STAMPing on BCR-ABL1: Asciminib Approved for Chronic Myeloid Leukemia

Targeted therapy for chronic myelogenous leukemia (CML) has been remarkably effective. However, living with CML remains challenging for many patients. As many as 30 to 40 percent of patients treated with second-generation tyrosine kinase inhibitors (TKIs) need to switch therapies during the first five years of treatment due to the development of disease resistance or intolerable adverse effects, and durable treatment-free remissions are currently only achieved in a minority of patients.^1,2  The recent approval of asciminib by the U.S. Food and Drug Administration (FDA) is notable not only because we have another agent in the arsenal against CML, but also because of the novel mechanism by which asciminib inhibits BCR-ABL1 activity.

In contrast to all other TKIs currently approved for CML, which target the ATP-binding site of BCR-ABL1, asciminib inhibits BCR-ABL1 kinase activity via allosteric binding at a different site. Known as a STAMP (specifically targeting the ABL myristoyl pocket) inhibitor, asciminib binds to the myristoyl pocket of ABL1, which restores autoinhibition of ABL1 kinase activity that is lost when ABL1 fuses to BCR.^3,4  A previous phase I study found that asciminib was well-tolerated with promising clinical activity in patients with CML who had been treated with multiple prior lines of therapy.

Dr. Delphine Réa and colleagues recently published the results of ASCEMBL (NCT03106779), a randomized phase III study that compared asciminib to bosutinib in adults with chronic-phase CML who had previously been treated with at least two prior TKIs. Eligible patients had experienced either treatment failure or intolerance to their most recent TKI. Patients with known T315I or V299L mutations (mutations known to cause bosutinib resistance) were excluded. Subjects were randomized in a 2:1 ratio to asciminib 40 mg twice daily or bosutinib 500 mg once daily. The primary endpoint was the rate of major molecular response (MMR; defined as BCR-ABL1^IS ≤ 0.1%) at 24 weeks.

This open-label study randomized 233 subjects to asciminib (n=157) or bosutinib (n=76). Baseline patient characteristics were relatively well-balanced between the two arms, though the bosutinib group had a slightly greater proportion of certain higher-risk groups of patients — those who had received prior ponatinib, who were on their fourth or greater line of therapy, and/or who had discontinued their last TKI due to lack of efficacy as opposed to intolerance. However, similar proportions of subjects in the two arms had at least one BCR-ABL1 mutation at baseline (12.7% in the asciminib group vs. 13.2% in the bosutinib group).

A higher MMR rate was observed at week 24 in the asciminib arm (25.5%) than in the bosutinib arm (13.2%), with a difference in MMR rates of 12.2 percent (95% CI, 2.19-22.3; p=0.029). Asciminib was favored across subgroups, including in subjects whose CML was resistant to the previous line of therapy. Additionally, more patients on the asciminib arm achieved deep molecular responses by week 24 compared to those on the bosutinib arm (rate of BCR-ABL1^IS ≤ 0.01% was 10.8% in asciminib group vs. 5.3% in the bosutinib group). Of note, however, secondary endpoints that require longer follow-up, including the rate of MMR at week 96, progression-free survival, and overall survival, have not yet been reported.

Asciminib was relatively well-tolerated. Common treatment-related adverse events in the asciminib arm included thrombocytopenia (19.9%), neutropenia (14.7%), headache (9.0%), anemia (5.1%), and gastrointestinal symptoms (nausea in 6.4%, diarrhea in 4.5%, and vomiting in 3.2%).

In the ascminib group, 5.8 percent of patients discontinued therapy due to adverse events, while 21.1 percent in the bosutinib group stopped treatment due to adverse events. Dose reductions occurred in 21.2 percent of subjects in the asciminib group and 42.1 percent of patients in the bosutinib group. It should be noted though that the dose of bosutinib studied (500 mg daily, which is the approved dose for CML that is resistant or intolerant to prior therapy) may be associated with more adverse effects than the 400 mg daily dose that is approved for newly diagnosed chronic-phase CML.