Asciminib is a potent and selective inhibitor of BCR::ABL1, with potential to avoid toxicity resulting from off-target kinase inhibition. Forty-nine patients treated with asciminib under a managed access program in the UK were evaluated for toxicity and response. Intolerance, rather than resistance (65% vs. 35%), was the most common reason for cessation of the last-line of treatment but asciminib was well tolerated, with most patients (29, 59%) remaining on treatment at a median of 14 months follow-up, and only 6 (12%) stopping for intolerance. Of 44 patients assessable for response, 29 (66%) achieved a complete cytogenetic response (CCyR) or better, with poorer responses seen in those stopping their last-line of therapy for resistance. Fewer patients with a prior history of a non-T315I-BCR::ABL1 single nucleotide variant (BSNV), or a non-T315I-BSNV detectable at baseline achieved CCyR. Serial tracking of BSNV by next generation sequencing demonstrated clonal expansion of BSNV-harbouring populations, which in some settings was associated with resistance (E459K, F317L, F359I), while in others was seen in the context of ongoing response, often with intensified dosing (T315I, I502F). These data suggest that asciminib exerts selective pressure on some BSNV-harbouring populations in vivo, some of which may respond to intensified dosing.

Asciminib 是一种有效的选择性 BCR：：ABL1 抑制剂，有可能避免脱靶激酶抑制引起的毒性。在英国的一项管理性访问计划下接受 asciminib 治疗的 49 例患者接受了毒性和反应评估。不耐受而不是耐药 （65% vs. 35%） 是停止最后一线治疗的最常见原因，但 asciminib 耐受性良好，大多数患者 （29， 59%） 在中位随访 14 个月时仍在接受治疗，只有 6 名 （12%） 因不耐受而停止治疗。在 44 名可评估反应的患者中，29 名 （66%） 实现了完全细胞遗传学反应 （CCyR） 或更好，而那些因耐药而停止最后一线治疗的患者的反应较差。既往有非 T315I-BCR：：ABL1 单核苷酸变异 （BSNV） 病史或在基线时可检测到的非 T315I-BSNV 的患者较少达到 CCyR。通过下一代测序对 BSNV 进行连续追踪显示 BSNV 携带群体的克隆扩增，这在某些情况下与耐药性有关（E459K、F317L、F359I），而在其他情况下则是在持续反应的情况下观察到的，通常剂量增加（T315I、I502F）。这些数据表明，asciminib 在体内对一些携带 BSNV 的群体施加选择压力，其中一些可能对强化给药有反应。