ASC4FIRST wk 144 analysis: Efficacy and safety and tolerability with asciminib (ASC) vs investigator-selected tyrosine kinase inhibitors (IS TKIs) in newly diagnosed (ND) chronic myeloid leukemia in chronic phase (CML-CP).

Abstract

6583 Background: In ASC4FIRST (NCT04971226) primary (wk 48) (Hochhaus A et al. N Engl J Med . 2024) and key secondary (wk 96) (Cortes JE et al. Blood . 2025) analyses, ASC had superior efficacy and improved safety/tolerability vs IS TKIs. ASC was approved for ND CML-CP in numerous countries. We report the ASC4FIRST wk 144 analysis (cutoff: Sep 29, 2025). Methods: In this multicenter, open-label, phase 3 study, patient (pts) with ND CML-CP were randomized 1:1 to ASC 80 mg once daily or an IS TKI at label doses, stratified by ELTS risk category and prerandomization-selected TKI (imatinib [IMA] or a second generation [2G] TKI). Primary endpoints were major molecular response (MMR) rates at wk 48 with ASC vs all IS TKIs, and ASC IMA vs IS TKI IMA . Results: Pts were randomized to ASC (n=201) or IS TKIs (n=204). Median follow-up was 38.1 mo with ASC vs 37.4 mo with all IS TKIs, 36.2 mo with ASC IMA vs 35.3 mo with IS TKI IMA , and 39.2 mo with ASC 2G vs 38.5 mo with IS TKI 2G . At cutoff, more pts were ongoing tx with ASC vs all IS TKIs (78.6% vs 55.9%), ASC IMA vs IS TKI IMA (81.2% vs 50.0%), and ASC 2G vs IS TKI 2G (76.0% vs 61.8%). MMR rate at wk 144 continued to be superior with ASC vs all IS TKIs (77.1% vs 53.4%; tx difference, 23.9%; P< .001 ) and ASC IMA vs IS TKI IMA (79.2% vs 47.1%; tx difference, 32.6%; P< .001 ), and higher with ASC 2G vs IS TKI 2G (75.0% vs 59.8%; tx difference, 15.2%; P= .01 ). MR 4 and MR 4.5 rates at wk 144 were higher with ASC vs all IS TKIs (56% vs 36%; 42% vs 25%), ASC IMA vs IS TKI IMA (58% vs 33%; 44% vs 20%), and ASC 2G vs IS TKI 2G (53% vs 39%; 41% vs 29%). Long-term outcomes with ASC vs all IS TKIs, ASC IMA vs IS TKI IMA , and ASC 2G vs IS TKI 2G included probability of event-free survival at wk 144 post randomization (85% vs 69%; 83% vs 63%; 87% vs 75%), and estimated progression-free survival (98% vs 95%; 97% vs 93%; 99% vs 97%) and overall survival (99% vs 97%; 99% vs 96%; 99% vs 99%), at 3 yrs post randomization. No new postbaseline mutations emerged with ASC after wk 96; 1 each emerged with IMA and nilotinib. Safety/tolerability remained favorable with ASC vs IMA vs 2G TKIs including grade ≥3 AEs (49% vs 52% vs 63%), AEs leading to discontinuation (6% vs 13% vs 14%), and AEs leading to dose adjustment/interruption (37% vs 44% vs 63%); exposure-adjusted arterial occlusive event rates were 1.3, 0.5, and 1.1 cases per 100 pt-tx yr, respectively. Median exposure duration was 37.4 mo, 33.8 mo, and 37.3 mo, respectively. No deaths occurred during tx or ≤30 d after last dose. Conclusions: At wk 144, ASC had consistently higher molecular response rates and favorable safety/tolerability vs all IS TKIs with no new tx-emergent mutations. Together with wk 48 and 96, this analysis reinforces ASC’s improved benefit-risk profile and supports ASC as a tx option for ND CML. Clinical trial information: NCT04971226 .