Efficacy and Safety of Selective RET Inhibitors in Patients with Advanced Hereditary Medullary Thyroid Carcinoma.

Two selective RET inhibitors (RETis) are effective in treating ()-altered medullary thyroid carcinoma (MTC), but clinical trials did not distinguish responses between hereditary MTC (hMTC) and sporadic MTC (sMTC) cases. We reviewed our single-center experience using a RETi to treat advanced hMTC. We conducted a retrospective cohort study of patients with hMTC treated with a selective RETi at a tertiary cancer center. The primary outcome was overall response rate using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary end points included overall survival (OS), progression-free survival (PFS), biochemical response rate, and safety. We identified 23 evaluable patients as follows: 15 (65%) multiple endocrine neoplasia (MEN)2A and 8 (35%) MEN2B. Median age at start of RETi was 51 years (range, 15-79). All patients had distant metastases, and 52% (12/23) had received prior systemic therapy (median = 1, range, 0-3). Patients were treated with selpercatinib ( = 13) or pralsetinib ( = 10), 57% (13/23) within a clinical trial. Median duration of RETi was 25 months (range, 3-72) with 11/23 (48%) patients remaining on drug at data cutoff due to an ongoing response. Median duration of follow-up was 49 months (range, 9-72). Best radiographical response was partial response in 18 (78%) and stable disease in 5 (22%) patients. Median OS was 51 months (confidence interval, 40.5-61.3); median PFS was not reached. Most common adverse events (AEs) were increased alanine aminotransferase (ALT) (48%) and aspartate aminotransferase (26%), dry mouth (39%), QT interval prolongation (39%), fatigue (35%), and hypertension (26%). AEs led to dose reductions in eight (35%) patients. No grade 5 treatment-related AEs occurred. While the germline nature of the pathogenic variant in hMTC could hypothetically result in increased drug-related toxicity, the incidence of most AEs, other than grade 1-2 ALT elevation and QT interval prolongation, was comparable to published clinical trials. In patients with advanced hMTC, selective RETis appear safe and effective with outcomes similar to clinical trial cohorts, which mostly comprised patients with sMTC. Duration of response and AE profile was similar to sMTC, although longer follow-up and larger patient numbers are needed to confirm this.