Cortes Jorge E, Lang Fabian, Rea Delphine, Hochhaus Andreas, Breccia Massimo, Goh Yeow Tee, Heinrich Michael C, Hughes Timothy P, Janssen Jeroen J W M, le Coutre Philipp, Minami Hironobu, Sasaki Koji, DeAngelo Daniel J, Sanchez-Olle Gessami, Pognan Nathalie, Cao Meng, Hoch Matthias, Mauro Michael J
Georgia Cancer Center at Augusta University, Augusta, GA, USA.
Department for Hematology/Oncology, Goethe University Hospital, Frankfurt am Main, Germany.
Leukemia. 2025 May;39(5):1124-1134. doi: 10.1038/s41375-025-02592-9. Epub 2025 Apr 9.
Data from in vitro and animal studies suggest that asciminib, the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), synergizes with adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) to prevent emergence of and overcome resistance. Combination therapy may provide new treatment options for patients with chronic myeloid leukemia (CML) with suboptimal responses to ATP-competitive TKI monotherapy. Preliminary analysis of asciminib combined with nilotinib, imatinib, or dasatinib in a phase 1 dose-escalation study suggested promising efficacy and safety for patients with CML in chronic phase or accelerated phase treated with prior ATP-competitive TKIs; herein, we present final results from the 3 combination therapy arms. Asciminib, in combination with ATP-competitive TKIs, demonstrated rapid efficacy offset by a decreased tolerability compared with asciminib monotherapy. Based on these safety, tolerability, and preliminary efficacy results, asciminib 40 mg twice daily (BID) plus nilotinib 300 mg BID, asciminib 40 or 60 mg once daily (QD) plus imatinib 400 mg QD, and asciminib 80 mg QD plus dasatinib 100 mg QD were identified as recommended doses for expansion. The maximum tolerated dose was reached at asciminib 60 mg QD plus imatinib 400 mg QD and was not reached with asciminib plus nilotinib or dasatinib.
来自体外和动物研究的数据表明，阿伐替尼是首个特异性靶向ABL肉豆蔻酰口袋（STAMP）的BCR::ABL1抑制剂，它与三磷酸腺苷（ATP）竞争性酪氨酸激酶抑制剂（TKIs）协同作用，以预防和克服耐药性的出现。联合治疗可能为对ATP竞争性TKI单药治疗反应欠佳的慢性髓性白血病（CML）患者提供新的治疗选择。在一项1期剂量递增研究中，对阿伐替尼联合尼洛替尼、伊马替尼或达沙替尼的初步分析表明，对于接受过ATP竞争性TKIs治疗的慢性期或加速期CML患者，具有有前景的疗效和安全性；在此，我们展示了3个联合治疗组的最终结果。与阿伐替尼单药治疗相比，阿伐替尼与ATP竞争性TKIs联合使用时，疗效迅速，但耐受性降低。基于这些安全性、耐受性和初步疗效结果，阿伐替尼40mg每日两次（BID）加尼洛替尼300mg BID、阿伐替尼40或60mg每日一次（QD）加伊马替尼400mg QD以及阿伐替尼80mg QD加达沙替尼100mg QD被确定为推荐的扩大剂量。在阿伐替尼60mg QD加伊马替尼400mg QD时达到了最大耐受剂量，而阿伐替尼加尼洛替尼或达沙替尼未达到最大耐受剂量。
