Clinical Activity of Selpercatinib in RET Mutant Pheochromocytoma-Case Reports

Activating RET gene alterations have been reported in solid tumors including the rare cancer, pheochromocytoma (PHEO) found sporadically and in familial multiple endocrine neoplasia type 2 (MEN2) syndromes. Selpercatinib is a highly selective and potent small molecule RET kinase inhibitor that has demonstrated marked and durable anti-tumor activity in diverse RET-altered solid tumors. Described are the initial 3 PHEO patients treated with selpercatinib (LIBRETTO-001/NCT03157128). Case 1: 70-year-old white male with MEN2A and a history of medullary thyroid cancer (MTC) and PHEO s/p thyroidectomy and adrenalectomy, received MIBG in 1991 and 2016 due to symptom reoccurrence. Progressive metastatic disease associated with severe hypertension was treated with Lutate in 2017 and germline RET mutation p.Cys634Phe was confirmed. After developing severe back pain due to a T6 vertebral metastasis, he began selpercatinib treatment. As of Mar 2020, he has a partial response (PR) as assessed by investigator; his back pain resolved, normetanephrine and metanephrine levels decreased, and has ceased alpha and beta blockers. He remains on treatment with only grade 1-2 adverse events, none requiring interruption or dose modification. Case 2: 51-year-old white female with MEN2A and history of MTC and PHEO s/p thyroidectomy and adrenalectomy in 2010. She developed metastatic PHEO in 2013, with multiple bone, omentum, lung, liver, and spleen metastases. Between 2013 and 2018 she was treated with multiple courses of radiation and, additional surgical resections; a PR with sunitinib lasted 13 months followed by temozolomide/capecitabine treatment. A bone lesion biopsy in 2018 confirmed RET C618S mutation and with her disease progression and uncontrolled bone pain, she began selpercatinib treatment, experiencing a PR. After 5.5 months in the study, she discontinued treatment due to disease progression. Case 3: 45-year-old African American female diagnosed with sporadic PHEO in 1996, s/p multiple surgical resections. She received 2 cycles of cyclophosphamide/vincristine/dacarbazine without clinical benefit. I-131-MIBG therapy with autologous stem cell rescue in 2017 improved blood pressure, palpitations, and flushing but without tumor shrinkage while abdominal pain persisted. Somatic M918T RET-mutation was confirmed, and she began selpercatinib treatment in 2018 with symptom resolution and improved plasma metanephrine levels. She required dose reduction for grade 3 palmar-plantar erthrodysesthesia and had stable disease for 22 months until a new bone metastasis was identified. Due to ongoing clinical benefit, she remains on treatment despite disease progression. Conclusion: These are the initial reports of RET-mutant PHEO patients treated with selpercatinib adding to the diversity of RET-altered tumor types that may benefit from a selective RET inhibitor.