Background
Phase 3, open-label, randomized controlled trial (ASCEMBL). N=233 patients with CP-CML who had received ≥2 prior TKIs (resistant or intolerant), excluding T315I-mutant patients (separate cohort). Randomized 2:1 to asciminib vs bosutinib. Asciminib 40 mg BID was used; this dose does not cover T315I (the T315I cohort used 200 mg BID). Asciminib is a STAMP inhibitor binding the myristoyl pocket. This was the registrational phase 3 trial for asciminib in previously treated CML. Published Blood 2021 with updates at 96 weeks (Leukemia 2023) and 156 weeks (Blood Adv 2025).
Interventions and follow up
Arm A: Asciminib 40 mg PO twice daily until progression or unacceptable toxicity
Arm B: Bosutinib 500 mg PO once daily until progression or unacceptable toxicity
Primary endpoint: MMR (BCR-ABL IS ≤0.1%) at 24 weeks
Median follow-up: 14.9 months (primary); 96 weeks (Leukemia 2023); 156 weeks (Blood Adv 2025)
Arm B: Bosutinib 500 mg PO once daily until progression or unacceptable toxicity
Primary endpoint: MMR (BCR-ABL IS ≤0.1%) at 24 weeks
Median follow-up: 14.9 months (primary); 96 weeks (Leukemia 2023); 156 weeks (Blood Adv 2025)
Results
MMR at 24 weeks: 25.5% (asciminib) vs 13.2% (bosutinib), risk difference +12.2%, P=.029
MMR at 96 weeks: 37.6% vs 15.8% (Leukemia 2023)
MMR at 156 weeks: ~40.8% vs ~15.8% (Blood Adv 2025)
MR4.5 at 96 weeks: 8.9% (asciminib) vs 1.3% (bosutinib)
T315I cohort (asciminib 200 mg BID, n=23), MMR at 24 weeks: 42%
On-treatment discontinuation: 5.8% (asciminib) vs 21.1% (bosutinib)
MMR at 96 weeks: 37.6% vs 15.8% (Leukemia 2023)
MMR at 156 weeks: ~40.8% vs ~15.8% (Blood Adv 2025)
MR4.5 at 96 weeks: 8.9% (asciminib) vs 1.3% (bosutinib)
T315I cohort (asciminib 200 mg BID, n=23), MMR at 24 weeks: 42%
On-treatment discontinuation: 5.8% (asciminib) vs 21.1% (bosutinib)
Adverse events
Hematologic: Thrombocytopenia grade ≥3 12.0% vs 5.6%; neutropenia grade ≥3 12.3% vs 7.1% (asciminib vs bosutinib)
Non-hematologic: Grade ≥3 AEs 50.6% vs 60.5%; diarrhea grade ≥3 0.6% vs 8.8%; nausea/vomiting grade ≥3 <2% vs 8–9%; hepatotoxicity grade ≥3 5.2% vs 16.7%; arterial cardiovascular AEs 3.0% vs 0.5%; discontinuation due to AEs 5.8% vs 21.1%, a major difference favoring asciminib
Non-hematologic: Grade ≥3 AEs 50.6% vs 60.5%; diarrhea grade ≥3 0.6% vs 8.8%; nausea/vomiting grade ≥3 <2% vs 8–9%; hepatotoxicity grade ≥3 5.2% vs 16.7%; arterial cardiovascular AEs 3.0% vs 0.5%; discontinuation due to AEs 5.8% vs 21.1%, a major difference favoring asciminib
Conclusions
Asciminib significantly improved MMR at 24 weeks versus bosutinib in ≥3rd-line CP-CML (25.5% vs 13.2%, P=.029), with sustained MMR advantage at 96 and 156 weeks and markedly lower treatment discontinuation due to superior tolerability. Asciminib has effectively replaced bosutinib as the preferred option in this setting.
Key Limitations
Open-label design may bias response assessment and treatment persistence. Bosutinib 500 mg QD is less tolerated than the 400 mg QD used first-line in BFORE; some control-arm patients may have had suboptimal exposure. Exclusion of T315I patients limits the primary analysis; the T315I cohort (n=23) is small. MMR at 24 weeks is a surrogate; PFS and OS in ≥3rd-line CML are not formally compared. Asciminib resistance mutations (myristoyl-pocket switch-control mutations) have been characterized and may emerge with treatment duration.
Clinical Context
ASCEMBL supported FDA accelerated approval of asciminib for CP-CML with ≥2 prior TKIs in October 2021 (confirmed 2024). Asciminib is now the preferred ≥3rd-line option, replacing bosutinib or ponatinib in most non-T315I patients. Ponatinib (OPTIC dose) or asciminib 200 mg BID remain preferred for T315I. For patients who fail ponatinib or asciminib, olverembatinib (Jabbour JAMA Oncol 2025) is an emerging option. Per ELN recommendations, asciminib is a preferred ≥3rd-line option for CP-CML. ESMO-MCBS: not assigned.