Asciminib as a new treatment option in later-line chronic myeloid leukaemia in chronic phase
The ASCEMBL study is an open-label, randomised, phase III trial comparing asciminib with bosutinib in patients with chronic myeloid leukaemia in chronic phase previously treated with two or more TKIs. In this trial, asciminib, a first-in-class STAMP inhibitor, demonstrated statistically significant and clinically meaningful superiority in efficacy compared with bosutinib, with deeper molecular response rates and a favourable safety profile.
Asciminib is the first BCR-ABL1 inhibitor that potently inhibits kinase activity of the BCR-ABL1 oncoprotein by specifically targeting the ABL Myristoyl pocket (STAMP). In the phase III ASCEMBL study, after a median follow-up of 14.9 months, asciminib demonstrated superior efficacy with better safety and tolerability compared to bosutinib in patients with chronic myeloid leukaemia in chronic phase (CML-CP) after at least two prior ATP-binding tyrosine kinase inhibitors (TKIs). At ASH 2021, updated efficacy and safety results were presented for patients in ASCEMBL, all of whom had at least one year (48 weeks) of treatment or discontinued treatment earlier.
ASCEMBL study design
Adults with CML-CP treated with ≥2 prior TKIs were randomly allocated in a 2:1 ratio to asciminib (40 mg twice daily [BID]) or bosutinib (500 mg once daily [QD]). Eligible patients were required to have experienced treatment failure (lack of efficacy) per 2013 European LeukemiaNet recommendations for second-line TKI therapy or show intolerance of the most recent TKI at screening. Patients intolerant of their most recent TKI were eligible only if they had BCR-ABL1 on the International Scale >0.1% at screening. Patients with known bosutinib-resistant T315I or V299L mutations were ineligible.
Results
In total, 233 patients were randomised and received either asciminib (N=157) or bosutinib (N=76). At the data cut-off in January 2021, treatment was ongoing in 56.7% and 22.4% of patients on asciminib and bosutinib, respectively. The most common reasons for discontinuation were lack of efficacy and adverse events. With longer follow-up (19.2 months), the rates of major molecular response (MMR) continued to be higher with asciminib as compared to bosutinib (29.3% versus 13.2%). A consistent treatment effect in favour of asciminib was seen across all lines of therapy. Furthermore, the cumulative incidence of MRR was consistently higher with asciminib than with bosutinib (25.0% versus 11.9% at 24 weeks and 33.2% versus 18.6% at 48 weeks). The probability of maintaining MMR for at least 48 weeks was 96.1% with asciminib compared to 90.0% with bosutinib. In total, 60 of 62 patients receiving asciminib and 17 of 18 patients receiving bosutinib were maintaining their MMR at the time of their last assessment. More patients receiving asciminib than bosutinib achieved BCR-ABL1IS ≤1% by week 48 (50.8% versus 33.7%), which is known to be a predictor of better long-term outcomes in this heavily pretreated patient population. Deep molecular response rates continued to be higher with asciminib than with bosutinib. MR4 rates at week 48 were 10.8% versus 3.9%, respectively, while corresponding values for MR4.5 were 7.6% and 1.3%. By data cut-off, fewer patients experienced treatment failure with asciminib (48.4%) than with bosutinib (80.3%). The Kaplan-Meier estimated proportion of patients without treatment failure by 12 months was 57.7% for asciminib compared to 25.0% for bosutinib, respectively. The median time to treatment failure was not reached with asciminib and was six months with bosutinib.
With a longer duration of exposure in the asciminib arm (15.4 months versus 6.8 months), the safety and tolerability profile in the current analysis remains similar to that at the primary analysis, with fewer grade ≥3 adverse events (AEs) with asciminib as compared to bosutinib (54.5% versus 67.1%). No patients died in either treatment arm since the primary analysis cut-off. The most common all-grade AEs leading to treatment discontinuation included thrombocytopenia (3.2%) and neutropenia (2.6%) with asciminib and increased alanine aminotransferase level (5.3%) and neutropenia (3.9%) with bosutinib. Fewer patients in the asciminib (7.1%) than bosutinib (25.0%) arm discontinued treatment due to AEs. Dose reduction and dose interruption due to AEs occurred in 23.1% and 40.4% of patients receiving asciminib and in 44.7% and 60.5% of those receiving bosutinib. Finally, the risk of arterial occlusive events remained constant and did not increase after additional time receiving asciminib.
Conclusion
After an additional median follow-up of approximately five months, asciminib continued to demonstrate a sustained superior efficacy compared with bosutinib. In addition, the safety profile of asciminib remained consistent with that at the time of the primary analysis, with no new or worsening safety findings. Therefore, these updated efficacy and safety results in ASCEMBL continue to support the use of asciminib as a new treatment option in CML-CP.
Reference
Mauro M, et al. Efficacy and Safety Results from Ascembl, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, Vs Bosutinib in Patients with Chronic Myeloid Leukemia in Chronic Phase after ≥2 Prior Tyrosine Kinase Inhibitors: Update after 48 Weeks. Presented at ASH 2021; abstract 310.
