CML-423 Trial in Progress: A Phase III Study of Asciminib vs an Investigator-Selected Tyrosine Kinase Inhibitor (TKI) in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Context: Four TKIs are approved for first-line (1L) use in CML-CP: the first-generation TKI imatinib and the second-generation (2G) TKIs bosutinib, dasatinib, and nilotinib. However, in 1L CML-CP, >50% of patients treated with imatinib develop resistance/intolerance to therapy, and 30%-40% of patients treated with a 2G TKI need to change therapy by 5 years. While 2G TKIs yield a higher major molecular response (MMR) than imatinib, they are associated with more adverse events (AEs). Asciminib is a recently approved BCR::ABL1 inhibitor that targets the ABL1 myristoyl pocket. In the phase III ASCEMBL trial in patients with CML-CP treated with ≥2 prior TKIs, asciminib resulted in improved MMR (25.5% vs 13.2%) at week 24 and fewer treatment discontinuations due to AEs (5.8% vs 21.1%) vs bosutinib. We present a phase III trial evaluating asciminib vs an investigator-selected approved TKI in 1L CML-CP. As of March 28, 2022, 69 patients were randomized and receiving treatment. Objective: To assess the efficacy of asciminib vs investigator-selected TKI and asciminib vs imatinib within the stratum of patients who selected imatinib as the prerandomization TKI, via the primary endpoint of MMR at week 48. The study will be positive if either of these objectives is met. Design: This is a multicenter, open-label, randomized, phase III study (NCT04971226). Newly diagnosed adults with CML-CP who have not received prior TKI therapy for CML, except for ≤2 weeks of imatinib, bosutinib, dasatinib, or nilotinib therapy, are eligible. Prior to randomization, patients and investigators will select a prerandomization TKI; 50% of patients who select imatinib and 50% who select a 2G TKI as their prerandomization TKI will be randomized to the investigator-selected TKI arm; the remaining 50% from each group will be randomized to receive asciminib. End of Study (EOS) is 5 years from the last patient first treatment. Interventions: Asciminib 80mg once daily (QD), or an investigator-selected TKI (imatinib, bosutinib, dasatinib, or nilotinib at their approved doses) until EOS or premature discontinuation. Main Outcome Measures: MMR at week 48 is the primary endpoint, with MMR at week 96, safety, and deep molecular responses as secondary endpoints.