ASH2024|Data of Olverembatinib to be Presented in Oral Reports

Olverembatinib as Second-Line (2L) Therapy in Patients (pts) with Chronic Phase-Chronic Myeloid Leukemia (CP-CML)

Format: Oral Presentation

Abstract#: 480

Session: 632. Chronic Myeloid Leukemia: Novel Molecules in Clinical Practice

Time: Sunday, December 8, 2024; 9:30 AM - 11:00 AM

First Author: Prof. Weiming Li, Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Highlights:

Background : Olverembatinib, a third-generation tyrosine kinase inhibitor (TKI), has demonstrated remarkable efficacy and a favorable safety profile in patients with CML resistant and/or intolerant to at least 2 TKIs or with the T315I mutation. The aim of this study was to assess the efficacy and safety of olverembatinib as a second-line treatment for patients with CP-CML without the T315I mutation.

Introduction : This is a single-arm, multicenter, open-label study designed to evaluate the efficacy, safety, and patients’ quality of life of orally administered olverembatinib (40 mg QOD) in patients with CP-CML who were resistant/intolerant to one prior line of TKIs (including imatinib, flumatinib, nilotinib, and dasatinib) without the T315I mutation.

Enrolled Patients and Study Methods : As of July 29, 2024, the study enrolled a total of 42 patients with non–T315I-mutant CML-CP. These patients received orally administered olverembatinib 40 mg every other day (QOD) in 28-day cycles.

Efficacy Results :

• As of July 29, 2024, 33 (78.6%) patients had at least one efficacy assessment, 28 (66.7%) had at least two, 23 (54.8%) had at least three. Three patients had not yet undergone their first efficacy assessment.

• At data cutoff, 75.0% (24/32) of patients achieved a complete cytogenetic response (CCyR) and 40.6% (13/32) achieved a major molecular response (MMR). The CCyR and MMR rates evaluated at the end of Cycles 6, 9, 12, and 18 were 53.4% and 28.6%, 64.8% and 32.5%, 69.1% and 32.5%, and 77.7% and 43.9%, respectively, suggesting that efficacy improved over time.

• In 32 efficacy-evaluable patients, 23 were pretreated with second-generation TKIs as first-line treatment, of whom 19 (82.68%) achieved CCyR, and 10 (43.5%) achieved MMR. In 9 patients who were pretreated with imatinib, 5 achieved CCyR (55.6%) and 3 achieved MMR (33.3%).

Safety Results : The median (range) treatment duration was 16.0 (1-18) months. A total of 37 (88.1%) patients experienced any-grade treatment-related adverse events (TRAEs), of whom 19 (45.2%) had grade ≥ 3 treatment-related adverse events (TRAEs) and 5 (11.9%) had olverembatinib-related serious AEs (SAEs). Nonhematologic TRAEs included skin hyperpigmentation (38.1%), hyperuricemia (23.8%), and creatine phosphokinase increased (21.4%). Most of these TRAEs were grade 1 or 2. Grade ≥ 3 hematologic toxicities included platelet count decreased (38.1%), neutropenia (21.4%), and anemia (7.1%). Possibly olverembatinib-related any-grade cardiovascular events included hypertension (4.8%) and atrial tachycardia (2.4%), all of which were grade 1 or 2. Olverembatinib-related SAEs included platelet count decreased (7.1%), anemia, myelosuppression, and pyrexia (2.4% each). No deaths were reported.

Conclusions : Olverembatinib may provide an effective and safe second-line treatment option for patients with CP-CML, especially those who have failed on second-generation TKIs in the first-line setting.

Olverembatinib (HQP1351) Overcomes Resistance/Intolerance to Asciminib and Ponatinib in Patients (pts) with Heavily Pretreated Chronic-Phase Chronic Myeloid Leukemia (CP CML): A 1.5-Year Follow-up Update with Comprehensive Exposure-Response (E-R) Analyses

Format: Poster Presentation

Abstract#: 3151

Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Poster II

Time: Sunday, December 8, 2024; 6:00 PM - 8:00 PM

First Author: Dr. Elias Jabbour, Department of Leukemia, The University of Texas MD Anderson Cancer Center

Highlights：

Introduction : New treatment options are needed for patients with CP-CML resistant/intolerant to third-generation (3G) TKI ponatinib and/or asciminib, a specifically targeting the ABL myristoyl pocket (STAMP) inhibitor. Olverembatinib is a well-tolerated TKI with potential to overcome resistance. This update presents efficacy and safety data of olverembatinib in patients with heavily pretreated CP-CML.

