Asciminib (Scemblix) is a first-in-class BCR::ABL1 inhibitor that works by specifically targeting the ABL myristoyl pocket (STAMP) and has potent activity against the T315I mutation. This study aimed to characterize the effect of asciminib exposure on disease progression and to elucidate factors influencing efficacy. Our analysis included 303 patients with chronic myeloid leukemia in chronic phase recruited in a phase I study with dose ranging from 10 to 200 mg twice a day (b.i.d.) or 40 to 200 mg once a day (q.d.) (NCT02081378) and in the phase III ASCEMBL (Study of Efficacy of CML-CP Patients Treated With ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs) study receiving asciminib 40 mg b.i.d. (NCT03106779). A total of 67 patients harbored the T315I mutation. A longitudinal pharmacokinetic/pharmacodynamic model was developed to characterize the exposure–efficacy relationship, in which the efficacy was assessed through BCR::ABL1 transcript levels over time. Specifically, a three-compartment model representing quiescent leukemic stem cells, proliferating bone marrow cells, and resistant cells was developed. Drug killing of the proliferating cells by asciminib was characterized by a power model. A subgroup analysis was performed on the patients with the T315I mutation using a maximum drug effect model to characterize the drug effect. The model demonstrated the appropriateness of a total daily dose of asciminib 80 mg in patients without the T315I mutation and 200 mg b.i.d. in patients with the T315I mutation with further validation in light of safety data. This model captured key characteristics of patients' response to asciminib and helped inform dosing rationale for resistant and difficult-to-treat populations.

中文翻译：

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Asciminib 在费城染色体阳性慢性粒细胞白血病慢性期的暴露-疗效分析

Asciminib (Scemblix) 是一流的 BCR::ABL1 抑制剂，通过特异性靶向 ABL 肉豆蔻酰口袋 (STAMP) 发挥作用，并且对 T315I 突变具有强大的活性。本研究旨在描述 asciminib 暴露对疾病进展的影响，并阐明影响疗效的因素。我们的分析包括在 I 期研究中招募的 303 名处于慢性期的慢性粒细胞白血病患者，剂量范围为 10 至 200 mg 每天两次（bid）或 40 至 200 mg 每天一次（qd）（NCT02081378） III ASCEMBL（接受 ABL001 与 Bosutinib 治疗的 CML-CP 患者的疗效研究，之前接受过 2 种或更多 TKI 治疗）研究接受 asciminib 40 mg bid (NCT03106779)。共有 67 名患者携带 T315I 突变。BCR::ABL1随时间推移的转录水平。具体而言，开发了代表静止白血病干细胞、增殖骨髓细胞和耐药细胞的三室模型。asciminib 对增殖细胞的药物杀伤以功率模型为特征。使用最大药物效应模型对具有 T315I 突变的患者进行亚组分析以表征药物效应。该模型证明了在没有 T315I 突变的患者中 80 mg asciminib 的每日总剂量和在有 T315I 突变的患者中每天 200 mg bid 的适当性，并根据安全性数据进行了进一步验证。该模型捕获了患者对 asciminib 反应的关键特征，并有助于为耐药和难以治疗的人群提供剂量依据。