Microscopic, photorealistic image of chronic myeloid leukemia (CML) cells – Generated with Adobe Firefly
As David Andorsky, MD, explains, the treatment landscape of chronic myeloid leukemia (CML) has changed significantly since the approval of imatinib (Gleevec), the first of 6 approved tyrosine kinase inhibitors (TKIs).
“The treatment of CML has really dramatically changed over the past 15 or 20 years, with the advent of the tyrosine kinase inhibitors,” Andorsky, medical oncologist at Rocky Mountain Cancer Centers said in an interview with Targeted Oncology.
Asciminib (Scemblix) is another TKI, approved by the FDA for the treatment of Philadelphia chromosome-positive CML in chronic phase (CML-CP) in October 2024.1 Unlike other TKIs that bind to the ATP pocket of the BCR::ABL protein, asciminib binds to a different site called the myristoyl binding pocket. This unique binding mechanism may contribute to its distinct side effect profile and its ability to overcome certain resistance mutations, such as the T315I mutation, which most other TKIs are not active against.
The ASC2ESCALATE trial (NCT05384587) is a phase 2, single-arm, open-label study designed to assess the efficacy and safety of asciminib in adult patients with CML-CP.2 The trial includes 2 cohorts: newly diagnosed (1L) patients and patients who had previously received 1 TKI (2L). An interim analysis specifically focused on the 2L cohort, which included patients who had discontinued their prior TKI due to insufficient efficacy or intolerance.
In the 2L cohort of the ASC2ESCALATE trial, patients initially received asciminib 80 mg once daily (QD). However, Andorsky noted that the unique aspect of the study design was the inclusion of dose escalation points. If a patient’s BCR::ABL1IS level was greater than 1% at week 24, their dose was increased to 200 mg QD. A further escalation was possible at week 48 if the BCR::ABL1IS level was still greater than 0.1%, either from 80 mg to 200 mg QD or from 200 mg QD to 200 mg twice daily. Patients experiencing significant grade 3/4 or persistent grade 2 toxicity were not eligible for dose escalation.
Primary end point of major molecular response
The interim analysis, including 63 patients evaluable for week 24 efficacy, showed high molecular response rates. At week 24, 82.5% of patients had a BCR::ABL1IS level less than 1%. The primary end point, major molecular response (MMR), was achieved by 44.4% of patients. Deeper molecular responses were also observed, with 25.4% achieving MR4 and 9.5% achieving MR4.5 at this early time point.
Regarding safety and toxicity, Andorsky noted that asciminib was generally well-tolerated. “In general, most of the adverse events [AEs] we saw were low grade. Grade 3 or higher AEs that were common were hypertension, which was seen about 8.9% of patients, thrombocytopenia seen in 6.9%, and neutropenia seen in 5.9%.”
The most common all-grade AEs (occurring in 20% or more of patients) were headache (22.8%) and nausea (20.8%). Overall, AEs led to dose adjustment/interruption in 26.7% of patients and discontinuation in only 4 patients (4.0%), with 2 of 3 discontinuations due to grade 2 but bothersome AEs. No arterial-occlusive events or on-treatment deaths were reported.
Patients in the 2L cohort had discontinued their prior TKI treatment due to either lack of efficacy (56.4% of patients) or intolerance (43.6% of patients). This indicates that asciminib is being evaluated in a population where previous TKI options were no longer suitable, highlighting its potential as a valuable second-line treatment option.
Future research will focus on longer follow-up to assess the durability of responses and the long-term tolerability of asciminib.
“For this particular study, I think what we’re looking for is longer follow-up,” Andorsky said. “How durable are these responses? How tolerable is the drug in the long term? Do we see higher incidence of side effects or treatment discontinuation?”
Another critical question is the effectiveness of the dose escalation strategy in allowing patients with suboptimal responses to remain on the same medication.
“I also think we really want to see what happens with the patients that do have the dose escalation. Is that an effective strategy to keep patients on the same medication, or are those patients are going to have to switch to a different TKI?” Andorsky asked.
Additionally, larger phase 3 trials comparing asciminib to other TKIs in the first-line setting, which will help to determine asciminib’s optimal position within the broader CML treatment landscape based on its efficacy and safety profile compared to existing options.
Based on current understanding, asciminib is considered an effective drug for many patients, and there are no specific biomarkers or known resistance mutations that would necessarily lead to its avoidance, except for the T315I mutation, against which asciminib is active. The toxicities of TKIs can be idiosyncratic, making it difficult to predict individual AEs. Therefore, at present, it’s not a matter of whether a patient should avoid asciminib, but rather where it fits into their individualized treatment plan given its efficacy and unique safety profile.