Pralsetinib in Patients with Advanced/Metastatic Rearranged During Transfection (RET)-Altered Thyroid Cancer: Updated Efficacy and Safety Data from the ARROW Study.

Rearranged during transfection () alterations are targetable oncogenic drivers in thyroid cancer. Primary data from the open-label, phase 1/2 ARROW study demonstrated clinical activity and manageable safety with pralsetinib, a selective RET inhibitor, in patients with advanced/metastatic -altered thyroid cancer. We present an updated analysis with more patients and longer follow-up. Adult patients with advanced/metastatic -mutant medullary thyroid cancer (MTC) or fusion-positive thyroid cancer who initiated oral pralsetinib at 400 mg once daily were included. Primary endpoints were overall response rate (ORR) by blinded independent central review (per RECIST v1.1) and safety. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival. Responses were assessed in three cohorts of patients with baseline measurable disease: patients with -mutant MTC who had received prior cabozantinib and/or vandetanib (C/V), treatment-naïve patients with -mutant MTC, and patients with previously treated fusion-positive thyroid cancer. Patient-reported outcomes (PROs) were an exploratory endpoint. As of October 18, 2021, the measurable disease population comprised of 61 patients with -mutant MTC and prior C/V, 62 treatment-naïve patients with -mutant MTC, and 22 patients with fusion-positive thyroid cancer who had received prior systemic therapy, including radioactive iodine. The ORR was 55.7% [confidence interval; 95% CI: 42.4-68.5] in patients with -mutant MTC and prior C/V, 77.4% [95% CI: 65.0-87.1] in treatment-naïve patients with -mutant MTC, and 90.9% [95% CI: 70.8-98.9] in patients with previously treated fusion-positive thyroid cancer. Median DoR and median PFS were both 25.8 months in patients with -mutant MTC and prior C/V, not reached in treatment-naïve patients with -mutant MTC, and 23.6 and 25.4 months, respectively, in patients with previously treated fusion-positive thyroid cancer. In the -altered thyroid cancer safety population ( = 175), 97.1% of patients reported a treatment-related adverse event (TRAE); these led to discontinuation in 5.7% and dose reduction in 52.6% of patients. There was one death (0.6%) due to a TRAE. PROs improved or remained stable after pralsetinib treatment. In this updated analysis of the ARROW study, pralsetinib continued to show deep and durable clinical activity and a manageable safety profile in patients with advanced/metastatic altered thyroid cancer. Clinical Trial Registration: NCT03037385.