proximal left femur). Calcitonin was 111,331 pg/mL. Given extensive disease and germline RET p.M918T, Selpercatinib was initiated with calcitonin decreasing to 22,749 pg/mL.
PET/CT also demonstrated bilateral adrenal masses enlarged (right 7.0 × 6.3 cm, SUV 4.1; left 6.9 × 3.7 cm, SUV 2.8). Plasma metanephrine/normetanephrine increased from 294/418 pg/mL (2020) to 4,314/6,482 pg/mL (Mar 2024). Bilateral pheochromocytomas were diagnosed and doxazosin was initiated. Follow-up showed response and approximately 8 months after Selpercatinib initiation a PET/CT demonstrated stable liver and lung MTC metastases, stable bone metastases, and a substantial reduction in adrenal mass size (left 4.4 × 3.9 cm, SUV 3.7; right 3.0 × 3.7 cm, SUV 3.7).
Conclusion
Marked adrenal tumor regression temporally associated with selpercatinib suggests potential activity of selective RET inhibition against MEN2B-associated pheochromocytoma, in addition to its established efficacy in RET-driven MTC.

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