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Clinical Trial
. 2025 Jan 1;11(1):28-35.
doi: 10.1001/jamaoncol.2024.5157.

Olverembatinib After Failure of Tyrosine Kinase Inhibitors, Including Ponatinib or Asciminib: A Phase 1b Randomized Clinical Trial

Elias Jabbour  1 , Vivian G Oehler  2 , Paul B Koller  3 , Omer Jamy  4 , Elza Lomaia  5 , Anthony M Hunter  6 , Olga Uspenskaya  7 , Svetlana Samarina  8 , Sudipto Mukherjee  9 , Jorge E Cortes  10 , Maria R Baer  11 , Vera Zherebtsova  12 , Vasily Shuvaev  13 , Anna Turkina  14 , Igor Davydkin  15 , Huanshan Guo  16 , Zi Chen  17 , Tommy Fu  18 , Lixin Jiang  18 , Cunlin Wang  18 , Hengbang Wang  17 , Dajun Yang  17   18   19 , Yifan Zhai  16   17   18 , Hagop Kantarjian  1
Affiliations
Clinical Trial

Olverembatinib After Failure of Tyrosine Kinase Inhibitors, Including Ponatinib or Asciminib: A Phase 1b Randomized Clinical Trial

Elias Jabbour et al. JAMA Oncol. .

Abstract

Importance: Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) resistant or intolerant to BCR-ABL1 tyrosine kinase inhibitors (TKIs) have limited treatment options. Olverembatinib, which is approved in China, has only been tested in Chinese patients.

Objective: To assess the pharmacokinetics, safety, efficacy, and recommended dose of olverembatinib in patients with CML or Philadelphia chromosome-positive ALL resistant or intolerant to at least 2 TKIs.

Design, setting, and participants: This multicenter phase 1b randomized clinical trial was conducted from January 28, 2020, to January 2, 2024, with a median (range) follow-up of 48 (0-166) weeks. Patients with CML or Philadelphia chromosome-positive ALL were enrolled. This bridging study was performed in part to confirm that there are no racial differences in the pharmacokinetic profile of olverembatinib.

Interventions: Patients were randomly assigned to 30, 40, or 50 mg of olverembatinib orally every other day in 28-day cycles.

Main outcomes and measures: Pharmacokinetic profile of olverembatinib.

Results: Of 80 included patients, 46 (58%) were male, and the median (range) age was 54.0 (21-80) years. The pharmacokinetic profile of olverembatinib was compatible with alternate-day dosing and similar to that in Chinese patients. Based on investigators' assessments, 60 patients (75%) experienced at least 1 treatment-related adverse event; 32 (40%) experienced grade 3 or higher treatment-related adverse events; and 12 (15%) experienced treatment-related serious adverse events, none of which were fatal. Frequently reported (10% or more) treatment-emergent adverse events included elevated blood creatine phosphokinase (all grades, 31 [39%]; grade 3 or higher, 10 [13%]) and thrombocytopenia (all grades, 23 [29%]; grade 3 or higher, 14 [18%]). Among evaluable patients with chronic-phase CML, complete cytogenetic response (CCyR) occurred in 31 of 51 patients (61%; 95% CI, 46.1-74.2), and major molecular response (MMR) occurred in 25 of 59 patients (42%; 95% CI, 29.6-55.9). Cytogenetic and molecular responses were similar in patients with or without T315I variants. A total of 15 of 26 patients with prior ponatinib treatment (58%; 95% CI, 36.9-76.6) achieved CCyR, and 11 of 30 (37%; 95% CI, 19.9-56.1) achieved MMR. A total of 4 of 8 patients with asciminib resistance (50%; 95% CI, 15.7-84.3) had CCyR, and 4 of 12 (33%; 95% CI, 9.9-65.1) had MMR. The recommended phase 3 dose of olverembatinib is 30 mg every other day in patients without T315I variants.

Conclusions and relevance: In this trial, olverembatinib had a favorable pharmacokinetic profile, was generally well tolerated, and showed strong antileukemic activity in patients with heavily pretreated chronic-phase CML with or without T315I variants, including prior ponatinib and/or asciminib failure. Olverembatinib may provide a viable new treatment option for patients after failure of 2 or more TKIs.

Trial registration: ClinicalTrials.gov Identifier: NCT04260022.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Jabbour reported grants from Amgen, Ascentage Pharma Group Inc., Pfizer, Novartis, Takeda, ASTX, Adaptive Biotechnologies, Kite, and Autolus as well as personal fees from Bristol Myers Squibb during the conduct of the study. Dr Oehler reported grants from Pfizer; consulting fees from Terns Pharmaceuticals and Novartis; and financial support from Ascentage Pharma Group Inc. outside the submitted work. Dr Koller reported personal fees from Ascentage Pharma Group Inc. during the conduct of the study; personal fees from Daiichi Sankyo, Bristol Myers Squibb, Novartis, and Takeda; and nonfinancial support from Treadwell Therapeutics outside the submitted work. Dr Jamy reported grants from Ascentage Pharma Group Inc. during the conduct of the study as well as personal fees from Ascentage Pharma Group Inc. outside the submitted work. Dr Lomaia reported personal fees from Novartis, Pfizer, Medconnect, and R-Pharm outside the submitted work. Dr Hunter reported research support from Ascentage Pharma Group Inc. during the conduct of the study; personal fees from GlaxoSmithKline, Cogent Biosciences, Blueprint Medicines, Incyte, PharmaEssentia, and CTI Biopharma; and research support from Incyte, Cogent Biosciences, Blueprint Medicines, Syntrix Biosystems, Novartis, and PharmaEssentia outside the submitted work. Dr Mukherjee reported grants from Celgene (now BMS); honorarium from Bristol Myers Squibb, Recordati (formerly EUSA), Blueprint Medicines, Genentech/AbbVie, and Novartis; and grants from Novartis and Jazz Pharmaceuticals outside the submitted work. Dr Cortes reported grants from Ascentage Pharma Group Inc. during the conduct of the study; grants from Novartis and Sun Pharma; and personal fees from Novartis, Sun Pharma, Takeda, Tern Pharma, Takeda, and Incyte outside the submitted work. Dr Turkina reported honoraria for lecturing from Novartis, Pfizer, and R-Pharm. Drs Guo, Fu, Jiang, C. Wang, and H. Wang reported stock options in Ascentage Pharma Group Inc. outside the submitted work. Dr Chen reported a patent for WO2020114348A1 issued as well as stock options in Ascentage Pharma Group Inc. outside the submitted work. Dr Yang holds fiduciary officer positions in Ascentage Pharma Group Inc. Drs Yang and Zhai reported a patent for WO2022105836A1 issued and a patent for WO2020114348A1 issued; own stock options in Ascentage Pharma Group Inc. outside the submitted work; and hold leadership positions in all Ascentage Pharma Group Inc. affiliates. Dr Kantarjian reported grants from AbbVie, Amgen, Ascentage Pharma Group Inc., Bristol Myers Squibb, Daiichi-Sankyo, ImmunoGen, Jazz Pharmaceuticals, and Novartis as well as payment or honoraria from AbbVie, Amgen, Amphista, Ascentage Pharma Group Inc., Astellas, Biologix, Ipsen, KAHR Medical, and Labcorp outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Trial Profile (Patient Disposition Flow Diagram)
See this image and copyright information in PMC

Comment in

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