Asciminib safer, more effective than bosutinib in chronic-phase chronic myeloid leukemia
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CHICAGO — Asciminib continued to confer superior efficacy and better safety and tolerability than bosutinib among patients with chronic-phase chronic myeloid leukemia, according to study results presented during ASCO Annual Meeting.
Researchers observed durable responses after 2 years of follow-up, with more patients assigned asciminib (ABL001, Novartis) experiencing major molecular response.
Rationale and methods
“Asciminib is a novel tyrosine kinase inhibitor [TKI] that specifically targets the ABL myristoyl pocket, which is a new site of binding. Other TKIs that we have had up until now are ATP-binding inhibitors, so by binding in this area, it creates a novel mechanism of action,” Jorge E. Cortes, MD, director of Georgia Cancer Center at Augusta University, said during his presentation. “Many of the mutations that cause resistance to other TKIs favor the active confirmation of ABL. Most of the other inhibitors only bind to the inactive confirmation, but asciminib can inhibit TKI activity in the context of the many known mutations for other TKIs.”
Asciminib has been approved for patients treated with two or more TKIs or who have the T315i mutation, Cortes added.
“Based on the primary analysis of the current study, the 24-week rate of major molecular response showed superiority in efficacy compared with bosutinib (Bosulif, Pfizer) and a very good safety profile,” he said. “Because we use TKIs in prolonged administration until disease progression in this patient population, it is important to understand the long-term efficacy and safety data of these new agents.”
Researchers randomly assigned 233 patients with chronic-phase chronic myeloid leukemia previously treated with two or more TKIs in a 2:1 ratio to 40 mg twice-daily asciminib (n = 157) or 500 mg once-daily bosutinib (n = 76).
Cortes presented data on major molecular response at 96 weeks — the key secondary endpoint predefined at the time of trial design.
Key findings, implications
At the time of data cutoff, 84 patients (53.5%) assigned asciminib and 15 patients (19.7%) assigned bosutinib remained on treatment for a median duration exposure of 23.7 months vs. 7 months. Lack of efficacy, the most common reason for treatment discontinuation, occurred in 24.2% of those assigned asciminib and 35.5% assigned bosutinib.
“The rate of discontinuation due to adverse events continued to be low on asciminib, with minimal increase since the primary analysis,” Cortes said.
Researchers additionally observed a 37.6% major molecular response rate at 96 weeks among those assigned asciminib compared with 15.8% among those assigned bosutinib, for a difference of 21.7% (95% CI, 10.5-32.9).
More patients on asciminib maintained a BCR::ABL1IS of 1% or less (45.1% vs. 19.4%), which was associated with improved survival in later lines of therapy, according to Cortes.
“Of the 69 patients assigned asciminib and 18 patients assigned bosutinib who achieved major molecular response, 67 patients and 17 patients maintained response at the time of last assessment. Of note, at the time of data cutoff, median duration of major molecular response was not reached in either treatment arm,” Cortes said.
“We also observed mutations that emerged during the course of treatment, both in the ATP-binding site and in the ABL myristoyl pocket,” Cortes added. “Patients who started the study with mutations certainly could have persistence or emergence of mutations when they develop resistance to either drug.”
Thromobcytopenia, the most common grade 3 or higher adverse event, occurred more often with asciminib (29.5% vs. 19.7%). No new treatment-associated deaths occurred.
“The benefit of asciminib, in terms of safety and efficacy, is maintained after 96 weeks of therapy, making the agent a viable treatment option for this patient population,” Cortes said.
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Rea D, et al. Abstract 7004. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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