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Abstract：
Asciminib targets the BCR::ABL1 myristoyl pocket, maintaining activity against BCR::ABL1T315I, which is resistant to most approved adenosine triphosphate-competitive tyrosine kinase inhibitors. We report updated phase I results (NCT02081378) assessing safety/tolerability and antileukemic activity of asciminib monotherapy 200 mg twice daily in 48 heavily pretreated patients with T315I-mutated chronic-phase chronic myeloid leukemia (CML-CP; data cutoff: January 6, 2021). With 2 years\' median exposure, 56.3% of patients continued receiving asciminib. Overall, 62.2% of evaluable patients achieved BCR::ABL1 ≤1% on the International Scale (IS); 47.6% and 81.3% of ponatinib-pretreated and -naive patients, respectively, achieved BCR::ABL1IS ≤1%. Of 45 evaluable patients, 48.9% achieved a major molecular response (MMR, BCR::ABL1IS ≤0.1%), including 34.6% and 68.4% of ponatinib-pretreated and -naive patients, respectively. MMR was maintained until data cutoff in 19 of 22 patients who achieved it. The most common grade ≥3 adverse events (AEs) included increased lipase level (18.8%) and thrombocytopenia (14.6%). Five (10.4%) patients experienced AEs leading to discontinuation, including 2 who discontinued asciminib and died due to COVID-19; these were the only deaths reported. These results show asciminib\'s effectiveness, including in almost 50% of ponatinib pretreated patients, and confirm its risk-benefit profile, supporting its use as a treatment option for T315I-mutated CML-CP.
摘要：
Asciminib靶向BCR::ABL1肉豆蔻酰基口袋，保持针对BCR的活动::ABL1T315I，对大多数批准的三磷酸腺苷竞争性酪氨酸激酶抑制剂具有抗性。我们报告了最新的I期结果（NCT02081378），评估了48例T315I突变的慢性期慢性髓细胞性白血病（CML-CP；数据截止时间：2021年1月6日）重度预治疗的48例接受T315I突变的慢性期慢性髓细胞性白血病患者的安全性/耐受性和抗白血病活性。平均暴露时间为2年，56.3%的患者继续接受asciminib。总的来说,62.2%的可评估患者达到BCR::ABL1≤1%的国际规模(IS);47.6%和81.3%的ponatinib预处理和-naive患者,分别,达到BCR::ABL1IS≤1%。在45名可评估的患者中，48.9%实现了主要分子反应(MMR，BCR::ABL1IS≤0.1%),包括34.6%和68.4%的普纳替尼预处理和初治患者，分别。MMR一直维持到22名患者中的19名达到数据截止为止。最常见的≥3级不良事件（AE）包括脂肪酶水平升高（18.8%）和血小板减少（14.6%）。5例（10.4%）患者出现AE导致停药，包括2名因COVID-19停药并死亡的患者;这是唯一报告的死亡病例。这些结果显示了阿西替尼的有效性，包括近50%的普纳替尼预处理患者，并确认其风险收益状况，支持将其用作T315I突变的CML-CP的治疗选择。
