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Asciminib Superior to Bosutinib in Chronic-Phase CML
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
PERSPECTIVES
( 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-ABL1 IS ( 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 .
Study authors report relationships with Novartis Pharmaceuticals , which sponsored and funded the study .
Reference Réa 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
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