Asciminib (ABL myristoyl-pocket “STAMP” inhibitor) sustains deeper molecular responses vs frontline ATP-competitive TKIs in ASC4FIRST (wk 144)

Asciminib (ASC) is a first-in-class allosteric BCR::ABL1 inhibitor that binds the ABL myristoyl pocket (vs ATP-site TKIs like imatinib/dasatinib/nilotinib/bosutinib). In the multicenter open-label Phase 3 ASC4FIRST trial in newly diagnosed Ph+ CML-CP (n=405), ASC 80 mg QD beat investigator-selected TKIs at week 144: MMR 77.1% vs 53.4% (Δ23.9%; P<.001), with higher MR4 (56% vs 36%) and MR4.5 (42% vs 25%); EFS probability at wk 144 was 85% vs 69%, while 3-year PFS/OS were high in both arms (PFS 98% vs 95%; OS 99% vs 97%). Tolerability favored ASC with fewer discontinuations (6% vs 13% with imatinib and 14% with 2G TKIs) and fewer dose adjustments/interruptions (37% vs 44% and 63%), with grade ≥3 AEs 49% vs 52% (imatinib) vs 63% (2G); exposure-adjusted arterial occlusive event rates were 1.3 vs 0.5 vs 1.1 per 100 pt-treatment years, and no on-treatment or ≤30-day deaths were reported (data cut: Sep 29, 2025; NCT04971226). Versus historical first-line benchmarks where 2G TKIs typically improve early/deeper molecular responses but at the cost of more toxicity than imatinib, ASC’s sustained MR4/MR4.5 separation and lower discontinuation rate suggest it may improve “staying on therapy long enough to get deep” without obviously compromising 3-year survival (which remains excellent with current SOC TKIs).