ASC4FIRST is a pivotal phase III, randomised study assessing the efficacy and safety of asciminib as compared with investigator-selected tyrosine kinase inhbitors (TKIs) in patients with newly diagnosed chronic myeloid leukaemia (CML). Asciminib was superior to investigator-selected TKIs considered together and of imatinib individually. The safety and side-effect profiles of asciminib were favourable as compared with those of imatinib and second-generation TKIs.
Although asciminib may offer a better benefit–risk profile than the full analysis set of investigator-selected TKIs, longer follow-up is required to understand the magnitude of response, particularly deep molecular response and eligibility for attempts at treatment-free remission, durability of response, survival outcomes, and long-term safety. The study primary results are reported at ASCO 2024 Annual Meeting along with a simultaneous publication by Dr. Andreas Hochhaus of the Klinik für Innere Medizin II, Universitätsklinikum Jena in Jena, Germany and colleagues on 31 May 2024 in The New England Journal of Medicine.
The authors wrote in the background that most patients with newly diagnosed chronic-phase CML are treated with one of four approved ATP-competitive TKIs: first-generation imatinib or second-generation nilotinib, dasatinib, or bosutinib. Second-generation TKIs produce faster, deeper molecular responses than imatinib in frontline therapy; however, they are associated with more adverse events. Many patients receiving frontline imatinib or second-generation TKIs switch treatments within their first year, mostly because of adverse effects. A frontline treatment with an acceptable side-effect profile is needed for patients with newly diagnosed CML.
Asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, was intentionally designed to enhance efficacy and reduce off-target effects to improve the safety and side-effect profile as compared with current ATP-competitive TKIs. Based on the results from the pivotal phase III ASCEMBL and phase I dose-finding studies, asciminib has been approved by regulatory authorities for the treatment of adults with chronic-phase CML who have been previously treated with at least two TKIs and, at a higher dose, for those with the T315I BCR::ABL1 resistance mutation. The high efficacy and acceptable safety profile in heavily treated patients provided a rationale for assessing asciminib in earlier lines of treatment.
In ASC4FIRST, phase III study, patients with newly diagnosed CML were randomly assigned in a 1:1 ratio to receive either asciminib or an investigator-selected TKI, with randomisation stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk) and by TKI selected by investigators before randomisation including imatinib and second-generation TKIs. The primary endpoints were major molecular response defined as BCR::ABL1 transcript levels ≤0.1% on the International Scale at week 48, for comparisons between asciminib and investigator-selected TKIs and between asciminib and investigator-selected TKIs in the prerandomisation-selected imatinib stratum.
A total of 201 patients were assigned to receive asciminib and 204 to receive investigator-selected TKIs. The median follow-up was 16.3 months in the asciminib group and 15.7 months in the investigator-selected TKI group. A major molecular response at week 48 occurred in 67.7% of patients in the asciminib group, as compared with 49.0% in the investigator-selected TKI group (difference 18.9 percentage points; 95% confidence interval [CI] 9.6 to 28.2; adjusted two-sided p < 0.001), and in 69.3% of patients in the asciminib group as compared with 40.2% in the imatinib group within the imatinib stratum (difference 29.6 percentage points; 95% CI 16.9 to 42.2; adjusted two-sided p < 0.001). The percentage of patients with a major molecular response at week 48 was 66.0% with asciminib and 57.8% with TKIs in the second-generation TKI stratum (difference 8.2 percentage points; 95% CI −5.1 to 21.5).
The study was not designed to enable a comparison of major molecular response at week 48 between asciminib and second-generation TKIs. The median times to response were shorter with asciminib than with all investigator-selected TKIs, imatinib, and second-generation TKIs. The study results may give an early indication of long-term efficacy with asciminib because early molecular response and deep molecular response at week 48 were more frequent with asciminib than with all investigator-selected TKIs, particularly imatinib.
The safety profile of asciminib was favourable as compared with imatinib and second-generation TKIs. Adverse events of grade 3 or higher that occurred in 10% or more of patients in any cohort were haematologic in nature. Adverse events of grade 3 or higher and events leading to discontinuation of the study regimen were less frequent with asciminib (38.0% and 4.5%) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%).
The percentage of patients with arterial occlusive events was 1.0% with asciminib, 0% with imatinib, and 2.0% with second-generation TKIs. Since the incidence of such events increases with continued exposure, additional follow-up is needed to better assess the long-term risk.
The number of new mutations identified was low across treatment groups. Myristoyl pocket mutations could in principle respond to other TKIs, whereas treatments for resistance due to other mechanisms are not well defined. Mutation profiles will become more established with additional follow-up.
The choice of a frontline therapy is nuanced and depends on the patient’s goals and other patient-specific factors. Patients with newly diagnosed CML need long-term treatment with high efficacy and safety.
The study was funded by Novartis.
Reference
Hochhaus A, Wang J, Kim D-W, et al. for the ASC4FIRST Investigators. Asciminib in Newly Diagnosed Chronic Myeloid Leukemia. NEJM; Published online 31 May 2024. DOI: 10.1056/NEJMoa2400858