Second-line ASC Monotherapy Safely Elicits High Molecular Response Rates in Non-T315l-Mutant CML-CP

Asciminib (ASC) monotherapy remains a safe and effective second-line treatment for patients with chronic myeloid leukemia in chronic phase (CML-CP) without a T315I mutation, according to the results of an interim analysis (IA) of the phase 2 ASC2ESCALATE study. The trial’s first author, David J. Andorsky, MD, of Rocky Mountain Cancer Centers, presented updated efficacy (week 24) and safety findings from the single-arm, open-label trial at the 2025 ASCO® Annual Meeting. At week 24, ASC was found to elicit high molecular response rates, with no new or worsening safety signals, supporting the promise of breakpoint cluster region-Abelson tyrosine kinase inhibitors (TKIs) in this patient population.

The IA included 101 patients with second-line CML-CP, all of whom had previously received and subsequently discontinued adenosine triphosphate-binding TKI therapy due to treatment failure (per ELN2020), warning, or intolerance (with BCR::ABL1^IS >0.1% at screening). Dasatinib (44.6%) and imatinib (42.6%) were the most commonly administered TKIs in the cohort, followed by nilotinib (9.9%) and bosutinib (5.0%).

By the cutoff (November 15, 2024), 92 patients (91.1%) remained on ASC. The median duration of ASC exposure was 26.1 weeks (range, 6 to 100 weeks). Participants evaluable for all efficacy analyses either completed assessments at weeks 4 (n=94), 12 (n=86), and 24 (n=63) or discontinued ASC ahead of these time points. Although discontinuation occurred predominantly due to adverse events (AEs; n=4), followed closely by patient decision (n=3), ASC was generally well tolerated, leading to few discontinuations overall.

Grade 3 or more AEs included hypertension (8.9 %), thrombocytopenia (6.9%), and neutropenia (5.9%). There were no arterial-occlusive events or on-treatment deaths.

The study’s primary end point was the percentage of patients who achieved major molecular response (MMR), defined as BCR::ABL1^IS 0.1% or less. At week 24, 82.5% of patients had BCR::ABL1^IS 1% or less, building on earlier ASC2ESCALATE data demonstrating BCR::ABL1^IS responses of 1% or less of 84.9% at week 12 and 46.8% at week 4. Deeper responses were observed at both week 24 (MMR, 44.4%; MR⁴, 25.4%; MR^4.5, 9.5%) and week 12 (MMR, 39.5%; MR⁴, 11.6%; MR^4.5, 2.3%).

ASC 80 mg was administered once daily (QD). If BCR::ABL1 was greater than 1% at week 24, the dose was increased to 200 mg QD. Seven patients were eligible for dose escalation based on their response levels at week 24 (n=3).

If BCR::ABL1^IS  is greater than 0.1% at week 48, the dose will be increased from 80 to 200 mg QD or from 200 mg QD to 200 mg twice daily; alternatively, patients can be taken off the study. Investigators continue to monitor the impact of ASC dose escalation, with AEs prompting dose adjustment or interruption in 27 patients (26.7%) overall.