ASCO24: Front-line CML study tilts scales in favour of Novartis' Scemblix
31 May 2024
Clinical ResultPhase 3Drug ApprovalASCO
Novartis' Scemblix (asciminib) could be enroute to securing a first-line label for Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML) after demonstrating superior efficacy and improved safety compared to standard tyrosine kinase inhibitor (TKI) therapies in a pivotal study of newly diagnosed patients.
Detailed results of the ASC4FIRST trial, which was top-lined in January, were presented during a late-breaker presentation at the American Society of Clinical Oncology (ASCO) annual meeting that got under way Friday.
The Phase III study, the first head-to-head trial comparing a novel CML treatment against approved first- and second-generation TKIs, met both primary endpoints with clinically meaningful and statistically significant results. Scemblix showed higher major molecular response (MMR) rates at week 48 versus investigator-selected TKIs, including Gleevec (imatinib) and second-generation TKIs such as Tasigna (nilotinib), Sprycel (dasatinib) and Bosulif (bosutinib).
'Nice balance' of efficacy, safety
"More than 40% of patients who are newly diagnosed with CML fail to achieve a major molecular response after a year of treatment, and then several also have to switch treatments because of adverse events," commented ASCO expert Oreofe Odejide, "so this is really striking that we have a therapy, [Scemblix], that has a nice balance of efficacy and tolerability."
Scemblix was originally approved in 2021 for Ph+ CML in the third-line setting, but researchers sought to test how it fared as a front-line treatment. ASC4FIRST recruited 405 adults with newly diagnosed Ph+ CML in chronic phase who were randomised to once-daily oral Scemblix versus investigator-selected first- or second-generation TKIs.
The study had two primary endpoints. In the first, 67.7% of patients treated with Scemblix achieved MMR at week 48, compared to 49% of those receiving investigator-selected TKIs, representing a benefit of nearly 19% in favour of Scemblix. When compared specifically to Gleevec, the advantage was nearly 30%; Scemblix's MMR rate was 69.3%, versus 40.2% observed with Gleevec alone.
Deeper molecular responses
Scemblix also demonstrated superior deeper molecular responses. "We know that a significant number of patients, more than half, do not get to the deep responses and the type of outcomes that we aim for now… treatment-free remission is becoming increasingly important," said senior study author Jorge Cortes.
"Although this is an early look, it is still important to see that we are seeing 35% to 40% of patients with [Scemblix] already reaching an MR4. This is better than [Gleevec], better than all TKIs," he said. Further, while the study wasn't powered specifically to compare to second-generation TKIs, Cortes said it showed "a good number of MR4.5's" also favouring Scemblix – about 16% to 18% of patients – compared to any of the control arms.
Safety profile 'mostly better'
Haematologic toxicities were "equivalent, but mostly better" with Scemblix, Cortes said, the most frequent Grade ≥3 adverse events with the drug being thrombocytopenia and neutropenia, which occurred at rates of 13% and 10%, respectively. The same was largely true for non-haematologic toxicity such as gastrointestinal and lab events.
"Overall, the safety profile seems to be equivalent or better for nearly all of these adverse events that we see with TKIs," said Cortes, adding there were "very few arterial occlusive events, just a handful of them with any of the arms and far fewer treatment discontinuations because of adverse events with [Scemblix]."
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