Pralsetinib in Patients with Advanced/metastatic RET-altered Thyroid Cancer: Updated Efficacy and Safety Data from the ARROW Study.

BACKGROUND: RET 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 RET-altered thyroid cancer. We present an updated analysis with more patients and longer follow-up.

METHODS: Adult patients with advanced/metastatic RET-mutant medullary thyroid cancer (MTC) or RET fusion-positive thyroid cancer who initiated oral pralsetinib at 400mg 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 RET-mutant MTC who had received prior cabozantinib and/or vandetanib (C/V); treatment-naïve patients with RET-mutant MTC; patients with previously treated RET fusion-positive thyroid cancer. Patient-reported outcomes (PROs) were an exploratory endpoint.

RESULTS: As of October 18, 2021, the measurable disease population comprised 61 patients with RET-mutant MTC and prior C/V, 62 treatment-naïve patients with RET-mutant MTC and 22 patients with RET fusion-positive thyroid cancer who had received prior systemic therapy, including radioactive iodine. The ORR was 55.7% (95% CI: 42.4-68.5) in patients with RET-mutant MTC and prior C/V, 77.4% (95% CI: 65.0-87.1) in treatment-naïve patients with RET-mutant MTC, and 90.9% (95% CI: 70.8-98.9) in patients with previously treated RET fusion-positive thyroid cancer. Median DoR and median PFS were both 25.8 months in patients with RET-mutant MTC and prior C/V, not reached in treatment-naïve patients with RET-mutant MTC, and 23.6 months and 25.4 months, respectively, in patients with previously treated RET fusion-positive thyroid cancer. In the RET-altered thyroid cancer safety population (N=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 following pralsetinib treatment.

CONCLUSIONS: 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 RET-altered thyroid cancer.