ASC4FIRST
A Phase III, Multi-center, Open-label, Randomized Study of Oral Asciminib Versus Investigator Selected TKI in Patients With Newly Diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase
Phase 3N = 405NCT04971226
- Population
- Adults (aged 18 years or older) with Philadelphia chromosome-positive CML in chronic phase diagnosed within 3 months before enrolment
- Design
- Open-label randomised phase 3 trial, 1:1. Randomisation was stratified by European Treatment and Outcome Study long-term survival (ELTS) score category and by the TKI the investigator selected before randomisation (imatinib or a second-generation TKI: nilotinib, dasatinib or bosutinib). Primary end points: major molecular response (BCR::ABL1 transcripts 0.1% or less on the International Scale) at week 48, for asciminib versus all investigator-selected TKIs and for asciminib versus investigator-selected TKIs in the imatinib stratum. Direct comparison with second-generation TKIs was not a primary objective; the week-96 paper calls it a secondary end point for which the study was not designed to formally confirm statistical significance.
- Primary endpoint
- MMR
- Arms
- Investigator-selected TKI (control, n = 204): Investigator-selected TKI at approved frontline doses (imatinib 400 mg daily, nilotinib 300 mg twice daily, dasatinib 100 mg daily or bosutinib 400 mg daily), chosen before randomisation
- Asciminib (experimental, n = 201): Asciminib 80 mg once daily
- People
- Hochhaus A, ASC4FIRST Investigators
Δ MMR+18.7 pointsΔ MMR+29.1 pointsΔ MMR+8.2 pointsΔ MMR+22.1 pointsΔ MMR+29.1 pointsΔ MMR+15.1 points
Show the numbers
| Endpoint | Analysis | Asciminib | Investigator-selected TKI | Effect |
|---|---|---|---|---|
| MMRAll randomised patients (201 asciminib, 204 investigator-selected TKIs)BCR::ABL1 transcript level 0.1% or less on the International Scale, at week 48 | primaryHochhaus 2024 | 67.7% | 49% | P<0.001Difference 18.9 percentage points (95% CI 9.6 to 28.2); adjusted two-sided P<0.001. Median follow-up 16.3 months with asciminib and 15.7 months with investigator-selected TKIs. |
| MMRImatinib stratum (101 asciminib, 102 imatinib); comparator arm: imatinibBCR::ABL1 transcript level 0.1% or less on the International Scale, at week 48 | primaryHochhaus 2024 | 69.3% | 40.2% | P<0.001In this stratum the comparator arm received imatinib. Difference 29.6 percentage points (95% CI 16.9 to 42.2); adjusted two-sided P<0.001. Second primary objective. |
| MMRSecond-generation TKI stratum (100 asciminib, 102 second-generation TKI: nilotinib 49, dasatinib 42, bosutinib 11); comparator arm: second-generation TKIsBCR::ABL1 transcript level 0.1% or less on the International Scale, at week 48 | exploratoryHochhaus 2024 | 66% | 57.8% | Difference 8.2 percentage points (95% CI -5.1 to 21.5); no P value given in the abstract. The abstract states that direct comparison between asciminib and second-generation TKIs was not a primary objective; the week-96 paper calls it a secondary end point and states the study was not designed to formally confirm statistical significance for it. 'Exploratory' is used here in the sense of non-confirmatory, because the analysis vocabulary has no 'secondary' value. |
| MMRFull analysis set: all randomised patients (201 asciminib, 204 investigator-selected TKIs)Major molecular response rate at week 96 (secondary analysis) | long term-updatemedian follow-up 2.2 yearsCortes 2026 | 74.1% | 52% | P<.001Treatment difference 22.4% (95% CI 13.6 to 31.3); 1-sided P<.001. A key secondary objective. |
| MMRImatinib stratum (101 asciminib, 102 imatinib); comparator arm: imatinibMajor molecular response rate at week 96 (secondary analysis) | long term-updatemedian follow-up 2.2 yearsCortes 2026 | 76.2% | 47.1% | P<.001Treatment difference 29.7% (95% CI 17.6 to 41.8); 1-sided P<.001. A key secondary objective. |
| MMRSecond-generation TKI stratum (100 asciminib, 102 second-generation TKI); comparator arm: second-generation TKIsMajor molecular response rate at week 96 (secondary analysis) | exploratorymedian follow-up 2.2 yearsCortes 2026 | 72% | 56.9% | P<.05Treatment difference 15.1% (95% CI 2.3 to 28.0); 1-sided P<.05. The paper states the study was not designed to formally confirm statistical significance for this secondary end point. |
