ASCO24: Novartis' Scemblix Favored in Front-line CML Study

In a recent pivotal study, Novartis’ Scemblix (asciminib) has shown promising results as a potential first-line treatment for Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML). The findings from the ASC4FIRST trial, which were initially highlighted in January, were presented at the American Society of Clinical Oncology (ASCO) annual meeting. This Phase III study is particularly noteworthy as it is the first to directly compare a novel CML treatment against existing first- and second-generation tyrosine kinase inhibitors (TKIs).

The ASC4FIRST trial enrolled 405 adults who were newly diagnosed with Ph+ CML in the chronic phase. Participants were randomly assigned to receive either once-daily oral Scemblix or an investigator-selected TKI from existing options, including Gleevec (imatinib) and second-generation TKIs like Tasigna (nilotinib), Sprycel (dasatinib), and Bosulif (bosutinib). The trial's two primary endpoints focused on major molecular response (MMR) rates at week 48.

Scemblix demonstrated significant efficacy, with 67.7% of patients achieving MMR at week 48, compared to 49% for those on investigator-selected TKIs. This translates to a near 19% benefit in favor of Scemblix. When directly compared to Gleevec, Scemblix's advantage was even more pronounced, with MMR rates of 69.3% versus 40.2% for Gleevec.

One of the standout aspects of Scemblix’s performance in this trial was its ability to achieve deeper molecular responses. According to senior study author Jorge Cortes, a substantial number of patients—35% to 40%—achieved an MR4 response with Scemblix, which is better than the outcomes observed with Gleevec and all other TKIs evaluated. Furthermore, although the study wasn't specifically designed to make direct comparisons with second-generation TKIs, early results indicating MR4.5 responses also favored Scemblix, with about 16% to 18% of patients achieving this deep molecular response.

The safety profile of Scemblix was another significant highlight of the study. Haematologic toxicities, such as thrombocytopenia and neutropenia, occurred at rates of 13% and 10%, respectively, which were deemed "equivalent, but mostly better" compared to the TKIs. Non-haematologic toxicities, including gastrointestinal and lab events, also showed an overall favorable profile for Scemblix. Importantly, the rate of arterial occlusive events was low, and there were fewer treatment discontinuations due to adverse events with Scemblix compared to the control arms.

ASCO expert Oreofe Odejide remarked on the significance of these findings, highlighting the balance of efficacy and tolerability shown by Scemblix. Given that more than 40% of newly diagnosed CML patients fail to achieve a major molecular response within a year of treatment and often need to switch therapies due to adverse events, Scemblix represents a promising alternative with the potential to improve patient outcomes and reduce treatment-related complications.

Originally approved in 2021 as a third-line treatment for Ph+ CML, Scemblix’s demonstrated efficacy and safety in the ASC4FIRST trial provide a compelling case for its use as a front-line therapy. If approved for first-line use, Scemblix could become a new standard of care for patients newly diagnosed with Ph+ CML, offering a significant improvement in achieving and maintaining molecular responses while also reducing the risk of adverse events.