Findings from the phase 3 ASCEMBL trial showed a consistent improvement in major molecular response rate and depth of response without any new or worsening adverse effects when treating with asciminib versus bosutinib in patients with chronic-phase chronic myeloid leukemia.
Findings from the phase 3 ASCEMBL trial (NCT03106779) showed a consistent improvement in major molecular response (MMR) rate and depth of response without any new or worsening adverse effects (AEs) when treating with asciminib (Scemblix) versus bosutinib (Bosulif) in patients with chronic-phase chronic myeloid leukemia (CP-CML) at the 2021 American Society of Hematology Annual Meeting & Exposition.1
At a median follow-up of 19.2 months, the MMR rate at 48 weeks was 29.3% with asciminib vs 13.2% with bosutinib, reflecting a 16.1% difference in favor of asciminib. Moreover, the BCR-ABL1IS rate of 1% or less was higher with asciminib vs bosutinib, at 42.3% vs 19.4%, respectively.
“After an additional median follow-up of approximately 5 months, asciminib continued to demonstrate sustained, superior efficacy compared with bosutinib,” lead study author Michael J. Mauro, MD, leader of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center, said in a presentation of the data. “Overall, these updated efficacy and safety results continue to support the use of asciminib as a new treatment option in CML, with the potential to transform standard of care in later-line CML.”
Asciminib is a first-in-class BCR-ABL1 inhibitor that works by targeting the ABL myristoyl pocket.
On October 29, 2021, the FDA granted an accelerated approval to asciminib for patients with CP-CML who have previously been treated with 2 or more TKIs. The regulatory agency also granted a full approval for the use of the agent in those with CP-CML with a T315I mutation.2
The regulatory decisions were based on findings from the phase 3 ASCEMBL trial, which evaluated asciminib in patients with CP-CML who previously received 2 or more TKIs, and the phase 1 CABL001X2101 trial (NCT02081378), which evaluated its use in patients with Philadelphia chromosome–positive CP-CML harboring a T315I mutation.
ASCEMBL enrolled 233 patients with CP-CML who had been previously treated with at least 2 TKIs and had failed or were intolerant to their prior TKI. Patients with intolerance of their most recent TKI must have had BCR-ABL1IS of at least 0.1% at screening.
The presence of T315l and V299L mutations served as exclusion criteria.
Patients were randomized 2:1 to receive 40 mg of asciminib twice-daily (n = 157) or 500 mg of bosutinib once-daily (n = 76) for at least 96 weeks.
Patients who met lack of efficacy criteria were required to discontinue treatment; patients who were randomized to bosutinib were only allowed to switch to asciminib upon demonstrated lack of efficacy benefit.
Week-24 MMR rate served as the primary end point of the study; the MMR rate at week 96 served as a key secondary end point.
Primary findings from ASCEMBL demonstrated that after a median follow-up of 14.9 months, asciminib led to an MMR rate of 25.5% at 24 weeks vs 13.2% with bosutinib, reflecting a difference of 12.2% (95% CI, 2.19%-22.30%; P = .029) after adjusting for major cytogenetic response at baseline in favor of asciminib.
Moreover, fewer grade 3 or greater AEs (50.6% vs 60.5%) and AEs leading to treatment discontinuation (5.8% vs 21.1%) were reported with asciminib vs bosutinib, respectively.
Updated analyses, which were performed after all patients had received at least 48 weeks of treatment or discontinued earlier, showed that treatment was ongoing in more than double the number of patients receiving asciminib vs bosutinib, at 56.7% vs 22.4%.
The primary reasons for treatment discontinuation in the asciminib vs bosutinib arms were lack of efficacy (23.6% vs 35.5%, respectively) and AEs (5.7% vs 23.7%, respectively).
Additional findings showed that asciminib led to higher week-48 MMR rates vs bosutinib across lines of therapy, respectively: (third line, 30.5% vs 26.7%; fourth line, 31.8% vs 6.9%; fifth or later line, 22.6% vs 0%).
The cumulative incidence and duration of MMR was also consistently higher with asciminib vs bosutinib. The 24-week MMR rates were 25.0% with asciminib vs 11.9% with bosutinib; the 48-week MMR rates were 33.2% vs 18.6%, respectively.
Moreover, the likelihood of maintaining MMR for at least 48 weeks was 96.1% (95% CI, 85.4%-99.0%) with asciminib vs 90.0% with bosutinib (95% CI, 47.3%-98.5%).
