Asciminib, an investigational first-in-class STAMP (specifically targeting the ABL myristoyl pocket) inhibitor, was superior to standard treatment with bosutinib (Bosulif) in patients with chronic-phase chronic myeloid leukemia (CML) who previously received 2 or more tyrosine kinase inhibitors (TKIs) in the phase 3 ASCEMBL clinical trial. The results were presented at a late-breaker session at ASH 2020 by lead investigator Andreas Hochhaus, MD, Director, Department of Hematology and Oncology, Klinik für Innere Medizin II, Jena, Germany.
In the ASCEMBL study, at 24 weeks, major molecular response, the primary end point, was 25.5% with asciminib versus 13.2% with bosutinib. After adjusting for baseline major cytogenetic response (MCyR) status, the absolute between-arm difference in major molecular response was 12%, favoring asciminib (P = .029).
“In this first controlled study comparing treatments for resistant or intolerant patients with CML, asciminib, a first-in-class STAMP inhibitor, demonstrated statistically significant and clinically meaningful superiority in efficacy compared with bosutinib, deeper molecular response rates, and a favorable safety profile,” stated Dr Hochhaus.
“These results support the use of asciminib as a new treatment option, particularly in resistant/intolerant patients who received 2 or more prior TKIs,” Dr Hochhaus added.
Based on these results, in December 2020, the FDA granted asciminib fast track review process for this indication.
“Most patients do well on one TKI or another, but there are patients who can’t tolerate these drugs or become resistant. The phase 3 ASCEMBL study showed statistically significant and clinically meaningful efficacy of asciminib compared to bosutinib, achieving deeper responses and improved safety,” commented ASH Secretary Robert A. Brodsky, MD, Professor of Medicine, and Director, Division of Hematology, Johns Hopkins University School of Medicine, Baltimore, MD.
“These data are likely to change practice for treatment of a subgroup of patients with chronic-phase CML who are refractory to or intolerant of TKIs,” Dr Brodsky emphasized.
A Novel Mechanism of Action
Asciminib is a potent, specific, orally bioavailable BCR-ABL1 inhibitor that does not bind to the ATP-binding site of the kinase. All the current TKIs that are approved for CML therapy have a similar mechanism of action.
By contrast, asciminib engages a vacant pocket at the site of the kinase domain that is normally occupied by the myristoylated N-terminal of ABL1. By binding to this site, asciminib restores the inhibition of kinase activity.
Improved Efficacy with Asciminib
The phase 3 ASCEMBL clinical trial included 223 patients with refractory or intolerant chronic-phase CML who previously received ≥2 TKIs. The patients were randomized in a 2:1 ratio to asciminib 40 mg twice daily or to bosutinib 500 mg once daily. Patients were stratified by MCyR status at baseline. The study excluded patients with known bosutinib-resistant T3151 or V299L mutations at baseline. Patients who did not respond to bosutinib treatment (per investigator’s judgment) were permitted to cross over to the asciminib arm.
At baseline, 12.7% of the asciminib group and 17.1% of the bosutinib group had ≥1 BCR-ABL1 mutations. The patients’ median age was 52 years, and 51% were female; approximately 75% were white, 14% Asian, and 5% black. In all, 80% of patients had Eastern Cooperative Oncology Group (ECOG) performance status 0, and 18% had ECOG performance status 1.
At a median follow-up of 14.9 months, the median time to major molecular response was 12.7 weeks with asciminib versus 14.3 weeks with bosutinib. Deep molecular responses—molecular response (MR) 4 and MR 4.5 (which is considered remission)—were reported in 10.8% and 8.9%, respectively, of patients in the asciminib group versus 5.3% and 1.3%, respectively, of patients in the bosutinib group.
At 24 weeks, subgroup analysis showed the superiority of asciminib over bosutinib across most major demographic and prognostic subgroups, including sex, race, age, number of previous TKI therapies, and presence of BCR-ABL1 mutation.
Lack of Efficacy
Lack of efficacy after 6 months of therapy was reported in more than twice as many patients in the bosutinib group versus the asciminib group: 10.8% of asciminib-treated patients and 25% for bosutinib.
At data cutoff on May 25, 2020, 37.6% of the patients in the asciminib group versus 69.7% of the bosutinib group had discontinued treatment. The most common reason for treatment discontinuation was lack of efficacy, including 21% of patients in the asciminib group and 31.6% in the bosutinib group.
Treatment discontinuation because of adverse events was reported in 5.1% and 21.1% of patients, respectively. Almost all patients who discontinued bosutinib because of lack of efficacy switched to asciminib therapy (ie, 22 of 24 patients).
Asciminib also had a better side-effect profile compared with bosutinib. Adverse events of all grades were reported in 89.7% of patients with asciminib versus 96.1% with bosutinib.
Grade 3 or 4 adverse events occurred in 50.6% and 60.5% of patients, respectively. Dose adjustments or interruptions because of adverse events were needed more often in the bosutinib group than the asciminib group.