Novartis' Scemblix® (asciminib) has received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP). This approval marks a significant advancement in CML treatment, offering a new first-line option with superior efficacy and a favorable safety profile compared to existing standard of care (SoC) therapies. The accelerated approval is based on data from the Phase III ASC4FIRST trial, which demonstrated that Scemblix achieved significantly higher major molecular response (MMR) rates at week 48 compared to investigator-selected (IS) SoC TKIs, including imatinib, nilotinib, dasatinib, and bosutinib.
Superior Efficacy and Safety Profile
The ASC4FIRST trial (NCT04971226) was a head-to-head, multi-center, open-label, randomized study involving 405 adult patients with newly diagnosed Ph+ CML-CP. Patients were administered Scemblix 80 mg QD orally versus IS first- or second-generation TKIs. The study's primary endpoints focused on comparing the efficacy of asciminib against IS SoC TKIs and against imatinib alone, based on the proportion of patients achieving MMR at week 48.
Data from the trial revealed that nearly 20% more patients treated with Scemblix achieved MMR compared to those on IS SoC TKIs (68% vs. 49%, p < 0.001). Furthermore, almost 30% more patients achieved MMR with Scemblix compared to imatinib alone (69% vs. 40%, p < 0.001) at week 48. Scemblix also demonstrated a more favorable safety and tolerability profile, with fewer treatment-related grade ≥3 adverse reactions (ARs) (25.5% vs. 33% and 42%), fewer dose reductions (6% vs. 14% and 24%), and half the rate of ARs leading to treatment discontinuation (4.5% vs. 11% and 9.8%) compared to imatinib and second-generation TKIs.
Patients treated with Scemblix also achieved deeper molecular responses, including MR4, compared to IS-TKIs and imatinib alone (41% vs. 22% and 16%) by week 48.
Addressing Unmet Needs in CML Treatment
While tyrosine kinase inhibitors (TKIs) have transformed CML into a chronic disease, challenges related to efficacy and safety continue to hinder long-term treatment success for many patients. Approximately half of CML patients do not meet efficacy milestones (MMR), and nearly one in four discontinue or switch treatment within one year due to intolerance. The approval of Scemblix offers a new treatment paradigm that addresses these unmet needs by providing a highly effective and well-tolerated first-line option.
Lee Greenberger, Ph.D., Chief Scientific Officer at The Leukemia & Lymphoma Society, noted, "Many patients who are newly diagnosed with CML struggle to navigate this chronic condition and may switch or even stop treatment because of side effects that interrupt their daily lives. That’s why approvals of new first-line treatment options are so important. For patients, finding a medicine that’s right for them at the very beginning of treatment may lead to better long-term disease control with fewer side effects."
Mechanism of Action and Clinical Significance
Scemblix (asciminib) is the first CML treatment that functions by Specifically Targeting the ABL Myristoyl Pocket (STAMP inhibitor). Current CML treatments are TKIs that target the ATP-binding site (ATP-competitive). This novel mechanism of action allows Scemblix to overcome some of the limitations associated with traditional TKIs, offering improved efficacy and a reduced risk of resistance.
Jorge Cortes, M.D., Director, Georgia Cancer Center, stated, "While there are a range of effective TKIs currently available for newly diagnosed patients, clinicians frequently have had to weigh sacrificing either efficacy or tolerability. In the first-of-its-kind ASC4FIRST trial, Scemblix achieved impressive results across all three parameters of efficacy, safety and tolerability versus all standard of care TKIs. This Scemblix data has the potential to be practice-changing."
Ongoing Studies and Future Directions
The ASC4FIRST trial is ongoing, with the next scheduled analysis at week 96 to evaluate the key secondary endpoint (MMR at week 96) and additional secondary endpoints. The approval was also supported by preliminary data from the Phase II ASC2ESCALATE study, which includes Ph+ CML-CP patients who have been previously treated with one prior TKI with discontinuation due to treatment failure, warning, or intolerance.
Novartis remains committed to addressing unmet patient needs in CML and reducing barriers to patient access and affordability. Novartis Patient Support is available to guide eligible patients through various aspects of starting treatment, including insurance coverage and financial assistance options.
