The ASC2ESCALATE trial is providing encouraging evidence for asciminib (Scemblix) as an effective second-line treatment option for patients with chronic myeloid leukemia in chronic phase (CML-CP). The phase 2, single-arm study's interim analysis reveals strong molecular response rates and a manageable safety profile in patients who experienced suboptimal response or intolerance to their first tyrosine kinase inhibitor (TKI).
Trial Design and Patient Population
The study enrolled 101 patients with second-line CML-CP who had previously received one TKI. All patients received at least one dose of asciminib 80 mg once daily. Prior treatments were predominantly dasatinib (Sprycel; 44.6%) and imatinib (Gleevec; 42.6%). Patients discontinued their prior TKI primarily due to lack of efficacy (56.4%) or intolerance (43.6%).
At the data cutoff on November 15, 2024, treatment persistence was notably high, with 91.1% of patients remaining on asciminib therapy. The median duration of asciminib exposure was 26.1 weeks, with discontinuations mostly attributed to adverse events or patient decision.
Efficacy Results Demonstrate Strong Molecular Responses
The 24-week efficacy evaluation, based on 63 patients, showed impressive molecular response rates. A substantial 82.5% of patients achieved a BCR::ABL1IS of ≤1%, indicating a significant reduction in leukemia burden. The trial also demonstrated meaningful deeper molecular responses, with 44.4% of patients achieving a major molecular response (MMR), 25.4% reaching MR4, and 9.5% achieving MR4.5.
Innovative Dose Escalation Strategy
A distinguishing feature of the ASC2ESCALATE trial is its adaptive dose escalation approach. The study incorporates two evaluation points at 6 and 12 months to optimize treatment outcomes. At the 6-month mark, if a patient's pathologic complete response (pCR) level has not reached less than 1%, the asciminib dose is escalated from the standard FDA-approved 80 mg daily to 200 mg daily.
A second escalation point occurs at 12 months, allowing for either a first-time or second dose increase if the patient's pCR has not reached less than 0.1%, signaling a major molecular response. In this interim analysis, seven patients underwent dose escalation, though investigators noted that the data for these patients requires more follow-up time for complete analysis of the strategy's impact.
Safety Profile Remains Consistent
The safety profile of asciminib remained consistent with previously reported data. The most common all-grade adverse events (≥20%) were headache (22.8%) and nausea (20.8%). Grade ≥3 adverse events occurring in ≥5% of patients included hypertension (8.9%), thrombocytopenia (6.9%), and neutropenia (5.9%).
Importantly, adverse events led to discontinuation in only four patients, demonstrating the drug's tolerability. No arterial-occlusive events or on-treatment deaths were reported during the study period.
Clinical Implications
According to David Andorsky, MD, oncologist at SCRI at Rocky Mountain Cancer Centers, The US Oncology Network, investigators aim to provide more follow-up time to thoroughly assess whether the escalation strategy effectively allows patients with suboptimal response to continue on the same medication at a higher dose.
These interim results underscore asciminib's potential as a tolerable and highly effective treatment option for patients with second-line CML-CP. The high molecular response rates and consistent safety profile support its use in this patient population, while the impact of the dose escalation strategy continues to be investigated as more data mature.
