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

IF 28.4 1区医学 Q1 Biochemistry, Genetics and Molecular Biology

Jama Oncology Pub Date : 2025-01-01 DOI:10.1001/jamaoncol.2024.5157

Elias Jabbour, Vivian G Oehler, Paul B Koller, Omer Jamy, Elza Lomaia, Anthony M Hunter, Olga Uspenskaya, Svetlana Samarina, Sudipto Mukherjee, Jorge E Cortes, Maria R Baer, Vera Zherebtsova, Vasily Shuvaev, Anna Turkina, Igor Davydkin, Huanshan Guo, Zi Chen, Tommy Fu, Lixin Jiang, Cunlin Wang, Hengbang Wang, Dajun Yang, Yifan Zhai, Hagop Kantarjian

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引用次数: 0

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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酪氨酸激酶抑制剂（包括 Ponatinib 或 Asciminib）治疗失败后的 Olverembatinib：1b期随机临床试验。

重要性：对BCR-ABL1酪氨酸激酶抑制剂（TKIs）耐药或不耐受的慢性髓性白血病（CML）或费城染色体阳性急性淋巴细胞白血病（ALL）患者的治疗选择有限。奥瑞巴替尼（Olverembatinib）已在中国获批，但目前仅在中国患者中进行了试验：目的：评估奥罗瑞巴替尼在对至少两种TKIs耐药或不耐受的CML或费城染色体阳性ALL患者中的药代动力学、安全性、疗效和推荐剂量：这项多中心1b期随机临床试验于2020年1月28日至2024年1月2日进行，中位（范围）随访48（0-166）周。CML 或费城染色体阳性 ALL 患者入组。这项桥接研究的部分目的是确认奥罗瑞巴替尼的药代动力学特征不存在种族差异：患者被随机分配到30、40或50毫克的olverembatinib，每隔一天口服一次，周期为28天：主要结果和测量指标：olverembatinib的药代动力学特征：在纳入的80例患者中，46例（58%）为男性，年龄中位数（范围）为54.0（21-80）岁。奥罗瑞巴替尼的药代动力学特征与隔日给药相符，与中国患者的药代动力学特征相似。根据研究人员的评估，60名患者（75%）至少出现过一次治疗相关不良事件；32名患者（40%）出现过3级或以上治疗相关不良事件；12名患者（15%）出现过治疗相关严重不良事件，其中无死亡病例。经常报告的（10%或以上）治疗相关不良事件包括血肌酸磷酸激酶升高（所有级别，31[39%]；3级或以上，10[13%]）和血小板减少（所有级别，23[29%]；3级或以上，14[18%]）。在可评估的慢性期CML患者中，51例患者中有31例出现完全细胞遗传学应答（CCyR）（61%；95% CI，46.1-74.2），59例患者中有25例出现主要分子应答（MMR）（42%；95% CI，29.6-55.9）。有或没有 T315I 变异的患者的细胞遗传学和分子反应相似。在 26 例曾接受过波那替尼治疗的患者中，共有 15 例（58%；95% CI，36.9-76.6）获得了 CCyR，30 例中有 11 例（37%；95% CI，19.9-56.1）获得了 MMR。在8例抗阿西米尼的患者中，共有4例（50%；95% CI，15.7-84.3）获得CCyR，12例中有4例（33%；95% CI，9.9-65.1）获得MMR。在没有T315I变异的患者中，奥罗瑞巴替尼的3期推荐剂量为30毫克，隔天一次：在这项试验中，olverembatinib具有良好的药代动力学特征，耐受性普遍良好，在重度预处理慢性期CML患者中显示出很强的抗白血病活性，无论是否存在T315I变异，包括既往使用过波那替尼和/或阿西米尼失败的患者。Olverembatinib可能会为2种或2种以上TKIs治疗失败的患者提供一种可行的新治疗方案：试验注册：ClinicalTrials.gov Identifier：NCT04260022。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Jama Oncology Medicine-Oncology

CiteScore

37.50

自引率

1.80%

发文量

423

期刊介绍： At JAMA Oncology, our primary goal is to contribute to the advancement of oncology research and enhance patient care. As a leading journal in the field, we strive to publish influential original research, opinions, and reviews that push the boundaries of oncology science. Our mission is to serve as the definitive resource for scientists, clinicians, and trainees in oncology globally. Through our innovative and timely scientific and educational content, we aim to provide a comprehensive understanding of cancer pathogenesis and the latest treatment advancements to our readers. We are dedicated to effectively disseminating the findings of significant clinical research, major scientific breakthroughs, actionable discoveries, and state-of-the-art treatment pathways to the oncology community. Our ultimate objective is to facilitate the translation of new knowledge into tangible clinical benefits for individuals living with and surviving cancer.