ASC4FIRST: Updated 96-Week Data Shows Benefits of Asciminib
- Extended 96-week data from the ASC4FIRST trial confirm that asciminib achieves superior molecular control versus standard TKIs in newly diagnosed CML.
- At 96 weeks, MMR rates were 74% with asciminib vs 52% with standard TKIs, with three-quarters of patients responding by two years.
- Nearly 49% achieved MR4 on asciminib versus 27.5% on other TKIs.
- Patient-reported outcomes also showed higher global health scores, confirming benefit beyond molecular response.
- “What we presented at ASH for the 96-week data were patient-reported outcomes,” Dr. Jorge Cortes, Director of the Georgia Cancer Center at Augusta University and study author, explains. “… this analysis showed that asciminib leads to a better quality of life — not only a better response rate.”
Standard frontline TKIs have transformed outcomes in chronic myeloid leukemia (CML), yet many patients fail to achieve optimal molecular responses or discontinue therapy due to intolerance. The ASC4FIRST trial addresses a key unmet need by evaluating whether asciminib can improve molecular outcomes from diagnosis while maintaining a favorable safety and tolerability profile. The trial showed extremely positive results.
Asciminib is a first-in-class allosteric BCR::ABL1 inhibitor that targets the myristoyl pocket of ABL1, restoring physiologic autoinhibition. Unlike ATP-competitive TKIs, this mechanism allows effective kinase suppression with potentially improved selectivity and tolerability, offering a distinct option for newly diagnosed patients.
Dr. Jorge Cortes, Director of the Georgia Cancer Center at Augusta University and a long-time leukemia clinician, led the study and presented the promising findings at ASH 2025.
“What we presented at ASH for the 96-week data were patient-reported outcomes,” Dr. Cortes explains. “And what this analysis showed is that asciminib leads to a better quality of life — not only a better response rate, but a better quality of life overall.”
Speaking to SurvivorNet Connect, Dr. Cortes emphasized the importance of evaluating not only early responses, but how efficacy and safety evolve over time in newly diagnosed patients.
ASC4FIRST: Evaluating The Data
ASC4FIRST (NCT04971226) is a phase III, randomized, open-label, multicenter study comparing asciminib 80 mg once daily with investigator-selected frontline TKIs (imatinib, nilotinib, dasatinib, bosutinib) in 405 adults with newly diagnosed Ph+ CML in chronic phase (CML-CP). Primary endpoints were major molecular response (MMR; BCR::ABL1 ≤0.1% IS) at 48 weeks versus all TKIs and versus imatinib alone. Key secondary endpoints included MMR at 96 weeks and deeper molecular responses (MR4, MR4.5).
“This was a randomized study of asciminib versus any of the available tyrosine kinase inhibitors for first-line therapy,” Dr. Cortes explains. “Importantly, these were patients who were newly diagnosed and had never received any prior treatment.”
- At 48 weeks, asciminib met both primary endpoints, achieving MMR in 67.7% of patients versus 49.0% receiving investigator-selected TKIs.
- Compared with imatinib, MMR rates were 69.3% versus 40.2%, marking the first phase III evidence of superior efficacy for an allosteric BCR::ABL1 inhibitor in the frontline setting and increasing the likelihood of achieving early molecular milestones associated with treatment-free remission (TFR).
Extended follow-up at 96 weeks confirmed sustained benefit, with MMR rates of 74.1% for asciminib versus 52.0% for all TKIs.
“The importance of this follow-up is that it allows us to see how the responses continue and how the safety continues — and what it shows is that the benefit in favor of asciminib not only remains, but has increased,” Dr. Cortes says.
Subgroup analyses demonstrated 76.2% versus 47.1% for asciminib versus imatinib and 72.0% versus 56.9% versus second-generation TKIs, confirming durable molecular control and a persistent efficacy advantage. “By 96 weeks, three quarters of patients have reached that response with asciminib,” Dr. Cortes says. “The difference is large, and it’s happening relatively early.”
While the 48-week analysis showed a non-significant trend toward superiority over second-generation TKIs, the 96-week results demonstrated a statistically significant improvement, highlighting the durability of asciminib’s efficacy and reinforcing its potential role as a frontline therapy in newly diagnosed CML-CP.
Depth of Response & TFR Potential
Deeper molecular responses also favored asciminib, with 48.8% of patients achieving MR4 compared with 27.5% receiving other TKIs. “Across all measures, we’ve seen better response rates,” Dr. Cortes says.
He adds that longer follow-up remains critical: “Ultimately, what we want to see is whether we can get more patients to meet criteria to stop therapy, which requires MR4.5 sustained for two years. The way this is going, it is likely we will see that.”
Safety & Tolerability
Across follow-up, asciminib demonstrated a favorable safety profile compared with standard TKIs. Patients experienced fewer grade ≥3 adverse events, dose modifications, and treatment discontinuations due to toxicity.
Hematologic adverse events, including thrombocytopenia and neutropenia, were generally manageable. This improved tolerability supports adherence and may contribute to achieving deeper molecular responses over time.
Extended patient-reported outcome (PRO) data presented at ASH 2025 further strengthened asciminib’s profile.
Patients treated with the drug reported higher global health scores, improved physical and emotional functioning, and reduced symptom burden, including pain and gastrointestinal effects.
Clinical Implications & Future Directions
The ASC4FIRST trial and ASH 2025 updates show that asciminib improves early and sustained molecular responses while offering a favorable safety and tolerability profile that reduces treatment interruptions. Regulatory momentum reflects these findings, with FDA accelerated approval for newly diagnosed adult Ph+ CML-CP and NCCN category 1 preferred status supporting its adoption in frontline care.
While longer-term outcomes such as overall survival and treatment-free remission remain to be defined, the growing body of evidence suggests asciminib may meaningfully reshape first-line CML treatment by aligning deeper molecular control with improved patient experience.
