Australian researchers have demonstrated significantly stronger suppression of the cancer-driving protein with asciminib, strengthening the case for its use as a frontline treatment.
A new Australian study has shown that asciminib suppresses the molecular driver of chronic myeloid leukaemia (CML) significantly more effectively than imatinib or nilotinib within just seven days of treatment.
Researchers from Adelaide University and the South Australian Health and Medical Research Institute (SAHMRI) found that asciminib achieved a median 83% inhibition of BCR::ABL1 kinase activity, compared with 56% for nilotinib and 23% for imatinib (p<0.0001 for both comparisons).
The findings, published as a research letter in Leukemia, provide the first direct clinical evidence of the superior potency of frontline asciminib in suppressing the abnormal protein responsible for driving CML cell proliferation.
The researchers also found that none of the asciminib-treated patients experienced the very low levels of kinase inhibition associated with poorer outcomes in previous studies.
“We found asciminib was much more powerful at suppressing the cancer-driving protein that causes the leukaemia cells to spread,” said lead author Associate Professor Chung Hoow Kok, from Adelaide University’s Centre for Cancer Biology and SA Pathology.
“This is a huge step forward in the search for better, frontline treatment options for patients who don’t respond to current medications. Currently, 25% of patients will develop a resistance or intolerance to existing treatments.”
The study assessed blood samples from 70 patients with newly diagnosed chronic-phase CML receiving frontline asciminib in the ASCEND study, comparing their results with previously collected data from 173 imatinib-treated and 73 nilotinib-treated patients.
Researchers measured in vivo kinase inhibition (IVKI) using phosphorylation of CRKL, a direct substrate of BCR::ABL1, to determine how effectively each treatment suppressed kinase activity during the first week of therapy.
Baseline kinase activity was similar across the three treatment groups, but asciminib produced significantly greater inhibition after seven days.
No patients receiving asciminib had IVKI below the previously established 11% threshold associated with inferior outcomes on imatinib, compared with 4% of nilotinib-treated patients and 23% of those receiving imatinib.
“Within just one week, asciminib achieved substantially stronger suppression of the cancer-driving protein than the currently available treatments,” said Professor Tim Hughes, leader of SAHMRI’s Chronic Myeloid Leukaemia Group.
“Importantly, none of the patients experienced the poorer responses sometimes seen with the existing drugs.
“This new biological evidence from our research supports the excellent clinical outcomes from recent trials of asciminib.”
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Asciminib is the first approved BCR::ABL1 inhibitor that specifically targets the ABL myristoyl pocket, offering a different mechanism of action from conventional ATP-competitive tyrosine kinase inhibitors (TKIs).
Its targeted action is associated with reduced off-target toxicity, while findings from the phase III ASC4FIRST trial have demonstrated favourable efficacy and safety compared with investigator-selected TKIs.
The researchers also examined whether the degree of kinase inhibition differed among patients with ASXL1 mutations, which have been linked to an increased risk of treatment failure.
Asciminib maintained strong BCR::ABL1 inhibition in patients with these variants, with median IVKI of 77% compared with 84% in patients without the mutations, a difference that was not statistically significant (p=0.11).
However, ASXL1 variants remained an independent predictor of inferior failure-free survival (p=0.002), while the degree of kinase inhibition itself was not significantly associated with this outcome.
The researchers suggested that the adverse impact of ASXL1 mutations may be driven by biological pathways independent of BCR::ABL1 activity, highlighting the importance of genomic profiling alongside treatment monitoring.
Further analysis found no significant differences in major molecular response rates at 24 months or MR4.5 rates at three years across quartiles of kinase inhibition among asciminib-treated patients.
The findings suggest that inadequate BCR::ABL1 suppression is unlikely to be the primary explanation for treatment failure in patients receiving asciminib.
The researchers also raised the possibility that asciminib’s potency could eventually allow lower frontline doses without compromising molecular responses. However, they stressed that prospective clinical trials would be needed before routine dose reductions could be recommended.
More than 7000 Australians are living with CML, a blood cancer driven by the BCR::ABL1 fusion gene.
Although advances in targeted therapies have transformed CML into a manageable chronic condition for many patients, resistance and intolerance remain significant
Professor Kok said the findings could help clinicians move towards more individualised treatment strategies by combining early assessments of drug activity with genomic information.
“This is an important step towards precision medicine, where treatment decisions are guided by the biology of each patient’s cancer rather than a one-size-fits-all approach,” he said.
“Our findings reinforce the importance of combining genomic testing with treatment monitoring to work out which patients may benefit from additional therapies or more frequent reviews.
“Our goal is to move beyond treating all patients in the same way. By understanding the biology of each person’s CML, we can work towards selecting the right treatment, for the right patient, at the right time.”
The researchers concluded that integrating early kinase inhibition measurements with molecular risk markers could improve risk-adapted frontline management, although further studies are needed to establish how best to incorporate these measures into routine clinical decisions.
