On March 5th, 2025,Ascentage Pharma announced that its drug, olverembatinib, has been granted a Breakthrough Therapy Designation (BTD) by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA), for combination with low-intensity chemotherapy for the first-line treatment of newly-diagnosed patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
This marks the third BTD granted to olverembatinib in China, with the first BTD granted in March 2021, for the treatment of patients with chronic-phase chronic myeloid leukemia (CML-CP) resistant and/or intolerant to first- and second-generation tyrosine kinase inhibitors (TKIs); and the second BTD granted in June 2023, for the treatment of patients with succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST) who had received first-line treatment.
Announced at the 66th Annual Meeting of the American Society of Hematology (ASH) 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.
Olverembatinib, a novel third-generation TKI, is well tolerated and exerts strong and durable antileukemic activity in pts with heavily pretreated CP-CML with or without T315I mutation. Investigational lisaftoclax, a novel BCL-2 inhibitor, has shown clinical antitumor benefits in pts with multiple hematologic malignancies. Currently, there are no effective treatment options available for pediatric pts 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.+
This was an open-label, phase 1b study (NCT05495035) that enrolled children and adolescents aged < 18 years with R/R Ph ALL resistant or intolerant to at least 1 tyrosine kinase inhibitor (TKI) (prior use of TKIs was not considered if pts had T315I mutation). Pts were required to have adequate Karnofsky/Lansky performance status score and organ function. Pts with symptomatic central nervous system disorders or significant bleeding, which were unrelated to PhALL, were excluded. Olverembatinib was administered orally at 40 mg adult equivalent dose (AED) every other day for 2 weeks (Days [D] 1-14), followed by same dose of olverembatinib in combination with lisaftoclax at an assigned dose of 200/400/600 mg (AED) daily (QD) on D13-42 (a 3-day dose ramp-up from D13-15 was needed). Dexamethasone 6 mg/m++ 2/day was administered orally QD from D15-42. The primary end points included safety assessments, overall response rate (ORR), measurable residual disease (MRD) negativity rate, and PK characteristics of olverembatinib alone/in combination with lisaftoclax.
From September 2022 to June 2024, a total of 10 pts were enrolled. The median (range) age was 13.0 (11-15) years, and 6 pts were male. The median (range) body weight was 49.85 (35.9-86.0) kg. Nine (90.0%) pts expressed the p190 transcript and 1 pt (10.0%) expressed the p210 transcript. Three pts harbored BCR-ABL1 mutations [2, T315I; 1, F317L (c.951C>A)] at baseline. After 1 pt discontinued from the trial because of seizure on D1 of Course 1 (C1D1), 9 eligible pts were included in the 3+3 dose escalation model (n = 6, R/R; n = 3, intolerant): 3 pts in each Arm (A, B, and C) at assigned lisaftoclax dose levels of 200, 400, and 600 mg (AED), respectively. These pts completed 42 days of treatment and were assessed for the primary end points. Six of 10 pts experienced grade ≥ 3 hematologic treatment-emergent adverse events, including anemia (3/10), neutropenia (7/10), and thrombocytopenia (3/10); 1 pt had grade 3 alanine aminotransferase increase leading to treatment discontinuation, and 1 pt had a seizure at C1D1 (who discontinued the trial). Among 6 pts evaluable for morphologic responses, ORR (complete remission [CR] + CR with incomplete count recovery), partial response, and no response rates were, respectively, 2 (33.3%), 2 (33.3%), and 2 (33.3%) at the end of olverembatinib monotherapy (EOM) and 5 (83.3%), 0, and 1 (16.7%) at the end of olverembatinib and lisaftoclax combination course (EOC). Five of 7 evaluable pts achieved MRD negativity, of which 1 was at EOM and 4 at EOC. Preliminary PK analyses revealed similar PK characteristics and comparable exposure between pediatric and adult populations for olverembatinib and lisaftoclax. There was no significant accumulation after multiple doses, and no drug-drug interactions were observed between olverembatinib and lisaftoclax.
These preliminary data showed that olverembatinib in combination with lisaftoclax appears to be a safe and effective regimen in patients with R/R Ph ALL. This regimen resulted in promising CR rates without intensive chemotherapy or immunotherapy. The study is currently in the dose-expansion phase.
At present, there are still many clinical trials of new anti-cancer technologies in China seeking patients. Consultation on new drugs and technologies, you can contact Beijing South Region Oncology Hospital International Department.
Phone Number：4008803716
Email：myimmnet@163.com
References
1.https://www.cde.org.cn/main/xxgk/listpage/9f9c74c73e0f8f56a8bfbc646055026d
2.发现和开发一流的小分子癌症疗法的领导者 - (ascentage.com)
Post time: Mar-12-2025