Background: Several tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 ATP-binding site are available to treat CML. However, new options are needed for patients (pts) with resistance/intolerance to these TKIs or who do not achieve treatment goals with them. Asciminib is a novel, potent and specific BCR-ABL1 inhibitor that targets the myristoyl pocket (Wylie, Nature 2017). Due to its distinct binding site, asciminib maintains activity against BCR-ABL1 mutants that confer resistance to ATP-binding site TKIs and offers the possibility for combination therapy with these TKIs. It therefore has the potential to address unmet needs in CML, including use in pts for whom ATP-binding site TKIs have failed or for combination with these TKIs in earlier lines, and in Philadelphia chromosome–positive acute lymphoblastic leukemia. In an ongoing phase 1 study in pts with resistance/intolerance to ≥ 2 TKIs (Hughes, Blood 2016 [abst 625]), asciminib has been well tolerated; 42% of pts achieved a major molecular response (MMR) by 12 mo with single-agent twice-daily asciminib. A recommended dose for asciminib monotherapy was identified for pts without T315I mutations (40 mg twice daily); in separate cohorts, dosing in select pt groups and combination dosing with ATP-binding site TKIs continues to be evaluated. Now, a phase 2 study of asciminib add-on therapy in pts without a deep molecular response on long-term frontline imatinib is planned, and a randomized phase 3 study of asciminib monotherapy vs bosutinib (an ATP-binding site TKI approved for third-line therapy) in the third or later line is enrolling. Here we describe this ongoing, open-label, phase 3 study (NCT03106779). Methods: Pts with CML in chronic phase (planned enrollment, N = 222) are randomized 2:1 to receive asciminib 40 mg twice daily or bosutinib 500 mg once daily. Eligible pts are ≥ 18 y old, previously treated with ≥ 2 TKIs, with failure/intolerance to the previous TKI, and have BCR-ABL1^IS≥ 1%. Pts with T315I or V299L mutations are excluded. MMR rate at 24 wk will be compared between arms (primary objective). The 96-wk MMR rate, progression-free and overall survival, safety, tolerability, and asciminib pharmacokinetics will also be evaluated. Clinical trial information: NCT03106779