The latest research data of Olverembatinib further validates its efficacy in patients resistant to ponatinib or Asciminib

Patients with chronic myelogenous leukemia (CML) who fail treatment with first- and second-generation tyrosine kinase inhibitors (TKIs) have a poor prognosis. Olverembatinib is a new third-generation TKI that shows strong anti-tumor activity in patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). One study reported the safety, efficacy, and pharmacokinetics (PK) of olverembatinib in CML and Ph+ ALL patients outside China, specifically in patients previously treated with the third-generation TKI Ponatinib and/or the allosteric STAMP inhibitor Asciminib.

Method: Oral administration once every other dayOlverembatinib (QOD). In the monotherapy cohort, patients were recruited after failure of at least 2 prior tki therapies (no limit on the number of prior tki therapies for patients harboring the T315I mutation) and randomized to receive 30, 40, or 50 mg of olverembatinib orally administered every other day in a 28-day cycle. In the combined cohort, at least one patient with second-generation TKI-resistant Ph+ B-cell precursor ALL (BCP-ALL) or lymphoid CML-BP (CML-LBP) was enrolled, and combined with oral administration of Olverembatinib (30 or 40 mg) every other day and the CD19/CD3 bispecific antibody (bispecific T cell engager) Blinatumomab.

Patients: As of June 30, 2023, a total of 76 patients have been enrolled, including 57 patients with chronic myelogenous leukemia (CML-CP) and 19 patients with advanced Ph+ leukemia (CML_AP, CML-LBP, Ph+ALL). The median (range) age was 54.5 (21-80) years, and 56.6% of patients were male. 11 (14.5%), 23 (30.3%), and 39 (51.3%) patients received 2, 3, and ≥4 TKIs, respectively.

A total of 40 patients (52.6%) had received ponatinib treatment, of which 67.5% were resistant to the drug, 25.0% were intolerant to the drug, and 7.5% failed due to other reasons. A total of 21 (27.6%) patients had received aceminib treatment, of which 71.4% were resistant to the drug, 19.1% were intolerant to the drug, and 9.5% failed for other reasons. At baseline, 31.6% of patients had the T315I mutation and 38.2% had hypertension. The median (range) duration of treatment was 24.1 (0-134) weeks. PK analysis showed that the PK profile of global patients was similar to the historical data of Chinese patients.

Efficacy results: Among 50 CML-CP patients who were evaluable for efficacy, 56.8% (25/44) achieved complete cytogenetic response (CCyR) and 42.9% (21/49) achieved major molecular response (MMR). Among CML-CP patients carrying T315I mutation, the incidence rates of CCyR and MMR were 60.0% (9/15) and 43.8% (7/16) respectively; in patients without T315I mutation, the incidence rates of CCyR and MMR were 55.2% (16/29) and 42.4% respectively. (14/33); in patients resistant to ponatinib, the incidence rates of CCyR and MMR were 53.3% (8/15) and 37.5% (6/16) respectively; in patients resistant to aceminib, the incidence rates of CCyR and MMR were 42.9% (3/7) and 37.5% (3/8) respectively.

Among 13 patients with advanced Ph+ leukemia who could be evaluated for efficacy, 23.1% (3/13) achieved MMR, of which 1 patient carried T315I mutation and 2 patients were negative for T315I gene mutation and were resistant to ponatinib. In the combined cohort, 2 patients with Ph+BCP ALL received olverembatinib 30 mg QOD combined with belintuzumab. Two patients achieved CCyR after 1 treatment cycle, and 1 patient achieved negative minimal residual disease (MRD) status.

Safety results: A total of 12 CML-CP patients and 7 patients with advanced Ph+ leukemia discontinued treatment due to adverse events (AE n=4), disease progression (n=7) and other reasons (n=8). A total of 54 (83.1%) patients experienced treatment-related AEs of any grade after receiving olverembatinib. Grade ≥3 TRAEs occurring in ≥3 patients included thrombocytopenia (17.0%), neutropenia (13.8%), increased blood creatine kinase (13.8%), leukopenia (7.7%), anemia (4.6%), and increased lipase (4.6%). Treatment-related serious adverse events (SAEs) occurred in 10 (15.4%) patients.

Conclusion: Regardless ofT315I mutation status, Olverembatinib monotherapy or combined with belintuzumab treatment is effective in severely pretreated chronic myelogenous leukemia (CML)Effective and well-tolerated in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), and effective in patients with resistance or intolerance to ponatinib and/or aximinib. Olverembatinib may provide an effective treatment option for patients with CML or Ph+ALL who have failed two or more TKIs.