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

Olverembatinib, which is approved in China, has only been tested in Chinese patients.

在中国获批的奥雷巴替尼仅在中国患者中进行了测试。

Background

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.

评估奥雷姆巴替尼在至少2种酪氨酸激酶抑制剂耐药或不耐受的慢性髓性白血病或费城染色体阳性急性淋巴细胞白血病患者中的药代动力学、安全性、疗效和推荐剂量。

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.

设计、设置和参与者：这项多中心1b期随机临床试验从2020年1月28日开始，至2024年1月2日结束，中位（范围）随访时间为48（0-166）周。

Patients with CML or Philadelphia chromosome-positive ALL were enrolled.

招募了患有慢性髓性白血病（CML）或费城染色体阳性急性淋巴细胞白血病（ALL）的患者。

This bridging study was performed in part to confirm that there are no racial differences in the pharmacokinetic profile of olverembatinib.

这项桥接研究部分是为了确认在奥雷姆巴替尼的药代动力学特征中不存在种族差异。

Methods

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

患者被随机分配接受每28天为一个周期，每周期隔日口服30、40或50毫克的olverembatinib。

main_outcomes_and_measures

Pharmacokinetic profile of olverembatinib.

olverembatinib的药代动力学特征。

Results

Of 80 included patients, 46 (58%) were male, and the median (range) age was 54.0 (21-80) years.

在纳入的80名患者中，46名（58%）为男性，中位年龄（范围）为54.0（21-80）岁。

The pharmacokinetic profile of olverembatinib was compatible with alternate-day dosing and similar to that in Chinese patients.

奥雷姆巴替尼的药代动力学特征与隔日给药相兼容，并且与在中国患者中的特征相似。

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%]).

根据研究者的评估，60名患者（75%）经历了至少1次与治疗相关的不良事件；32名（40%）经历了3级或更高级别的与治疗相关的不良事件；12名（15%）经历了与治疗相关的严重不良事件，但均未致命。频繁报告（10%或更多）的治疗后不良事件包括血清肌酸激酶升高（所有级别，31名[39%]；3级或更高级别，10名[13%]）和血小板减少症（所有级别，23名[29%]；3级或更高级别，14名[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).

在可评估的慢性期CML患者中，完全细胞遗传学反应（CCyR）发生在51名患者中的31名（61%；95% 置信区间, 46.1-74.2），主要分子反应（MMR）发生在59名患者中的25名（42%；95% 置信区间, 29.6-55.9）。

Cytogenetic and molecular responses were similar in patients with or without T315I variants.

具有或不具有T315I变异的患者的细胞遗传学和分子反应相似。

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.

在接受过ponatinib治疗的26名患者中，共有15名（58%；95%置信区间，36.9-76.6）达到了完全细胞遗传学反应（CCyR），而在30名患者中，有11名（37%；95%置信区间，19.9-56.1）达到了主要分子反应（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.

在8名对asciminib耐药的患者中，共有4名患者(50%; 95% 置信区间, 15.7-84.3)实现了CCyR，而在12名患者中，有4名(33%; 95% 置信区间, 9.9-65.1)实现了MMR。

The recommended phase 3 dose of olverembatinib is 30 mg every other day in patients without T315I variants.

在没有T315I变异的患者中，olverembatinib的推荐III期剂量为隔日30毫克。

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.

在这项试验中，olverembatinib具有良好的药代动力学特性，通常耐受性良好，并且在经过重度预处理的慢性期CML患者中显示出强大的抗白血病活性，无论是否携带T315I变异，包括之前对ponatinib和/或asciminib治疗失败的患者。

Olverembatinib may provide a viable new treatment option for patients after failure of 2 or more TKIs.

olverembatinib可能为在两种或更多TKIs治疗失败后的患者提供一种可行的新治疗选择。

trial_registration

ClinicalTrials.gov Identifier: NCT04260022.

临床试验注册号：NCT04260022。