Background
Phase 1b, open-label, dose-escalation/expansion, global multicenter trial. N=80 patients with CML (all phases) or Ph+ ALL whose disease had failed or was intolerant to prior TKIs including ponatinib or asciminib, the most heavily pretreated population in a TKI trial. Olverembatinib (HQP1351) is a 3rd-generation BCR-ABL1 inhibitor with activity against T315I and compound mutations. Published JAMA Oncology 2025.
Interventions and follow up
Regimen: Olverembatinib administered on an alternate-day oral dosing schedule across dose-escalation and dose-expansion cohorts
Primary endpoint: Safety and tolerability
Secondary endpoints: CCyR, MMR in CP-CML
Median follow-up: 48 weeks
Primary endpoint: Safety and tolerability
Secondary endpoints: CCyR, MMR in CP-CML
Median follow-up: 48 weeks
Results
CCyR (CP-CML, all evaluable): ~61%
MMR (CP-CML): ~42%
T315I-mutant CP-CML: CCyR and MMR similar to overall population
Prior-ponatinib-failure CCyR: ~58%
Prior-asciminib-failure: responses observed
MMR (CP-CML): ~42%
T315I-mutant CP-CML: CCyR and MMR similar to overall population
Prior-ponatinib-failure CCyR: ~58%
Prior-asciminib-failure: responses observed
Adverse events
Hematologic: Thrombocytopenia the most common hematologic AE, grade ≥3 ~25%; anemia grade ≥3 ~10%
Non-hematologic/vascular: Hypertension grade ≥3 ~8%; pleural effusion any grade ~10%; arterial thrombotic event rate lower than continuous-daily ponatinib, attributed in part to alternate-day dosing reducing peak drug exposure
Non-hematologic/vascular: Hypertension grade ≥3 ~8%; pleural effusion any grade ~10%; arterial thrombotic event rate lower than continuous-daily ponatinib, attributed in part to alternate-day dosing reducing peak drug exposure
Conclusions
Olverembatinib achieved ~61% CCyR and ~42% MMR in heavily pretreated CP-CML, including patients who had failed both ponatinib and asciminib. Activity was irrespective of T315I or compound mutations, with an alternate-day schedule that may reduce cumulative cardiovascular toxicity.
Key Limitations
Phase 1b with small N (CP-CML evaluable subset smaller still); single-arm with no randomized comparator. The alternate-day dosing schedule is unconventional with limited real-world adherence data. Long-term durability of response and cumulative ATE rates require extended follow-up. Cross-trial comparisons with ponatinib (OPTIC) and asciminib (ASCEMBL) are not valid given differing populations and endpoints.
Clinical Context
Olverembatinib addresses a growing unmet need in CML patients exhausting ponatinib and asciminib. It is approved by China's NMPA for T315I-mutant or multiresistant CML (2021). This global phase 1b provides the first Western registrational data supporting global regulatory submission, and positions olverembatinib as an emerging option in the ≥3rd-line and post-3rd-generation-TKI setting per ELN-aligned management. ESMO-MCBS: not assigned.