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Asciminib shows superior tolerability over nilotinib in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase, enhancing treatment options and patient outcomes.
In patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in chronic phase (CP; Ph+ CML-CP), asciminib (Scemblix; Novartis) demonstrated significantly superior tolerability compared with nilotinib (Tasigna; Novartis) based on time to treatment discontinuation due to adverse events (TTDAE), according to findings from the ASC4START (NCT05456191) clinical trial, which were presented at the 2025 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois. Although this trial is ongoing with additional tolerability and efficacy analyses planned, the findings further support the potential of ASC as a preferred therapy for patients with newly diagnosed CML-CP.1,2
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Trial Name: A Study to Investigate Tolerability and Efficacy of Asciminib (Oral) Versus Nilotinib (Oral) in Adult Participants (≥18 Years of Age) With Newly Diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase (Ph+ CML-CP) (ASC4START)
ClinicalTrials.gov ID: NCT05456191
Sponsor: Novartis Pharmaceuticals
Completion Date (Estimated): July 7, 2031
Asciminib is the first treatment for CML that works by specifically targeting the ABL myristoyl pocket. It is approved by the FDA for the treatment of patients with Ph+ CML-CP who were previously treated with 2 or more tyrosine kinase inhibitors, as well as for adult patients with Ph+ CML in CP with the T315I mutation. Asciminib received an accelerated approval for newly diagnosed adults with Ph+ CML-CP following earlier results from the ASC4FIRST (NCT04971226) trial that demonstrated positive major molecular response rates.3,4
The ASC4START trial, which is a multicenter, open-label, randomized phase 3 trial, enrolled 568 patients with Ph+ CML-CP across 120 participating sites. These patients were randomly assigned to receive either 80 mg of asciminib (n = 284) administered once per day or 300 mg of nilotinib (n = 284) administered orally twice per day under fasting conditions.1,2
The primary end point was TTDAE, which was defined as the date of the first dose to the date of treatment discontinuation because of an AE. These events included AEs which led to either discontinuation related to treatment or death because of AEs. Secondary end points included safety and molecular response.1,2
At a median follow-up of 9.7 months and a cutoff of September 3, 2024, approximately 10.9% and 17.3% of patients discontinued asciminib and nilotinib, respectively, most commonly because of AEs (4.9% vs 11.6%) and unsatisfactory therapeutic effect (2.5% vs 2.8%). Notably, the study met its primary end point, demonstrating a statistically significant difference in TTDAE in favor of asciminib with a cause-specific hazard ratio of about 0.45 (95% CI, 0.25–0.81; P = .004). Fewer patients discontinued because of AEs with asciminib (n = 16, 5.6%) than with nilotinib (n = 34, 12.1%). There were 3 deaths recorded during the study due to AEs, with 1 suicide occurring in the asciminib group and 1 cardiac arrest in each group.1
Additionally, the median duration of exposure was about 39.1 weeks with asciminib compared with 38.0 weeks with nilotinib, and the mean relative dose intensities were 94.8% and 92.6%, respectively. Any-grade AEs were less common in the asciminib group (80.3%) than in the nilotinib group (86.5%), as well as grades 3 or higher AEs (25.0% and 31.9%, respectively). Further, AEs that led to dose adjustment or interruption occurred in 24.3% of patients receiving asciminib and 30.1% receiving nilotinib.1
The most common any-grade AEs (≥10%) thrombocytopenia (15.1% vs 13.8%), headache (10.2% vs 13.1%), myalgia (10.2% vs 8.2%), rash (8.5% vs 16.3%), and increased alanine aminotransferase (3.2% vs 12.4%) in the asciminib and nilotinib groups, respectively. AEs of special interest included arterial occlusive events (0.7% vs 2.1%), acute pancreatitis (clinical events; 0.4% vs 2.5%), and hepatotoxicity (including laboratory terms; 8.1% vs 24.8%) in these groups.1
Although the tolerability and efficacy analyses are planned and the ASC4START trial remains ongoing, the investigators note their optimism in asciminib demonstrating superior tolerability based on TTDAEs. They wrote that these findings support asciminib’s potential as a preferred therapy in patients with newly diagnosed Ph+ CML-CP, allowing for patients to meet their treatment goals without switching their regimens.1
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