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Asciminib plus nilotinib, imatinib, or dasatinib were effective in patients with CML in chronic or accelerated phase.
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Asciminib (Scemblix) in combination with adenosine triphosphate (ATP)–competitive TKIs showed promising efficacy in patients with chronic myeloid leukemia (CML) in chronic or accelerated phase, according to data from a phase 1 study (NCT02081378) published in Leukemia.
At any time point, evaluable patients with CML in chronic or accelerated phase who received asciminib/nilotinib (Tasigna; n = 8/22), asciminib/imatinib (Gleevec; n = 11/20), or asciminib/dasatinib (Sprycel; n = 15/26) experienced a major molecular response (MMR). The median times to onset of MMR were 20.1 weeks, 20.9 weeks, and 22.1 weeks, respectively. At week 96, the respective MMR rates were 31.8%, 45.0%, and 46.2%. At week 432, these rates were 36.4%, 55.0%, and 57.7%, respectively.
The maximum tolerated dose (MTD) of asciminib was 60 mg once daily in combination with imatinib 400 mg once daily. The MTD was not reached for asciminib plus nilotinib or dasatinib. The recommended doses for expansion were 40 mg of asciminib twice daily plus nilotinib 300 mg twice daily; asciminib at a dose of 40 mg or 60 mg once daily plus imatinib 400 mg once daily; and asciminib 80 mg plus dasatinib 100 mg both administered once daily.
“This study provides evidence of asciminib plus nilotinib, imatinib, or dasatinib as potential treatment strategies that may help some patients with limited therapeutic options after several lines of therapy achieve their goals,” the study authors wrote in the publication.
The open-label, multicenter study enrolled patients who were at least 18 years old with Philadelphia chromosome–positive CML in chronic or accelerated phase. To be eligible for the trial, patients also needed to have an ECOG performance status of 0 to 2 and have received prior treatment with at least 2 TKIs, or with T315I with at least 1 previous TKI.
Patients received asciminib based on available monotherapy dose-escalation data and the anticipated risk when combining the agent with nilotinib, imatinib, or dasatinib. Patients in the asciminib/nilotinib arm received 20 mg or 40 mg of asciminib twice daily in combination with the standard dose of nilotinib (300 mg twice daily). In the asciminib/imatinib arm, patients received asciminib at a dose of 40 mg twice daily, or 40 mg, 60 mg, or 80 mg once daily, plus standard-dose imatinib (400 mg once daily). Patients in the asciminib/dasatinib arm were treated with dasatinib at the standard dose (100 mg once daily) in combination with 40 mg of asciminib twice daily or 80 mg or 160 mg once daily.
The primary end points were to determine the MTD and/or the recommended dose for expansion by the incidence of dose-limiting toxicities (DLTs) during the first cycle of treatment. Secondary end points included preliminary efficacy, safety and tolerability, and pharmacokinetic measures.
At baseline, the median age in the asciminib plus nilotinib (n = 26), imatinib (n = 25), and dasatinib (n = 32) arms was 55.5 years (range, 23-78), 57 years (range, 22-79), and 53 years (range, 19-76), respectively. Most patients in each arm were White (80.8% vs 68.0% vs 62.5%) and had an ECOG performance status of 0 (73.1% vs 68.0% vs 78.1%). Patients in each arm previously received 2 (38.5% vs 40.0% vs 53.1%), 3 (23.1% vs 20.0% vs 28.1%), 4 (30.8% vs 24.0% vs 15.6%), or 5 or more (7.7% vs 16.0% vs 3.1%) TKIs. Prior TKIs consisted of bosutinib (Bosulif; 38.5% vs 48.0% vs 31.3%), dasatinib (88.5% vs 76.0% vs 56.3%), imatinib (69.2% vs 68.0% vs 75.0%), nilotinib (69.2% vs 92.0% vs 75.0%), ponatinib (Iclusig; 30.8% vs 28.0% vs 28.1%), or radotinib (7.7% vs 4.0% vs 3.1%).
In the asciminib plus nilotinib, imatinib, and dasatinib arms, respectively, the median duration of asciminib exposure was 3.0 years (range, 0.2-7.4), 5.2 years (range, 0.5-6.6), and 2.8 years (range, 0.2-6.3). The median duration of TKI treatment in the respective arms was 1.6 years (range, 0.0-7.2), 1.6 years (range, 0.0-6.6), and 1.7 years (range, 0.2-5.8).
At week 24, the MMR rates in the nilotinib, imatinib, and dasatinib arms were 22.7%, 35.0%, and 30.8%, respectively. The 48-week MMR rates were 27.3%, 40.0%, and 38.5%, respectively; the 144-week rates were 36.4%, 45.0%, and 53.8%, respectively; and the 312-week rates were 36.4%, 55.0%, and 57.7%, respectively.
In terms of safety, adverse effects (AEs) leading to dose adjustments or interruptions of asciminib occurred at rates of 65.4%, 60.0%, and 68.8% in the nilotinib, imatinib, and dasatinib arms, respectively. DLTs were reported at rates of 6.3%, 24.0%, and 9.1%, respectively. No deaths were reported during treatment or within 30 days following the last therapy. Any-grade AEs of special interest occurring in at least 30% of patients in any arm in the nilotinib, imatinib, and dasatinib arms included gastrointestinal toxicity (61.5% vs 84.0% vs 65.6%), hypersensitivity (46.2% vs 48.0% vs 40.6%), myelosuppression (42.3% vs 48.0% vs 43.8%), hepatotoxicity (34.6% vs 36.0% vs 18.8%), thrombocytopenia (30.8% vs 32.0% vs 37.5%), edema and fluid retention (26.9% vs 28.0% vs 43.8%), and pancreatic events (42.3% vs 36.0% vs 34.4%).
“Asciminib, in combination with ATP-competitive TKIs, demonstrated rapid efficacy offset by a decreased tolerability compared with asciminib monotherapy,” the study authors concluded.
Cortes JE, Lang F, Rea D, et al. Asciminib in combination with imatinib, nilotinib, or dasatinib in patients with chronic myeloid leukemia in chronic or accelerated phase: phase 1 study final results. Leukemia. 2025;39(5):1124-1134. doi:10.1038/s41375-025-02592-9