Skip to Main Content

Advertisement intended for health care professionals

Skip Nav Destination

Asciminib Shows Durable Clinical Activity in Heavily Pretreated CML

December 30, 2021

In a phase I, dose-escalation study, treatment with asciminib was active and associated with durable responses in more than half of patients with chronic myeloid leukemia (CML), with "low-grade reversible toxic effects," according to findings published in the New England Journal of Medicine.

"Although tyrosine kinase inhibitor (TKI) therapy has transformed the natural history of CML, many patients have TKI failure – frequently due to the emergence of resistance mutations in the BCR-ABL1 kinase domain," the researchers, led by Timothy P. Hughes, MD, from the South Australian Health and Medical Research Institute and the University of Adelaide, explained.

Unlike approved TKIs, which mainly target the ATP-binding site of BCR-ABL1, the investigational agent asciminib is an allosteric inhibitor that binds to a myristoyl site of the BCR-ABL1 protein, "mimicking myristate and restoring inhibition of kinase activity," they continued. This distinct mechanism of action is predicted to increase the agent's selectivity and reduce toxicity.

This trial included 150 patients with Philadelphia chromosome–positive CML that was relapsed or refractory to at least 2 different TKIs but not in blast crisis. A total of 141 had chronic-phase CML and 9 had accelerated-phase CML. Patients with a BCR-ABL1 T315I mutation also were eligible for enrollment if they had been treated with at least one TKI because no other effective treatment was available.

Overall, 105 participants (70%) had received at least 3 TKIs. At study entry, 46 patients (31%) had at least one BCR-ABL1 kinase domain mutation, the most frequent being the "gatekeeper" T315I mutation (n=33; 22%), which is associated with resistance to all clinically available TKIs, the authors reported.

Asciminib was administered once or twice daily, at doses ranging from 10 to 200 mg.

At the time of the analysis, the median follow-up was 59 weeks (range = 0.1-167) and the maximum tolerated dose of asciminib (the primary endpoint) had not been reached.

The most commonly observed adverse events (AEs) included fatigue, headache, arthralgia, hypertension, and thrombocytopenia, most of which were grades 1 or 2. Overall, 5 patients experienced clinical pancreatitis, a common AE associated with CML TKI therapies, and the authors noted that all cases resolved within 5 to 10 days of asciminib discontinuation. One patient was rechallenged with asciminib and was able to continue treatment at a lower dose.

The investigational agent asciminib mimics myristate and restores inhibition of kinase activity — a mechanism of action distinct from approved tyrosine kinase inhibitors.

In the efficacy analysis, hematologic, cytogenetic, and molecular responses were observed across all asciminib dose levels and schedules. Among 37 patients with chronic-phase CML and no T315I mutation, 34 (92%) with a hematologic relapse at baseline had a complete hematologic response (CHR). Of 57 patients without a complete cytogenetic response (CCyR) at baseline, 31 (54%) experienced a CCyR within a median of 24 weeks (range = 4-126). Patients who harbored a T315I mutation also experienced CCyRs and major molecular responses (MMRs; defined as BCR-ABL1IS ≤0.1%), as seen in the TABLE.

Responses appeared to be durable, the authors noted, with 40 of 44 patients (91%) with chronic-phase CML and no T315I mutation maintaining their MMR for a median of 61 weeks (range = 4-154).

The CHR rate also was high among the 9 patients with accelerated-phase CML, the authors added: 7 of 8 (88%) with hematologic disease at baseline had a CHR, while 1 had an MMR. Responses were maintained for a median of longer than 11 weeks.

Most patients who harbored a T315I mutation and who had a response were treated with twice-daily asciminib at >150 mg, higher than doses that are necessary to achieve response in patients without this mutation. "This finding mirrors preclinical in vitro observations, in which the concentrations of asciminib that were required to achieve half the maximum inhibitory concentration were 5 to 10 times higher in cell lines expressing T315I-mutated BCR-ABL1 than in cell lines expressing non–T315I-mutated BCR-ABL1," the researchers wrote.

They also noted that, although recent research has suggested the possibility of a high rate of emergence of new ABL kinase mutations with inhibition of the myristoyl pocket, only 4 of 86 evaluable patients receiving asciminib (5%) developed these mutations.

Although the authors concluded that asciminib monotherapy showed durable clinical activity in most patients with chronic-phase CML, the findings from this early-phase study are limited by the lack of a comparator arm.

Study authors reported relationships with Novartis, which sponsored this study.

Reference

Hughes TP, Mauro MJ, Cortes JE, et al. Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure. N Engl J Med. 2019;381:2315-2326.

Advertisement intended for health care professionals

Connect with us:

CURRENT ISSUE
October 2024

Advertisement intended for health care professionals

Close Modal

or Create an Account

Close Modal
Close Modal

Advertisement intended for health care professionals