Primary endpoint results of the phase 3b ASC4START trial of asciminib (ASC) vs nilotinib (NIL) in newly diagnosed chronic phase chronic myeloid leukemia (CML-CP): Time to treatment discontinuation due to adverse events (TTDAE).

6501 Background: ASC, the first BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket, recently received FDA Accelerated Approval for newly diagnosed CML-CP based on major molecular response (MMR) rates in the ASC4FIRST trial (NCT04971226). We present results from ASC4START (NCT05456191), with the primary objective of assessing the tolerability of ASC vs second-generation tyrosine kinase inhibitor NIL in patients (pts) with newly diagnosed CML-CP. Methods: Adults were randomized 1:1 to receive ASC 80 mg once daily or NIL 300 mg twice daily, stratified by ELTS risk category. The primary endpoint is TTDAE. Events included AEs leading to treatment (tx) discontinuation and deaths due to AEs. Secondary endpoints include molecular response and safety. Results: Pts were recruited by 120 participating sites across 24 countries and randomized to ASC (n=284) or NIL (n=284). Two pts who did not receive NIL were excluded from safety analyses. Median follow-up was 9.7 mo. At cutoff (Sep 3, 2024), 10.9% and 17.3% of pts discontinued ASC and NIL, respectively, most commonly due AEs (4.9% vs 11.6%) and unsatisfactory therapeutic effect (2.5% vs 2.8%). The study met its primary endpoint, showing statistically significant difference in TTDAE in favor of ASC with a cause-specific hazard ratio of 0.45 (95% CI, 0.25-0.81; P =.004). Fewer pts discontinued due to AEs with ASC (16/284 [5.6%]) vs NIL (34/282 [12.1%]). There were 3 deaths on study due to AEs (ASC: cardiac arrest and suicide, n=1 each; NIL: cardiac arrest, n=1). Median duration of exposure was 39.1 wk with ASC vs 38.0 wk with NIL. Mean relative dose intensity was 94.8% vs 92.6%, respectively. Any-grade AEs occurred in 80.3% of pts with ASC vs 86.5% with NIL. Grade ≥3 AEs occurred in 25.0% and 31.9% of pts, respectively. AEs leading to dose adjustment/interruption occurred in 24.3% of pts with ASC vs 30.1% with NIL. Most frequent any-grade AEs (≥10%) with ASC vs NIL were thrombocytopenia (15.1% vs 13.8%), headache (10.2% vs 13.1%), myalgia (10.2% vs 8.2%), rash (8.5% vs 16.3%) and increased alanine aminotransferase (3.2% vs 12.4%). AEs of special interest included arterial occlusive events (0.7% vs 2.1%), acute pancreatitis (clinical events; 0.4% vs 2.5%), and hepatotoxicity (including laboratory terms; 8.1% vs 24.8%). BCR::ABL1 IS ≤10% (89.8% vs 82.0%), BCR::ABL1 IS ≤1% (69.0% vs 52.5%), MMR (22.9% vs 10.2%), MR 4 (4.6% vs 1.1%), and MR 4.5 (2.5% vs 0.4%) rates by wk 12 were higher with ASC vs NIL. Conclusions: The study met the primary endpoint with ASC showing significantly superior tolerability vs NIL based on TTDAE. The study is ongoing with additional analyses planned for tolerability and efficacy. The findings further support the potential for ASC to be a preferred therapy for newly diagnosed CML-CP, allowing more pts to meet tx goals without requiring tx switch. Clinical trial information: NCT05456191 .