The median duration of MMR was not reached in either arm; 60 of 62 patients on asciminib and 17 of 18 patients on bosutinib maintained their MMR at the time of their last evaluation.
The cumulative incidence of BCR-ABL1IS of 1% or less also deepened over time in favor of asciminib, going from 41.6% at 24 weeks to 50.8% at 48 weeks; these rates were 25.2% and 33.7%, respectively, with bosutinib.
Deep molecular responses characterized by MR4 (10.8% vs 3.9%) and MR4.5 (7.6% vs 1.3%) continued to be superior with asciminib vs bosutinib at 48 weeks, respectively.
Furthermore, fewer patients experienced treatment failure with asciminib vs bosutinib, at 48.4% vs 80.3%, respectively (HR, 0.4; 95% CI, 0.3-0.6; P < .0001). The estimated percentage of patients without treatment failure at 12 months was 57.7% (95% CI, 49.5%-65.0%) vs 25.0% (95% CI, 15.9%-35.1%), respectively.
The median time to treatment failure was not reached with asciminib vs 6 months with bosutinib.
The median duration of exposure was 15.4 months (range, 0.0-37.3) with asciminib vs 6.8 months (range, 0.2-34.3) with bosutinib.
“When interpreting the results on safety, it’s important to consider that the median duration of exposure was much longer for patients on asciminib than on bosutinib,” said Mauro.
In terms of safety, the rate of all-grade AEs was 91.0% with asciminib vs 97.4% with bosutinib.
Fewer grade 3 or greater AEs were reported with asciminib vs bosutinib, at 54.5% vs 67.1%, respectively.
The rate of fatal AEs remained unchanged since the primary analysis, at 1.3% in both arms.
AEs leading to dose reduction and interruption, respectively, occurred in 23.1% and 40.4% of patients on asciminib vs 44.7% and 60.5% of patients on bosutinib.
The most common all-grade AEs leading to treatment discontinuation included thrombocytopenia (3.2%) and neutropenia (2.6%) with asciminib vs increased alanine aminotransferase (ALT; 5.3%) and neutropenia (3.9%) with bosutinib.
The most common all-grade AEs that occurred in at least 20% of patients in the asciminib vs bosutinib arms, respectively, were thrombocytopenia (29.5% vs 19.7%), neutropenia (23.1% vs 21.1%), diarrhea (11.5% vs 71.1%), nausea (11.5% vs 46.1%), rash (7.7% vs 23.7%), vomiting 7.1% vs 26.3%), increased ALT (3.8% vs 28.9%), and increased aspartate aminotransferase (5.1% vs 21.1%).
“The safety and tolerability profile of asciminib remained consistent with that at the time of the primary analysis and, despite the longer duration of exposure, continued to be better [with asciminib] than bosutinib,” said Mauro.
Notably, most AEs with asciminib occurred within the first 6 months of treatment, and recurring AEs were manageable.
The primary hematologic AEs in the asciminib arm were thrombocytopenia, neutropenia, and anemia, which decreased in frequency over time. Within the first 6 months, 6 to 12 months, 12 to 18 months, and 18 months or beyond, thrombocytopenia decreased in incidence from 28.8% to 18.8%, 12.5%, and 6.8%, respectively. With regard to neutropenia, these rates largely decreased from 21.8% to 7.0%, 4.8%, and 5.1%, respectively. Finally, the rates of anemia decreased from 9.6% to 3.1%, 1.9%, and 1.7%, respectively.
Notably, the risk of arterial occlusive events (AOEs) remained consistent with the primary analysis, with an exposure-adjusted AOE rate per 100 patient-years of 3.4 vs 3.3 in the primary analysis.
Two new AOEs occurred after the primary analysis, and of the 7 patients with AOEs on asciminib, 7 had previously received nilotinib (Tasigna), 5 had received dasatinib (Sprycel), and 3 had received ponatinib (Iclusig).
“It’s important to note that the majority of patients who experienced AOEs had preexisting cardiovascular risk factors or a history of cardiovascular disease,” said Mauro, adding that the high early discontinuation rate of patients on bosutinib prevented a meaningful comparison of AOEs between the treatment arms.
1. Mauro MJ, Minami Y, Rea D, 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: 2021 ASH Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 310.
2. FDA approves Novartis Scemblix (asciminib), with novel mechanism of action for the treatment of chronic myeloid leukemia. News release. Novartis. October 29, 2021. Accessed October 29, 2021. https://bit.ly/3bm9lNR