A phase 3 study of olverembatinib (HQP1351) in patients with chronic-phase chronic myeloid leukemia: POLARIS-2 trial in progress.

TPS6608 Background: Chronic myeloid leukemia (CML) is driven by the BCR::ABL1 oncogenic fusion protein. Although tyrosine kinase inhibitors (TKIs) have transformed CML management, normalizing life expectancy for many patients, treatment resistance and intolerance remain significant clinical challenges. Olverembatinib is a novel third-generation BCR::ABL1 TKI with activity against wild-type BCR::ABL1, multiple resistance-conferring mutations including T315I, and challenging compound mutations. The POLARIS-2 study evaluates olverembatinib efficacy and safety in patients with relapsed/refractory chronic phase CML (CP-CML). Methods: This global, multicenter, open-label, randomized phase 3 registrational study includes two patient cohorts based on T315I mutation status (ClinicalTrials.gov identifier: NCT06423911; internal study number: HQP1351CG301). Part A randomly allocates patients with CP-CML previously treated with at least two approved TKIs to receive either olverembatinib or bosutinib (2:1 randomization). The primary endpoint is major molecular response (MMR) rate at 24 weeks. Part B is a single-arm study evaluating olverembatinib in patients with CP-CML with the T315I mutation at screening, and the primary endpoint is MMR rate by 24 weeks. Key inclusion criteria include age ≥18 years, diagnosis of CP-CML, Eastern Cooperative Oncology Group performance status ≤ 2, and adequate organ function. Key exclusion criteria include prior hypersensitivity to study drugs and pregnancy or lactation. Patients in Part A receiving bosutinib who do not achieve MMR by 24 weeks are eligible to cross over to olverembatinib. The study hypothesis posits that olverembatinib will demonstrate superior MMR compared to bosutinib in Part A and provide clinical benefit in T315I-positive patients in Part B. Clinical trial information: NCT06423911 .