KL590586 RET-Targeted TKI Yields 63% ORR and 78% 2-Year PFS in Advanced Medullary Thyroid Cancer

KL590586 (A400/EP0031) is a next-generation, brain-penetrant selective RET inhibitor engineered to tackle resistance mutations. In the phase I dose-escalation/expansion KL400-I/II-01 study (NCT05265091) in China, 27 adults with advanced RET-mutant medullary thyroid cancer—84% previously exposed to multikinase inhibitors but SRI-naïve—received 20-90 mg once daily. Confirmed ORR reached 63% (17/27) with 100% disease control; responses were durable (mDOR not reached, longest 25.8 mo) and median PFS was also not reached, translating to a 24-mo PFS rate of 77.8%. Grade ≥3 treatment-related AEs occurred in 22% (chiefly ALT/AST elevations); no discontinuations or deaths were treatment-related, suggesting a manageable hepatic signal. By comparison, the approved first-generation RET TKIs pralsetinib report ORR 56-77% and mPFS ≈25.8 mo, but with grade ≥3 TRAEs in ~39% and 6% discontinuations, positioning KL590586 as comparable on efficacy with potentially improved toxicity—while adding coverage of resistance mutations.