Asciminib is effective in patients previously treated with CML

According to The results of the phase 3 ASCEMBL trial (NCT03106779) presented at the 2023 American Society of Hematology Annual Meeting, chronic patients who have received 2 or more tyrosine kinase inhibitors (TKIs) treatment Patients with chronic myeloid leukemia (CML-CP) benefit more from Asciminib than Bosutinib. Most patients with chronic phase chronic myelogenous leukemia who receive long-term TKI therapy do have the potential to develop long-term chronic health problems, and those who fail at least 2 TKIs face additional challenges, such as high frequencies of drug resistance that lead to mutations and toxicity.

The results of the ASCEMBL trial showed that aximinib had better efficacy and a good safety profile compared with bosutinib at 24 weeks and 96 weeks in these patients with chronic phase chronic myelogenous leukemia who had received at least 2 previous TKIs. At week 156 (end of study), the major molecular response (MMR) rate for aximinib (33.8%) continued to be higher than that for bosutinib (10.5%). After adjusting for baseline, the difference in major cytogenic response was 23.2% (95% CI, 13.1%-33.2%; 2-sided P < .001). Among patients without a major cytogenic response at baseline (23.2%), the rate of BCL-ABL1 ≤1% at 156 weeks after treatment with aximinib continued to be higher than that with bosutinib (43.0% vs 11.1%). In terms of progression-free survival (PFS) and overall survival (OS), the researchers found that the 3-year PFS rate of aceminib was 85.2% (95% CI, 76.8%-90.7%), and that combined with bosutinib was 84.0% (95% CI, 67.5%-92.6%). The 5-year OS rate of aximinib was 87.8% (95% CI, 78.7%-93.1%), and the 5-year OS rate of bosutinib was 89.7% (95% CI, 76.3%-95.7%).

According to the 2013 ELN recommendations, a total of 233 patients with chronic myeloid leukemia and chronic pancreatitis who developed intolerance or lack of efficacy after receiving ≥ 2 TKIs were randomly assigned to the asiminib cohort (n=156) or the bosutinib cohort (n=76) in a 2:1 ratio. Patients received either 40 mg of aximinib twice daily or 500 mg of bosutinib once daily. The researchers noted that if patients receiving bosutinib did not meet the treatment criteria recommended by the 2013 ELN, they could switch to aximinib and analyze it separately. Patients who are intolerant to bosutinib and discontinue treatment should not be switched to aximinib.

atOf the 28 patients who discontinued bosutinib due to poor efficacy, 25 patients were switched to aximinib. Nearly every patient who converted (96%) had received BCL-abl1 > 10% therapy before conversion. None of the converted patients achieved MMR at or before week 48 after conversion. At week 48, 24% of patients had BCL-ABL1 ≤10% and 8% had BCL-ABL1 ≤1%.

At the end of the study treatment cut-off date, 77 (49.4%) and 8 (10.5%) patients were still receiving aximinib and bosutinib, respectively. Patients who showed beneficial activity at the end of the study, as assessed by the investigators, continued treatment after the trial. The common reason for discontinuing treatment was poor response in 40 patients (25.5%) who received aceminib and 28 patients (36.8%) who received bosutinib. Although the median exposure to asiminib was longer (156.0 [0.1-256.3] weeks) compared with bosutinib (30.5 [1.0-239.3] weeks), the safety and tolerability of aximinib was superior to that of bosutinib, consistent with previous analyses.

Two patients in the study discontinued treatment due to adverse events (AEs) after the cutoff of Week 96. One patient receiving aximinib reported pregnancy and another patient receiving bosutinib reported diarrhea. The discontinuation rate was lower with aximinib (8.3%) than with bosutinib (27.6%). The most common (≥10%) grade 3 AEs of aximinib vs. bosutinib were thrombocytopenia (22.4% vs. 9.2%), neutropenia (18.6% vs. 14.5%), diarrhea (0% vs. 10.5%), and increased alanine aminotransferase (0.6% vs. 14.5%). Most AEs occurred within the first 6 months of treatment.

During the survival follow-up period, 6 deaths occurred in the Asiminib group due to chronic myelogenous leukemia (3 cases) and hemorrhagic stroke, multiple organ dysfunction syndrome, and COVID-19 (1 case each). Three patients received bosutinib treatment, one had chronic myelogenous leukemia, one had respiratory distress, and one had COVID-19. The safety profile of asiminib remained consistent in patients who switched compared with patients who received asiminib during randomization. The most common (≥10%) grade 3 AEs were neutropenia (32.0%) and thrombocytopenia (24.0%). 8% ofswitchedpatients experiencedAEs and discontinued treatment.

Since the cutoff of Week 96, the exposure-adjusted arterial occlusive event (AOE) rate for aceminib has decreased from 3.0 to 2.2 per 100 patient-years, with no new AOEs occurring for either drug, emphasizing that the risk of AOE does not increase over time. No new mutations occurred in patients who discontinued treatment due to lack of response or disease progression since the Week 96 cutoff. By the end of the study, emerging mutations had not changed since week 96, with mutations occurring in 7.6% of patients on aximinib and 2.6% of patients on bosutinib.