• ASC4FIRST, a pivotal phase 3 study of asciminib (ASC) vs investigator-selected tyrosine kinase inhibitors (IS TKIs) in newly diagnosed patients (pts) with chronic myeloid leukemia (CML): Primary results.

Background: We present primary results from ASC4FIRST (NCT04971226), the first study in CML comparing all current standard-of-care frontline TKIs with a novel agent, ASC, in newly diagnosed pts. ASC Specifically Targets the ABL Myristoyl Pocket (STAMP). Methods: Adults with CML were randomly assigned 1:1 to receive ASC 80 mg once daily or an IS TKI at standard label doses, stratified by ELTS risk category and prerandomization selected (PRS) TKI (imatinib [IMA] or second-generation [2G] TKIs), which was selected by investigators before randomization, accounting for pt preference. Pts diagnosed within 3 mo before enrollment with no prior treatment (Tx) except IMA/2G TKIs for ≤2 wk prior to randomization were eligible. Primary objectives were to demonstrate superior major molecular response (MMR) rate at wk 48 with ASC vs IS TKI and ASC vs IS TKI within the stratum of pts with IMA as PRS TKI (ASCIMA vs IS TKIIMA). The study is positive if either objective is met. Comparing MMR rate of ASC vs IS TKI at wk 48 within the stratum of pts with 2G TKIs as PRS TKI (ASC2G vs IS TKI2G) was an unpowered secondary objective. Results: Pts received ASC (n=201: ASCIMA, n=101; ASC2G, n=100) or IS TKI (n=204: IS TKIIMA, n=102; IS TKI2G, n=102 [nilotinib, 48%; dasatinib, 41%; bosutinib, 11%]). Median follow-up was 16.3 and 15.7 mo for ASC and IS TKI, respectively (cutoff: Nov 28, 2023). At cutoff, Tx was ongoing in 86%, 62%, and 75% of pts on ASC, IMA, and 2G TKIs, respectively, with pts most commonly discontinuing due to unsatisfactory therapeutic effect (6%, 21%, 10%) (Tx failure per ELN2020 [5%, 16%, 8%], MMR loss [0.5%, 0%, 0%], physician decision [0.5%, 5%, 2%]) and adverse events (AEs) (5%, 11%, 10%). MMR rate at wk 48 (per ITT) was superior with ASC (67.7%) vs IS TKI (49.0%) and with ASCIMA (69.3%) vs IS TKIIMA (40.2%), meeting both primary objectives with high statistical significance; rate difference was 18.9% [95% CI, 9.6%-28.2%] and 29.6% [95% CI, 16.9%-42.2%], respectively, both with adjusted 1-sided P<.001. MMR rate at wk 48 was higher with ASC2G vs IS TKI2G (66.0% vs 57.8%). BCR::ABL1IS ≤1% rate at wk 48 was 87% with ASC vs 73% with IS TKI and 84% with ASCIMA vs 62% with IS TKIIMA. At wk 48, MR4 and MR4.5 rates were higher with ASC vs IS TKI (39% vs 21%; 17% vs 9%), ASCIMA vs IS TKIIMA (43% vs 15%; 18% vs 5%), and ASC2G vs IS TKI2G (35% vs 26%; 16% vs 13%). ASC had markedly favorable safety and tolerability vs IMA and 2G TKIs, with less grade ≥3 AEs (38%, 44%, 55%), half the rate of AEs leading to Tx discontinuation (5%, 11%, 10%), and less dose adjustments/interruptions to manage AEs (30%, 39%, 53%). Rate of arterial occlusive events was 1%, 0%, and 2%, respectively. Conclusions: ASC is the only agent to show a statistically significant superior efficacy and excellent safety and tolerability vs all current standard-of-care frontline Tx, with potential to be the therapy of choice for CML. Clinical trial information: NCT04971226.