| Time to discontinuation due to adverse eventsTreated patients: all asciminib-treated patients (n = 200) versus patients treated with second-generation TKIs (n = 102), per the full-text statistical methodsTime to discontinuation of treatment because of adverse events, asciminib versus second-generation TKIs (week 96 analysis) | long term-updateCortes 2026 | — | — | HR 0.460 (95% CI 0.215–0.997)Hazard ratio below 1 favours asciminib; the upper confidence limit is close to 1. Reported in the abstract without a P value. The full text calls this comparison a secondary safety objective; the hazard ratios for asciminib versus all investigator-selected TKIs (0.42, 95% CI 0.216-0.814) and versus imatinib (0.38, 95% CI 0.178-0.818) were supplementary analyses and are not recorded here. |
| Endpoint | Analysis | Asciminib | Investigator-selected TKI | Effect |
|---|---|---|---|---|
| MMRAll randomised patients (201 asciminib, 204 investigator-selected TKIs)BCR::ABL1 transcript level 0.1% or less on the International Scale, at week 48 | primaryHochhaus 2024 | 67.7% | 49% | P<0.001Difference 18.9 percentage points (95% CI 9.6 to 28.2); adjusted two-sided P<0.001. Median follow-up 16.3 months with asciminib and 15.7 months with investigator-selected TKIs. |
| MMRImatinib stratum (101 asciminib, 102 imatinib); comparator arm: imatinibBCR::ABL1 transcript level 0.1% or less on the International Scale, at week 48 | primaryHochhaus 2024 | 69.3% | 40.2% | P<0.001In this stratum the comparator arm received imatinib. Difference 29.6 percentage points (95% CI 16.9 to 42.2); adjusted two-sided P<0.001. Second primary objective. |
| MMRSecond-generation TKI stratum (100 asciminib, 102 second-generation TKI: nilotinib 49, dasatinib 42, bosutinib 11); comparator arm: second-generation TKIsBCR::ABL1 transcript level 0.1% or less on the International Scale, at week 48 | exploratoryHochhaus 2024 | 66% | 57.8% | Difference 8.2 percentage points (95% CI -5.1 to 21.5); no P value given in the abstract. The abstract states that direct comparison between asciminib and second-generation TKIs was not a primary objective; the week-96 paper calls it a secondary end point and states the study was not designed to formally confirm statistical significance for it. 'Exploratory' is used here in the sense of non-confirmatory, because the analysis vocabulary has no 'secondary' value. |
| MMRFull analysis set: all randomised patients (201 asciminib, 204 investigator-selected TKIs)Major molecular response rate at week 96 (secondary analysis) | long term-updatemedian follow-up 2.2 yearsCortes 2026 | 74.1% | 52% | P<.001Treatment difference 22.4% (95% CI 13.6 to 31.3); 1-sided P<.001. A key secondary objective. |
| MMRImatinib stratum (101 asciminib, 102 imatinib); comparator arm: imatinibMajor molecular response rate at week 96 (secondary analysis) | long term-updatemedian follow-up 2.2 yearsCortes 2026 | 76.2% | 47.1% | P<.001Treatment difference 29.7% (95% CI 17.6 to 41.8); 1-sided P<.001. A key secondary objective. |
| MMRSecond-generation TKI stratum (100 asciminib, 102 second-generation TKI); comparator arm: second-generation TKIsMajor molecular response rate at week 96 (secondary analysis) | exploratorymedian follow-up 2.2 yearsCortes 2026 | 72% | 56.9% | P<.05Treatment difference 15.1% (95% CI 2.3 to 28.0); 1-sided P<.05. The paper states the study was not designed to formally confirm statistical significance for this secondary end point. |
| Time to discontinuation due to adverse eventsTreated patients: all asciminib-treated patients (n = 200) versus patients treated with second-generation TKIs (n = 102), per the full-text statistical methodsTime to discontinuation of treatment because of adverse events, asciminib versus second-generation TKIs (week 96 analysis) | long term-updateCortes 2026 | — | — | HR 0.460 (95% CI 0.215–0.997)Hazard ratio below 1 favours asciminib; the upper confidence limit is close to 1. Reported in the abstract without a P value. The full text calls this comparison a secondary safety objective; the hazard ratios for asciminib versus all investigator-selected TKIs (0.42, 95% CI 0.216-0.814) and versus imatinib (0.38, 95% CI 0.178-0.818) were supplementary analyses and are not recorded here. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| Time to discontinuation due to adverse events | 0.46 | 0.215–0.997 |
Appears in
Sources
Hochhaus A, Wang J, Kim DW, Kim DDH, Mayer J, Goh YT, et al. Asciminib in Newly Diagnosed Chronic Myeloid Leukemia. N Engl J Med. 2024;391(10):885-898.
Cortes JE, Hughes TP, Wang J, Kim DW, Kim DDH, Mayer J, et al. Asciminib demonstrates superior efficacy and safety in newly diagnosed chronic myeloid leukemia in the ASC4FIRST trial. Blood. 2026;147(13):1433-1446.