BACKGROUND Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown. METHODS In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months. RESULTS Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia. CONCLUSIONS Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.).

中文翻译：

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阿西米尼 (Asciminib) 治疗 ABL 激酶抑制剂失效后的慢性粒细胞白血病。


背景阿西米尼是一种变构抑制剂，可结合 BCR-ABL1 蛋白的肉豆蔻酰位点，通过与所有其他 ABL 激酶抑制剂不同的机制将 BCR-ABL1 锁定为失活构象。 Asciminib 靶向天然和突变的 BCR-ABL1，包括守门人 T315I 突变体。阿西米尼在费城染色体阳性白血病患者中的安全性和抗白血病活性尚不清楚。方法 在这项 1 期剂量递增研究中，我们招募了 141 名慢性期患者和 9 名加速期慢性粒细胞白血病 (CML) 患者，这些患者对至少两种先前的 ATP 竞争性酪氨酸激酶抑制剂产生耐药性或出现不可接受的副作用（TKIs）。主要目的是确定阿西米尼的最大耐受剂量或推荐剂量（或两者）。阿西米尼每天给药一次或两次（剂量为 10 至 200 mg）。中位随访时间为 14 个月。结果 患者接受了大量的预处理； 70%（150 名患者中的 105 名）接受过至少三种 TKI。未达到阿西米尼的最大耐受剂量。在慢性期 CML 患者中，34 名（92%）血液学复发患者出现了完全血液学缓解； 31 名（54%）在基线时没有完整的细胞遗传学反应的人有完整的细胞遗传学反应。在可评估的 48% 患者中，主要分子缓解达到或维持了 12 个月，其中 14 名患者中的 8 名 (57%) 被认为对 ponatinib 有耐药性或出现不可接受的副作用。基线时有 T315I 突变的 5 名患者 (28%) 达到或维持了 12 个月的主要分子缓解。临床反应持久； 44 名患者中有 40 名维持了主要分子学反应。 剂量限制性毒性作用包括脂肪酶水平无症状升高和临床胰腺炎。常见的不良事件包括疲劳、头痛、关节痛、高血压和血小板减少。结论 阿西米尼对于接受过多次治疗、对 TKI 产生耐药性或出现不可接受的副作用的 CML 患者有效，包括普纳替尼治疗失败的患者和具有 T315I 突变的患者。 （由诺华制药资助；ClinicalTrials.gov 编号，NCT02081378。）。