Asciminib (BCR::ABL1 STAMP inhibitor) delivers durable molecular responses in T315I-mutant CML

Asciminib, an allosteric inhibitor that targets the ABL1 myristoyl pocket rather than the ATP-binding site, was evaluated at 200 mg twice daily in a nonrandomized Phase 1 trial (NCT02081378) of heavily pretreated T315I-mutated chronic-phase CML (n=48; 45 molecularly evaluable). After median exposure of 3.5 years and up to approximately 6 years of treatment, 53.3% achieved major molecular response (MMR), including 73.7% of ponatinib-naive and 38.5% of ponatinib-pretreated patients; 20 of 24 responders maintained or deepened MMR, with an estimated 86% maintaining their first MMR for at least 144 weeks. Grade≥3 AEs occurred in 60.4%, but did not increase with the additional 1.4 years of exposure; 8.3% discontinued for AEs, while the exposure-adjusted arterial occlusive event rate was 4.4 per 100 patient-years. For context, ponatinib produced a 58% MMR rate in T315I-mutated CML-CP in PACE, but only an estimated 60% of responders maintained MMR at 5 years; asciminib is already FDA-approved in the US for T315I-mutated CML-CP at this dose.