What type of study is this?

This is a Pre-Registered Trial study.

What question did this study set out to answer?

To evaluate the long-term tolerability and safety of asciminib compared to investigator-selected tyrosine kinase inhibitors in patients with chronic myeloid leukemia in chronic phase.

December 8, 2025

Improved long-term tolerability with asciminib (ASC) vs investigator-selected (IS) tyrosine kinase inhibitors (TKIs) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): Week 96 exploratory analysis of the phase 3 ASC4FIRST trial

Puntos clave

To evaluate the long-term tolerability and safety of asciminib compared to investigator-selected tyrosine kinase inhibitors in patients with chronic myeloid leukemia in chronic phase.
Randomized adults with newly diagnosed chronic myeloid leukemia to receive asciminib or investigator-selected TKI.
Conducted exploratory post hoc analyses including adverse event burden and AE-free days.
Percentage of adverse event-free days calculated from treatment duration.
Patients on asciminib reported fewer adverse events and a higher percentage of AE-free days.
More patients continued treatment with asciminib compared to tyrosine kinase inhibitors at week 96.
Lower rates of dose reductions and discontinuations were observed in the asciminib group.

Resumen

Abstract Introduction Long-term CML treatment (Tx) requires assessing adverse event (AE) burden over time to optimize safety, tolerability, and efficacy. ASC4FIRST (NCT04971226) results demonstrated superior efficacy and favorable safety/tolerability of ASC vs IS-TKIs in newly diagnosed CML-CP. A prior report showed a lower risk of discontinuation due to AEs with ASC vs second-generation (2G) TKIs in a time to Tx discontinuation due to AEs (TTDAE) analysis (hazard ratio, 0.46; 95% CI, 0.215-0.997), suggesting better tolerability with ASC. We report exploratory post hoc analyses, including an innovative analysis of AE-free days, further evaluating the tolerability of ASC vs IS-TKI (imatinib IMA/2G TKIs) by the wk 96 analysis cutoff (Oct 22, 2024). Methods Adults with newly diagnosed CML-CP were randomized 1:1 to receive ASC or IS-TKI (at label dose), stratified by ELTS risk category and prerandomization IS-TKI (IMA/2G TKIs). Dose modifications occurred per protocol for ASC and at investigator's discretion for IS-TKIs. All reported AEs occurred on Tx or ≤30 days after last dose. Exploratory tolerability analyses included frequency/grade/type of AEs; relative dose intensity; rate of dose adjustment, interruption, or discontinuation; percentage of AE-free days (number of days pt was on Tx without any-grade AEs divided by Tx duration in days, censored at the wk 96 visit; a value of 100% indicates no AEs were experienced on Tx); and pt-reported outcome (PRO) measures (PRO-CTCAE and FACIT GP5). Results Safety analyses included all pts who received Tx in IMA (ASCIMA n=100; IS-TKIIMA n=99) and 2G TKI (ASC2G n=100; IS-TKI2G n=102) strata. Median follow-up was similar across groups (ASCIMA 25.1 mo; IS-TKIIMA 24.3 mo; ASC2G 28.2 mo; IS-TKI2G 27.7 mo). More pts were continuing Tx at cutoff with ASCIMA (83.0%) vs IS-TKIIMA (52.5%) and ASC2G (81.0%) vs IS-TKI2G (69.6%). More pts had relative dose intensity of 90% with ASCIMA (86.0%) vs IS-TKIIMA (79.8%) and ASC2G (88.0%) vs IS-TKI2G (68.6%). The proportion of pts with dose reductions was lower with ASCIMA (n=19, 19.0%) vs IS-TKIIMA (n=23, 23.2%) and ASC2G (n=18, 18.0%) vs IS-TKI2G (n=56, 54.9%). A similar number of pts with ASCIMA (47.0%) vs IS-TKIIMA (47.5%) and fewer pts with ASC2G (46.0%) vs IS-TKI2G (63.7%) had dose interruptions for any reason (included AEs, dosing/dispensing error, physician/pt decision, and technical problems); interruptions due to AEs were fewer with ASC vs IS-TKIs (ASCIMA 33.0% vs IS-TKIIMA 37.4%; ASC2G 33.0% vs IS-TKI2G 51.0%). Less pts with ASC vs IS-TKIs had dose adjustment and/or interruption (ASCIMA 13.0% vs IS-TKIIMA 18.2%; ASC2G 14.0% vs IS-TKI2G 31.4%) and discontinuation (ASCIMA 3.0% vs IS-TKIIMA 6.1%; ASC2G 1.0% vs IS-TKI2G 7.8%) due to grade 1/2 nonhematologic AEs, most common (≥3%) being diarrhea, fatigue, COVID-19, nausea, and pleural effusion. A lower proportion of pts with ASC vs IS-TKIs discontinued due to grade ≥3 nonhematologic AEs (ASCIMA 2.0% vs IS-TKIIMA 4.0%; ASC2G 2.0% vs IS-TKI2G 3.9%). Dose adjustment and/or interruption due to grade ≥3 nonhematologic AEs occurred in 17.0% vs 8.1% of pts with ASCIMA vs IS-TKIIMA and 11.0% vs 17.6% with ASC2G vs IS-TKI2G. Pts with ASC vs IS-TKIs had a higher median percentage of AE-free days by wk 96 (ASCIMA 15.7% vs IS-TKIIMA 3.5%; ASC2G 22.6% vs IS-TKI2G 4.3%) and vs individual 2G TKIs (nilotinib 13.5%; dasatinib 4.2%; bosutinib 0.1%) in this arm. Pts with ASC had a higher proportion of symptomatic (nonhematologic, nonlaboratory AEs) AE–free days (ASCIMA 31.2% vs IS-TKIIMA 9.9%; ASC2G 34.2% vs IS-TKI2G 15.7%; and vs individual 2G TKIs: nilotinib 30.3%; dasatinib 8.5%; bosutinib 0.1%). When analyzing maximum scores in PRO-CTCAE reported from baseline to wk 96, symptoms reported with ASC vs IS-TKIs were generally less frequent and less severe, with a smaller impact on daily life. At wk 96, more pts reported being not at all bothered by Tx side effects with ASC vs IS-TKIs per FACIT GP5 (67.0% vs 46.1%). Conclusions Pts with ASC had more days free from AEs, especially symptomatic AEs, and reported a lower symptom burden. Effective relative dose intensity (90%) was higher with ASC vs IS-TKIs, with generally fewer pts requiring dose reduction, interruption, or discontinuation. These results from ASC4FIRST further support ASC'sfavorable tolerability vs all current frontline TKIs.

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