To date, many newly diagnosed patients with chronic myeloid leukaemia (CML) do not achieve optimal response with standard tyrosine kinase inhibitor (TKI) therapy. The ASC4FIRST study is the only head-to-head trial of asciminib versus all current standard-of-care frontline TKIs in patients with newly diagnosed CML. At EHA 2024, primary results from this phase III study demonstrated superior efficacy and tolerability of asciminib versus imatinib and second-generation TKIs.
Asciminib specifically targets the ABL Myristoyl Pocket (STAMP) and was intentionally designed to improve efficacy and reduce off-targets effects as compared to current ATP-competitive TKIs. The ASC4FIRST study assessed asciminib versus investigator-selected TKIs in patients with newly-diagnosed CML in chronic phase. It is the first study to evaluate a novel agent against all current standard-of-care TKIs in this setting.
Study design
The multicentre, randomised, open-label phase III ASC4FIRST study investigated the effectiveness, safety and tolerability of asciminib versus an investigator-selected TKI (imatinib, nilotinib, dasatinib or bosutinib) in adult patients with newly diagnosed Philadelphia chromosome positive (Ph+) CML in chronic phase that had not been previously treated. Either imatinib, bosutinib, dasatinib, or nilotinib was allowed for ≤2 weeks prior to randomisation. Treatment with other TKIs prior to randomisation was not permitted. Pre-randomisation TKI was selected by the physician in consultation with the patient. Patients were stratified by ELTS risk category and pre-randomisation TKI selection (imatinib vs. second-generation TKI). Patients were randomised (1:1) to treatment with 80 mg asciminib once daily or treatment with another TKI at label dose. However, within both groups a distinction continued to be made between patients who had been selected for treatment with imatinib before randomisation (imatinib stratum) and patients who were treated with a second-generation TKI (2G-TKI stratum). Co-primary endpoints of the study were the major molecular response (MMR) at week 48 with asciminib vs. all investigator-selected TKIs and MMR at week 48 with asciminib vs. investigator-selected TKIs within the imatinib stratum. The study is positive if either objective is met. The MMR rate at week 48 in the 2G-TKI stratum was a secondary outcome measure.
Results
Baseline patient characteristics between both treatment arms were very similar. However, more patients in the imatinib stratum vs. 2G TKI stratum were aged ≥65 years and had higher cardiovascular disease risk, reflecting physician preference for imatinib in these subgroups. In total, 201 patients were treated with asciminib, of which 101 in the imatinib-stratum and 100 in the 2G-TKI stratum. In the TKI-group, 102 patients were treated in the imatinib-stratum and 102 in the 2G-TKI stratum. Median follow-up was 16.3 months in the asciminib-arm and 15.7 months in the TKI-arm. The MRR rate at week 48 in the ITT population was found to be superior upon treatment with asciminib, both in the overall population (67.7% vs. 49.0%) and in the imatinib-stratum (69.3% vs. 40.2%), meeting both primary objectives with high statistical significance (both p< 0.001). The cumulative incidence of MMR by week 48 was 66.5% in the asciminib-group vs. 46.3% in the TKI-group. Also in the imatinib-stratum higher rates of cumulative incidence of MRR by week 48 were reported with asciminib as compared to TKI (69.1% vs. 38.0%). A higher proportion of patients achieved major, early and deep molecular responses with asciminib as compared to investigator-selected TKIs.
The most common adverse events (AEs) were thrombocytopenia (asciminib: 28.0%, imatinib: 28.3%, 2G TKI: 34.3%), neutropenia (25.0%, 31.3%, 34.3%), diarrhoea (15.5%, 26.3%, 25.5%) and anaemia (11.5%, 26.3%, 22.5%). AEs of grade ≥3 were reported in 38.0% of patients receiving asciminib, in 44.4% of patients in the imatinib-subgroup and in 54.9% of patients in the 2G-TKI subgroup. Arterial occlusive events were noted in 1%, 0% and 2% of the patients, respectively. AEs leading to discontinuation were less frequent with asciminib as compared to the other regimens (asciminib: 4.5%; imatinib: 11.1%; 2G-TKI: 9.8%) and the treatment dosing was less often adapted as compared to treatment with a TKI (respectively 30.0%, 39.4%, 52.9%).
Conclusion
In the ASC4FIRST study, asciminib demonstrated superior efficacy versus all standard-of-care frontline TKIs. Both primary objectives in ASC4FIRST were met with high statistical significance. In addition, asciminib had a favourable safety and tolerability profile, with fewer grade ≥3 adverse events and half the rates of adverse events leading to treatment discontinuation vs. all investigator-selected TKIs.
Reference
Hochhaus A, et al. Asciminib (ASC) provides superior efficacy and excellent safety and tolerability vs tyrosine kinase inhibitors (TKI) in newly diagnosed chronic myeloid leukemia (CML) in the pivotal ASC4FIRST study. Presented at EHA 2024; Abstract S103.
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