Enrolled Patients and Study Methods :

• Adults with CP-CML previously treated with ≥2 TKIs and/or a STAMP inhibitor, adequate organ function, and no major molecular response (MMR) were eligible.

• As of July 28, 2024, 67 pts with CP-CML were enrolled; median (range) follow-up was 74.3 (0.1-217.1) weeks; median (range) age, 50 (21-80) years; and 38 (56.7%) patients were male.

• Patients were randomly allocated to receive olverembatinib at doses of 30, 40, or 50 mg orally every other day (QOD) in 28-day cycles, with stratification based on T315I mutation status. Comprehensive E-R analyses were performed.

Efficacy Results :

• No patient had efficacy at baseline. 35 of 60 (58.3%) evaluable patients achieved CCyR and 29/64 (45.3%) achieved MMR. At 12 months, the overall MMR rate was 61.4% (27/44). CCyR was achieved by 66.7% of patients with the T315I mutation vs 54.8% without it, and MMR was achieved by 50.0% vs 43.5%, respectively.

• Of 28 cytogenetic response-evaluable patients with ponatinib-failed CP-CML, 15 (53.6%) achieved CCyR. The CCyR rates in patients with prior ponatinib resistance and intolerance were 52.2% (12/23) and 75.0% (3/4), respectively. In the 30 molecular response-evaluable patients who were previously treated with ponatinib, 12 (40.0%) achieved MMR, including 47.8% (11/23) of those with prior resistance and 16.7% (1/6) with intolerance. No patient above had efficacy at baseline.

• In evaluable patients with asciminib treatment failure, 37.5% (6/16) achieved CCyR and 30% (6/20) achieved MMR, including a CCyR rate of 30.8% (4/13) and an MMR rate of 26.7% (4/15) in those with prior resistance, and a CCyR rate of 50.0% (1/2) and an MMR rate of 25.0% (1/4) in those with intolerance. No patient had efficacy at baseline.

• CCyR and MMR rates in patients previously treated with both ponatinib and asciminib were 30% and 25%, respectively. No patient had efficacy at baseline.

Safety Results : Among 66 subjects receiving olverembatinib, a total of 62 (93.9%) reported treatment-emergent adverse events (TEAEs) of any grade, with 44 (66.7%) experiencing grade ≥ 3 TEAEs. In addition, 60 (90.9%) patients reported TRAEs of any grade. Common TRAEs (≥20%) were elevated creatine phosphokinase (37.9%), thrombocytopenia (24.2%), and increased alanine aminotransferase (22.7%).

Conclusions : Olverembatinib was well tolerated and showed strong and durable antileukemic activity in patients with heavily pretreated CP-CML. The registrational study is recruiting.

Safety and Efficacy of Olverembatinib (HQP1351) Combined with Lisaftoclax (APG-2575) in Children and Adolescents with Relapsed/Refractory Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia (R/R Ph+ ALL): First Report from a Phase 1 Study

Format: Poster Presentation

Abstract#: 1443

Session: 613. Acute Lymphoblastic Leukemias: Therapies Excluding Allogeneic Transplantation: Poster I

Time: Saturday, December 7, 2024; 5:30 PM - 7:30 PM

First Author: Prof. Jingliao Zhang, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences

Highlights：

Background : Olverembatinib, a novel third-generation TKI, is well tolerated and exerts strong and durable antileukemic activity in patients with heavily pretreated CP-CML with or without the T315I mutation. Investigational lisaftoclax, a novel Bcl-2 inhibitor, has shown clinical antitumor benefits in patients with multiple hematologic malignancies. Currently, there are no effective treatment options available for pediatric patients with R/R Ph+ ALL. This study was designed to explore the safety, efficacy, and pharmacokinetic (PK) profile of olverembatinib alone or combined with lisaftoclax in children and adolescents with R/R Ph+ ALL.

Methods :

• This was an open-label, Phase Ib study that enrolled children and adolescents aged < 18 years with R/R Ph+ ALL resistant or intolerant to at least 1 TKI (prior use of TKIs was not considered if patients had T315I mutation). Patients were required to have adequate Karnofsky/Lansky performance status score and organ function. Patients with symptomatic central nervous system disorders or significant bleeding, which were unrelated to Ph+ ALL, were excluded.