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

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.