The ASCEMBL study is an open-label, randomised, phase III trial comparing asciminib with bosutinib in patients with chronic myeloid leukaemia in chronic phase previously treated with two or more tyrosine kinase inhibitors. In this trial, asciminib, a first-in-class STAMP inhibitor, demonstrated statistically significant and clinically meaningful superiority in efficacy compared with bosutinib, with deeper molecular response rates and a favourable safety profile.
EXPERT OPINION OF DR. NIKKI GRANACHER, HAEMATOLOGIST, ZNA
“Asciminib has recently become available in Belgium via ETA (Early Temporary Access) provided by Novartis. This means that chronic phase CML patients, intolerant or refractory to ≥ 2 previous TKIs, can now be treated with asciminib. Through its novel mechanism of action as a STAMP inhibitor, asciminib has the potential to transform standard of care in this patient population.”
Adenosine triphosphate (ATP)–competitive tyrosine kinase inhibitors (TKIs) have transformed chronic myeloid leukaemia in chronic phase (CML-CP), from a fatal disease to one associated with near-normal life expectancy. Unfortunately, some patients experience primary resistance, loss of response or intolerance. Available therapies for patients with resistance or intolerance to at least two previous TKIs are often limited by modest efficacy and safety concerns. Thus far, all approved TKIs for CML bind to the ATP site of the BCR-ABL1 oncoprotein to inhibit aberrant kinase activity. Asciminib is a novel, first-in-class Specifically Targeting the ABL Myristoyl Pocket (STAMP) inhibitor that potently inhibits the kinase activity of BCR-ABL1 via allosteric binding. The ASCEMBL study compared the efficacy and safety of asciminib versus bosutinib, a second-generation TKI, in patients with CML in chronic phase who were previously treated with at least two TKIs.
The ASCEMBL study was designed as a randomised, open-label, multicentre phase III trial that enrolled patients with CML-CP previously treated with at least two TKIs. Eligible patients were at least18 years old and had experienced treatment failure (lack of efficacy) or intolerance of the most recent TKI therapy. Patients with known bosutinib-resistant BCR-ABL1 mutations of T315I or V299L were not selected. Between 2017 and 2019, a total of 233 patients were randomised (2:1) to asciminib 40 mg twice daily (N= 157) or bosutinib 500 mg once daily (N= 76). The primary endpoint was the rate of MMR (BCR-ABL1IS≤ 0.1%) at week 24. To be counted as being in MMR, patients must have been on study treatment with BCR-ABL1IS≤ 0.1% at week 24 and not have met any treatment failure criteria (lack of efficacy or treatment discontinuation for any reason) before week 24.
At the data cut-off, median follow-up was 14.9 months. In total, 59 (37.6%) patients in the asciminib arm and 54 (71.1%) patients in the bosutinib arm had discontinued therapy. Before completing 24 weeks of therapy, the main reasons for discontinuation were adverse events (AEs) (4.5% vs. 14.5%, asciminib and bosutinib arms, respectively) and lack of efficacy (4.5% vs. 6.6%). The MMR rate at week 24 was 25.5% with asciminib vs. 13.2% with bosutinib, meeting the primary objective of the study. Regardless of BCR-ABL1 levels at baseline, more patients on asciminib than on bosutinib had BCR-ABL1IS ≤10% at week 12 (63.1% vs. 43.4%) and BCR-ABL1IS ≤1% at week 24 (49.0% vs. 23.7%). The cumulative incidence of MMR by week 24 was 25.0% with asciminib vs. 12.0% with bosutinib.
Of the patients evaluable for safety, 140 (89.7%) and 73 (96.1%) patients receiving asciminib and bosutinib experienced all-grade AEs, respectively. Fewer grade ≥ 3 AEs (50.6% vs. 60.5%), treatment-related AEs (63.5% vs. 88.2%), and AEs leading to treatment discontinuation (5.8% vs. 21.1%) occurred with asciminib than with bosutinib, respectively. The most common AEs leading to treatment discontinuation included thrombocytopenia with asciminib and increased alanine aminotransferase (ALT) with bosutinib. During the study, four patients (2.6%) in the asciminib arm and one patient (1.3%) in the bosutinib arm died.
The ASCEMBL study reported superior efficacy of asciminib compared with bosutinib in the treatment of patients with CML-CP previously treated with at least two TKIs. Asciminib nearly doubled the MMR rate of bosutinib at week 24, meeting the primary objective of the study (25.5% vs. 13.2% for asciminib and bosutinib, respectively). Asciminib also demonstrated favourable safety and tolerability. Fewer grade ≥3 AEs and AEs leading to treatment discontinuation occurred with asciminib than with bosutinib. These findings support the use of asciminib as a new therapy in this setting, having the potential to transform standard of care in this population through its novel mechanism of action as a STAMP inhibitor.