AL2846, a Novel Multi-Kinase Inhibitor, for Previously Treated Radioiodine-Refractory Differentiated Thyroid Cancer: Exploratory Clinical Results From the Phase Ib Study

PURPOSE: This exploratory phase Ib study aimed to evaluate the efficacy and safety of AL2846, a multi-kinase inhibitor, in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) following disease progression on prior VEGFR-targeted therapy. PATIENTS AND METHODS: This multi-center, open-label, phase Ib study enrolled patients with RR-DTC treated with prior tyrosine kinase inhibitor (TKI) therapy. Eligible patients received oral 90 mg or 120 mg of AL2846 capsules, once daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and safety. RESULTS: From February 16, 2023 to March 13, 2025, 33 patients (90 mg, n = 21; 120 mg, n = 12) were enrolled in this study. All patients had disease progressed following one or two prior VEGFR-targeted therapy. The median age was 59 years (47, 63), and 17 (51.5%) patients were female. The ORR was 12.12%, with two partial responses observed in each dose group. The DCR was 100% in the 90 mg group and 91.67% in the 120 mg group, respectively. The median PFS in 90 mg was 18.33 months [95% confidence interval (CI), 10.97-not estimable], with a 6-month PFS rate of 94.4% and a 12-month PFS rate of 70.8%. The most common treatment-related adverse events (TRAE) included aspartate aminotransferase/alanine aminotransferase increased, hypertension, proteinuria, hypocalcemia, and hand-foot syndrome. Grade ≥3 TRAEs occurred in 47.62% of patients in the 90 mg group and 41.67% in the 120 mg group. CONCLUSIONS: AL2846 showed an acceptable safety profile and a promising antitumor activity in previously TKI-treated patients with RR-DTC, with 90 mg having a more favorable effect.