Blood cancers

Novel STAMP inhibitor potentially practice changing in CML


The novel agent asciminib out-performed bosutinib in a phase III trial of patients with heavily pretreated chronic phase chronic myeloid leukaemia (CML), according to results presented at the ASH 2020 meeting.

Asciminib is a first-in-class STAMP inhibitor that specifically targets the ABL myristoyl pocket. This differs from all approved tyrosine kinase inhibitors, which bind to the ATP site of BCR-ABL.

The ASCEMBL trial compared asciminib and bosutinib in a total of 233 patients with CML; patients were included if they had received at least two prior TKIs.

“The study met its primary objective,” said Dr Andreas Hochhaus, of Klinik für Innere Medizin II in Jena, Germany, who presented the results.

During a press briefing, he added: “My personal expectation is that the first-line response will be even stronger, even better.” This is because the agent is a specific inhibitor of BCR-ABL, which would make it more effective in early therapies for a malignancy driven by BCR-ABL.

The rate of major molecular response (MMR) at 24 weeks was 25.5% with asciminib, compared with 13.2% with bosutinib (P = 0.029).

“A consistent treatment effect was observed across the subgroups assessed, supporting the benefit of asciminib treatment,” Dr. Hochhaus said.

Patients treated with asciminib fared better whether or not they had major cytogenetic response (MCyR) at baseline, and across any number of prior lines of therapy.

The probability of achieving an MMR by 24 weeks was 25.0% with asciminib, compared with 11.9% with bosutinib; the difference in MMR between the groups became apparent after 12 weeks of treatment.

An analysis that adjusted for the presence of MCyR did not change the results, with an odds ratio favoring asciminib of 2.35 (95% CI, 1.08-5.12). The rate of complete cytogenetic response at 24 weeks was 40.8% with asciminib and 24.2% with bosutinib.

Adverse events of grade 3 or higher were seen in 50.6% of patients receiving asciminib and in 60.5% of those receiving bosutinib. There were two fatal AEs with asciminib and one with bosutinib, all deemed unrelated to study therapy.

More patients receiving bosutinib discontinued therapy due to adverse events, at 21.1% compared with 5.8%. Dose interruptions or adjustments were required in 60.5% of those receiving bosutinib and in 37.8% of those receiving asciminib.

“Asciminib demonstrated statistically significant superior efficacy compared with bosutinib, and a favorable safety profile,” Dr Hochhaus concluded.

“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.”

Dr Robert Brodsky, of Johns Hopkins University, who was not involved with the research, called the study “practice-changing” during a press briefing.

“The results signal that asciminib may provide a good opportunity for third-line treatment in CML patients,” he said.

A phase II study in Germany is now testing asciminib in combination with other TKIs as first-line therapy for CML.

“Third line treatment will not be the only indication for asciminib, but it will certainly be the first indication,” Dr Hochhaus said.

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