The FDA has granted accelerated approval to asciminib (Scemblix, Novartis) 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 first-line CML therapy, offering a novel mechanism of action and improved tolerability compared to existing treatments.
The approval was based on data from the Phase 3 ASC4FIRST trial (NCT04971226), a head-to-head study comparing asciminib to investigator-selected standard-of-care tyrosine kinase inhibitors (TKIs), including imatinib, nilotinib, dasatinib, and bosutinib. The trial enrolled 405 patients who were randomized to receive either asciminib 80 mg once daily or standard-of-care TKIs at their approved doses.
The primary endpoint of the study was major molecular response (MMR) at 48 weeks. Results showed that asciminib achieved a significantly higher MMR rate of 68% compared to 49% with standard-of-care TKIs (p < .001). When compared to imatinib alone, asciminib demonstrated an even greater advantage, with MMR rates of 69% versus 40%.
"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," said Lee Greenberger, PhD, chief scientific officer at The Leukemia & Lymphoma Society. "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."
Novel Mechanism of Action
Asciminib is the first CML treatment that works by specifically targeting the ABL myristoyl pocket, a distinct mechanism from traditional TKIs that bind to the ATP-binding site of the BCR-ABL1 kinase. This unique mechanism allows asciminib to overcome resistance mutations that may arise with other TKIs.
Improved Tolerability
In addition to superior efficacy, asciminib also demonstrated a favorable safety and tolerability profile in the ASC4FIRST trial. Patients treated with asciminib experienced fewer treatment-related grade 3 or higher adverse events (25.5%) compared to imatinib alone (33%) and second-generation TKIs (42%). Dose reductions were also less frequent with asciminib (6%) compared to imatinib (14%) and second-generation TKIs (24%). The rate of adverse events leading to treatment discontinuation was also lower with asciminib (4.5%) compared to imatinib (11%) and second-generation TKIs (9.8%).
The most common adverse events reported with asciminib included musculoskeletal pain, rash, fatigue, upper respiratory tract infection, headache, abdominal pain, and diarrhea. The safety profile in newly diagnosed patients was consistent with prior studies, and no new safety concerns were identified.
Clinical Implications
"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," said Jorge Cortes, MD, director of Georgia Cancer Center. "In the first-of-its-kind ASC4FIRST trial, [asciminib] achieved impressive results across all three parameters of efficacy, safety and tolerability versus all standard of care TKIs. [These asciminib] data [have] the potential to be practice-changing."
The accelerated approval of asciminib provides a valuable new first-line treatment option for patients with Ph+ CML-CP, offering the potential for improved efficacy and tolerability compared to existing therapies. Continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial.
