FDA Grants Priority Review to Novartis' Scemblix for Newly Diagnosed CML
Key Insights
The FDA has granted priority review to Novartis' Scemblix (asciminib) for treating newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (search) (Ph+ CML-CP).
The decision is based on the Phase III ASC4FIRST trial, which demonstrated Scemblix's superior major molecular response (MMR) rates compared to standard-of-care tyrosine kinase inhibitors (TKIs).
Scemblix showed a favorable safety and tolerability profile, with fewer adverse events and treatment discontinuations compared to standard TKIs in the ASC4FIRST trial.
The FDA has granted priority review to Novartis' Scemblix (asciminib) for the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (search) in the chronic phase (Ph+ CML-CP). This regulatory decision, announced by Novartis, is based on data from the Phase III ASC4FIRST clinical trial, which demonstrated Scemblix's superior efficacy and safety compared to standard-of-care tyrosine kinase inhibitors (TKIs). The priority review underscores the potential for Scemblix to address a critical need for more effective and tolerable treatment options in CML.
ASC4FIRST Trial Results
The ASC4FIRST trial (NCT04971226) was a multicenter, open-label, randomized study involving 405 adult patients with newly diagnosed Ph+ CML-CP who were TKI-naive. Patients were randomized 1:1 to receive either 80 mg of Scemblix once daily or an investigator-selected TKI (imatinib, nilotinib, dasatinib, or bosutinib). The primary endpoint was the major molecular response (MMR) rate at week 48.
The results, presented at the 2024 ASCO Annual Meeting and published in The New England Journal of Medicine, showed that Scemblix achieved superior MMR rates compared to investigator-selected TKIs. At week 48, the MMR rate was 67.7% in the Scemblix arm versus 49.0% in the TKI arm (P < .001). Notably, in the imatinib stratum, the 48-week MMR rates were 69.3% vs 40.2% for Scemblix and imatinib, respectively (P < .001).
Safety and Tolerability Profile
In addition to superior efficacy, Scemblix demonstrated a more favorable safety and tolerability profile compared to standard TKIs. The incidence of grade ≥3 adverse events was lower in the Scemblix arm (38%) compared to the TKI arm (44% for imatinib and 55% for second-generation TKIs). Furthermore, Scemblix was associated with fewer dose adjustments (30% vs 39% and 53%) and a lower rate of adverse events leading to treatment discontinuation (5% vs 11% and 10%). The safety profile of Scemblix in newly diagnosed patients was consistent with that observed in previous registration studies, with no new safety concerns reported.
Clinical Significance
Chronic myeloid leukemia (search) is a myeloproliferative neoplasm characterized by the Philadelphia chromosome, resulting in the BCR-ABL1 (search) fusion protein, a constitutively active tyrosine kinase. TKIs, such as imatinib, nilotinib, dasatinib, and bosutinib, have revolutionized CML treatment, transforming it from a life-threatening illness to a chronic condition. However, a significant proportion of patients do not achieve optimal molecular responses, and intolerance to TKIs remains a challenge. Discontinuation rates due to adverse events can be as high as 25% within five years of treatment.
Scemblix, which works by specifically targeting the ABL myristoyl pocket, offers a novel mechanism of action compared to traditional ATP-binding site TKIs. This unique mechanism may contribute to its improved safety and tolerability profile. Rodney Gillespie, Senior Vice President, Therapeutic Area Head, US Oncology, Novartis, stated that the ASC4FIRST data indicate that Scemblix, if approved, has the potential to address a critical gap in CML by offering a highly effective treatment along with a favorable safety and tolerability profile.
Regulatory Status and Future Directions
Scemblix has already been approved by the FDA, the European Medicines Agency, and other regulatory authorities for use in adults with Ph+ CML-CP who have been previously treated with two or more TKIs. The FDA previously granted Scemblix breakthrough therapy designation for newly diagnosed CML patients. The agent is currently under evaluation by the FDA’s Real-Time Oncology Review program. The ongoing ASC4FIRST trial will continue to evaluate key secondary endpoints, including MMR at week 96, as well as additional safety and efficacy measures.