The FDA has granted accelerated approval to asciminib (Scemblix, Novartis AG) for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase (CP). This decision, announced on October 29, 2024, is based on the Phase 3 ASC4FIRST trial, which demonstrated superior efficacy and a favorable safety profile compared to standard-of-care tyrosine kinase inhibitors (TKIs). The approval offers a new first-line treatment option for patients navigating this chronic condition.
ASC4FIRST Trial Results
The ASC4FIRST trial (NCT04971226) was a multicenter, randomized study comparing asciminib to investigator-selected TKIs, including imatinib, nilotinib, dasatinib, or bosutinib. The trial enrolled 405 patients who were randomized 1:1 to receive either asciminib (80 mg once daily) or the investigator's choice of TKI at standard doses. Key stratification factors included pre-randomization TKI selection (imatinib vs second-generation TKI) and European Treatment and Outcome Study long-term survival score (high vs intermediate vs low).
The primary endpoint was the major molecular response (MMR) rate at 48 weeks. Results showed a statistically significant difference in MMR rates, with 68% (95% CI: 61-74) for asciminib compared to 49% (95% CI: 42-56) for the TKI group (p < 0.001). In the imatinib stratum, the MMR rate was 69% for asciminib versus 40% for TKIs (p < 0.001).
Further analysis indicated that asciminib also led to higher rates of deep molecular responses. The MR4 rates at week 48 were 38.8% for asciminib versus 20.6% for TKIs, and MR4.5 rates were 16.9% versus 8.8%, respectively. The 12-week early molecular response (EMR) rate was 89.6% in the asciminib group versus 70.1% in the TKI group.
Safety and Tolerability
Regarding safety, the most common adverse reactions reported in at least 20% of patients included musculoskeletal pain, rash, fatigue, upper respiratory tract infection, headache, abdominal pain, and diarrhea. Laboratory abnormalities seen in over 40% of patients included decreased lymphocyte count, leukocyte count, platelet count, neutrophil count, and corrected calcium levels.
Grade 3 or higher adverse effects occurred in 38% of patients treated with asciminib, compared to 44.4% for imatinib and 54.9% for second-generation TKIs. Discontinuation due to adverse effects was lower with asciminib at 4.5%, compared to 11.1% for imatinib and 9.8% for second-generation TKIs. Dose adjustments or interruptions due to AEs were also less frequent in the asciminib arm (30.0%) compared to the imatinib (39.4%) and second-generation TKI groups (52.9%).
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 the Georgia Cancer Center. "In the first-of-its-kind ASC4FIRST trial, [asciminib] achieved impressive results across all 3 parameters of efficacy, safety, and tolerability vs all standard-of-care TKIs. This [asciminib] data has the potential to be practice-changing."
The recommended dosage of asciminib is either 80 mg orally once daily or 40 mg orally twice daily, taken approximately every 12 hours. This approval offers a valuable new option for patients with Ph+ CML, potentially leading to better long-term disease control with fewer side effects.
