Asciminib, a first-in-class allosteric inhibitor that Specifically Targets ABL Myristoyl Pocket (STAMP), was more effective at achieving major molecular response (MMR) than bosutinib in patients with resistant/intolerant chronic myeloid leukemia (CML), according to late-breaking results of the ASCEMBL study presented at the 2020 American Society of Hematology (ASH) Annual Meeting.
"Asciminib, unlike all approved tyrosine kinase inhibitors [TKIs] that bind to the ATP site of BCR-ABL, is a first-in-class STAMP inhibitor that specifically targets the ABL myristoyl pocket," said Andreas Hochhaus, MD, of Jena University Hospital, in Jena, Germany, who presented the results. "The ASCEMBL data support the use of asciminib as a new treatment option in CML, particularly in patients with resistance or intolerance to at least two TKIs."
The ASCEMBL trial randomized 233 patients with chronic-phase CML to either asciminib 40 mg twice daily (n=156) or bosutinib 500 mg daily (n=76). All patients had been previously treated with two or more TKIs; patients intolerant of their most recent TKI were eligible if they had BCR-ABL1IS greater than 0.1%. Patients with treatment failure on bosutinib were able to switch to asciminib per investigator judgement.
Patient characteristics were similar between treatment arms, but Dr. Hochhaus noted that more patients with prior intolerance were observed in the asciminib arm than in the bosutinib arm (37.6% vs. 28.9%). Also, 52.2% of patients on asciminib received exactly two prior TKIs, compared with 39.5% of bosutinib-treated patients. "Consequently, a lower proportion of patients pretreated with three or more prior lines of therapy were enrolled in the asciminib arm," he added.
At data cutoff (May 25, 2020), a higher proportion of patients in the asciminib arm were continuing on initially assigned therapy compared with those assigned to bosutinib (61.8% vs. 30.3%). Lack of efficacy was the most common reason for treatment discontinuation (21% in the asciminib group and 31.6% in the bosutinib group). Twenty-two of 24 patients who discontinued bosutinib due to lack of efficacy eventually switched to asciminib. Overall, the median duration of exposure was 43.4 weeks for asciminib and 29.2 weeks for bosutinib.
At a median follow-up of 14.9 months, the MMR rate at 24 weeks in the asciminib arm was twice that in the bosutinib arm (25.5% vs. 13.2%), meeting the study's primary objective. The between-arm difference in MMR at 24 weeks was 12.2%, after adjustment for major cytogenetic response status at baseline (p=0.029), Dr. Hochhaus reported.
Response was superior with asciminib compared to bosutinib across most major demographic and prognostic subgroups, including patients who had prior treatment with three or more TKIs, those who had discontinued prior TKI due to treatment failure, and those with or without baseline cytogenetic response.
"To understand the potential impact of imbalances between treatment arms observed on the primary study results, a logistic regression model was performed including the stratification factor major cytogenetic response and important covariates," Dr. Hochhaus said. After adjustment, the odds ratio (OR) remained similar to the unadjusted OR (2.35 vs. 2.38 respectively), which indicates that the treatment effect is still significant while accounting for these imbalances, he said.
Looking at cumulative incidence of MMR, the researchers determined that the probability of achieving MMR by 24 weeks was 25.0% with asciminib and 11.9% for bosutinib. The increased likelihood of achieving MMR with asciminib over bosutinib became evident starting at 12 weeks.
Rates of complete cytogenetic response also were higher in the asciminib arm: 40.8% versus 24.2%. In addition, a higher proportion of patients achieved 4- or 5-log molecular remission (MR4 or MR5) at 24 weeks with asciminib than with bosutinib (MR4: 10.8% vs. 5.3%; MR5: 8.9% vs. 1.3%).
Adverse events (AEs) grade ≥3 were observed in 50.6% of patients assigned asciminib and 60.5% of patients assigned bosutinib. The most frequently reported AEs that led to treatment discontinuation were thrombocytopenia and neutropenia for asciminib, and increased ALT/AST ratio for bosutinib. Two patients assigned to asciminib died due to CML during study follow-up.
Together, these safety and efficacy results "support the use of asciminib as a new treatment option in CML, particularly in patients with resistance/intolerance to two or more TKIs," Dr. Hochhaus concluded. In the future, he expects asciminib to demonstrate even greater efficacy as an earlier-line therapy, leading to a more rapid molecular response than is seen with other TKIs.
Study authors report relationships with Novartis, which sponsored the trial.
Reference
Hochhaus A, Boquimpani C, 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 (BOS) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors (TKIs). Abstract LBA-4. Presented at the 2020 American Society of Hematology Annual Meeting, December 8, 2020.
