Endocrine Abstracts

Background: Mutations in the RET proto-oncogene occur in about 70% of medullary thyroid cancers (MTC) and is central in its pathogenesis. Two highly selective RET inhibitors, selpercatinib and pralsetinib, are FDA/EMA-approved in RET-altered thyroid cancers. We share our experience of these drugs in metastatic MTC.

Methods: Data were collected retrospectively from 19 patients commenced on selective RET inhibitors for MTC at our institution between November 2019 and December 2022.

Results: Of the 19 patients, 6 (32%) patients received pralsetinib and 13 (68%) patients received selpercatinib. 15 had received prior kinase inhibitors. All patients had distant metastatic disease. Median age was 58 (range 14-77) years and sex were evenly distributed. 15 (79%) of cases were sporadic and 4 (21%) had germline RET mutations. Median follow-up duration was 3 months. There were 3 deaths. Overall response rate (ORR) was 95%. The most common toxicities of all grades experienced by patients on pralsetinib were hypertension (n=5, 83%), infection (n=4, 67%), fatigue (n=3, 50%) and neutropenia (n=3, 50%). The most common toxicities in the selpercatinib group were hypertension (n=5, 38%), fatigue (n=5, 38%) and QTc prolongation (n=5, 38%). Of particular interest were 2 instances of grade 2 pneumonitis in the pralsetinib group and 1 case of grade 3 myocarditis in the selpercatinib group. The only grade 4 adverse event was a case of pulmonary emboli in the pralsetinib group. The majority of patients had dose interruptions (n=14, 74%). Dose reductions (n=12, 63%) due to toxicities were common, with hypertension, infections, and gastrointestinal disturbances as the most frequently reported. There were no permanent cessations due to toxicity.

Conclusion: Selective RET inhibitors represent a significant advancement in the treatment of MTC and although well-tolerated, clinicians ought to be vigilant to potentially serious complications such as pneumonitis or myocarditis.