KL-590586 (A400/EP0031): A Comprehensive Profile of a Next-Generation Selective RET Inhibitor for the Treatment of RET-Altered Malignancies

Executive Summary

KL-590586, also designated A400/EP0031, is an orally bioavailable, next-generation selective rearranged during transfection (RET) kinase inhibitor under development by Sichuan Kelun-Biotech and its global partner, Ellipses Pharma. This investigational agent is engineered to address the primary clinical limitations of first-generation selective RET inhibitors (SRIs), namely acquired resistance and the progression of central nervous system (CNS) metastases. Clinical data from the foundational Phase I/II KL400-I/II-01 study have demonstrated robust and durable anti-tumor activity across a range of RET-altered solid tumors.

In treatment-naïve patients with RET fusion-positive non-small cell lung cancer (NSCLC), KL-590586 has achieved an objective response rate (ORR) as high as 80.8%, positioning it as a highly potent first-line therapeutic option.[1] The agent has also shown significant efficacy in heavily pre-treated NSCLC patients, with an ORR of approximately 63% to 70%, and has produced meaningful clinical responses in patients who have progressed on prior first-generation SRI therapy, confirming its ability to overcome established resistance mechanisms.[3] Furthermore, KL-590586 exhibits compelling intracranial efficacy, with a CNS disease control rate of 100% and observations of complete tumor shrinkage in brain lesions, addressing a critical unmet need in this patient population.[3]