Asciminib was more effective than bosutinib at improving the rate of a major molecular response in patients with chronic myeloid leukemia in chronic phase (CP-CML) who had been previously treated with at least two tyrosine kinase inhibitors (TKIs), according to findings from a phase III study published in Blood.
Lead author Delphine Réa, MD, PhD, of the Hôpital Saint-Louis in Paris, France, noted that as a first-in-class allosteric inhibitor specifically targeting the ABL myristoyl pocket (STAMP), asciminib is positioned “to transform care in this population through its novel mechanism of action, [given its] potential to overcome resistance or intolerance to approved TKIs.”
A total of 233 patients with CP-CML in the study had previously received at least two TKIs, but had experienced either treatment failure or intolerance to their most recent TKI. Prior TKIs in the overall cohort included imatinib (82.8%), nilotinib (68.7%), dasatinib (84.1%), ponatinib (17.6%), radotinib (2.6%), or other agents (3.9%).
Patients were randomly assigned to receive either:
- asciminib 40 mg twice daily (n=157)
- bosutinib 500 mg once daily (n=76)
Investigators randomized patients based on baseline major cytogenetic response (MCyR) status. After randomization, the proportions of patients in MCyR at baseline were 29.3% in the asciminib group and 28.9% in the bosutinib group.
The median age was 52 years for patients in both the asciminib and bosutinib groups. A majority of patients in the bosutinib arm were female (59.2% vs. 47.8%), and most patients had an Eastern Cooperative Oncology Group performance status score of 0 (80.3% for asciminib and 81.6% for bosutinib). Most patients in both the asciminib and bosutinib treatment arms discontinued their last TKI due to lack of efficacy (60.5% vs. 71.1%, respectively), while most of the remaining patients discontinued their last TKI due to lack of tolerability (37.6% vs. 28.9%).
In all randomized patients, the median follow-up was 14.9 months. At the cut-off period, all patients either completed their 24-week visit or had already discontinued the study at an earlier time. After 24 weeks, treatment was ongoing in 61.8% of patients treated with asciminib (n=97), compared with 28.9% of patients treated with bosutinib (n=22). A higher proportion of patients in the bosutinib arm had discontinued therapy (37.6% vs. 71.1%).
At week 24, the major molecular response (MMR) rates were 25.5% in the asciminib group, compared with 13.2% in the bosutinib group (p=0.029). At 24 weeks, more patients treated with asciminib had BCR-ABL1IS (49.0%, vs. 23.7% for bosutinib), and cumulative incidence of MMR was 25.0% vs. 12.0% in the asciminib and bosutinib groups, respectively.
Asciminib led to fewer grade ≥3 adverse events (AEs; 50.6% vs. 60.5%) and fewer AEs that led to discontinuation of treatment (5.8% vs. 21.1%). Treatment-related AEs were reported in 63.5% of patients in the asciminib group and 88.2% of patients in the bosutinib group.
Limitations of the study include its small sample size and heterogeneous population.
Researchers reported financial conflicts of interest with Novartis Pharmaceuticals, which sponsored and funded the study.
Rea D, Mauro MJ, Boquimpani C, et al. A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after ≥2 prior TKIs [published online ahead of print, 2021 Aug 18.] Blood. doi: 10.1182/blood.2020009984.
Asciminib provides a much-needed therapeutic option for patients with CP-CML receiving therapy in the third line and beyond, given higher rates of disease progression and death in this population. Clinically meaningful responses were reported among heavily pre-treated patients receiving asciminib on the ASCEMBL trial. At 24 weeks, 40.8% of patients experienced a first complete cytogenetic response (CCyR). In addition, the MMR rate among patients treated with asciminib was almost twice as high as seen in the bosutinib group (25.5% vs. 13.2%, respectively). This treatment effect was observed regardless of line of therapy and despite demographic and prognostic variables that were imbalanced between the treatment arms at baseline. While up to 25% of patients with CML discontinue therapy due to AEs, asciminib was well-tolerated in the phase I and ASCEMBL studies.
Based on these results, I would consider asciminib, if available, in patients with multiple intolerances to prior TKIs. Compared with bosutinib, fewer patients treated with asciminib required dose reductions, treatment interruptions, or discontinued therapy for AEs. Bosutinib is approved in later line therapy at a dose of 500 mg daily, but is better tolerated at lower doses.
As reported in the phase I study, asciminib at higher doses is also active in highly resistant T315I-mutated CML, where few therapeutic options exist. For patients with resistant CML in later line therapy, the decision between potent third-generation TKIs ponatinib and asciminib is more nuanced. This is a worrisome group for whom I generally consider ponatinib and hematopoietic cell transplant. The phase II PACE study of ponatinib in heavily pre-treated patients with CP-CML reported CCyR in 46% and MMR in 34%, but also identified a significant risk for arterial occlusive events (AOEs). The incidence of AOEs on asciminib with limited follow-up is low. However, more events were reported in patients treated with asciminib, compared with bosutinib, and longer follow-up is required to clarify any risk.
Additional areas of interest to explore include identifying the most effective asciminib dose in later line therapy, as well as examining the efficacy of asciminib in earlier lines of therapy and in combination with TKIs to overcome resistance due to mutations and to promote deep molecular responses.
Vivian Oehler, MD
Fred Hutchinson Cancer Research Center