Background: Multiple tyrosine kinase inhibitors (TKIs) that target the BCR-ABL1 ATP-binding site are available for treating chronic myeloid leukemia (CML). However, additional therapeutic strategies are needed for patients resistant to or intolerant of these TKIs or who fail to achieve treatment goals with them. Asciminib is a novel, potent, and specific TKI that targets the myristoyl pocket of BCR-ABL1 (Wylie et al, Nature 2017). This distinct binding site allows asciminib to maintain activity against BCR-ABL1 mutants that confer resistance to ATP binding-site TKIs and offers the possibility for combination therapy with these TKIs. Thus, it has the potential to address unmet needs in CML and Philadelphia chromosome–positive acute lymphoblastic leukemia.
In an ongoing phase 1 study in patients resistant to or intolerant of ≥2 TKIs (Hughes et al, Blood 2016; abstract 625), asciminib has been well tolerated; 42% of patients with CML receiving single-agent asciminib twice daily achieved a major molecular response (MMR; BCR-ABL1 ≤0.1% on the International Scale [IS]) by 12 months. A recommended asciminib monotherapy dose was identified for patients without T315I mutations (40 mg twice daily); in separate cohorts, dosing in select patient groups and combination dosing with ATP binding-site TKIs are being evaluated. Currently, a phase 2 study of asciminib add-on therapy in patients without a deep molecular response on long-term frontline imatinib is planned to further investigate combination dosing. Additionally, a randomized phase 3 study of asciminib monotherapy vs bosutinib (an ATP binding-site TKI approved for third-line therapy) in the third line or later is enrolling.
Objectives: Here we describe the ongoing, open-label, phase 3 study (NCT03106779).
Methods: Patients 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 patients are ≥18 years old, were previously treated with ≥2 TKIs, with failure of/intolerance to the previous TKI, and have BCR-ABL1 IS ≥1%. Patients with T315I or V299L mutations are excluded. The MMR rate at 24 weeks will be compared between arms (primary objective).
Results: Not applicable.
Conclusions: Asciminib has the potential to address unmet needs in CML and Philadelphia chromosome–positive acute lymphoblastic leukemia. A planned phase 2 study will examine asciminib added to frontline imatinib, while the ongoing phase 3 trial described here will assess the safety and efficacy of asciminib in third-line or later treatment.
Pharmaceutical sponsorship: This trial is sponsored by Novartis Pharmaceuticals Corporation.
Abstract encore information: This abstract was presented at the American Society of Clinical Oncology Annual Meeting, June 1-5, 2018, Chicago, IL; at the European School of Haematology 20th Annual John Goldman Conference on Chronic Myeloid Leukemia: Biology and Therapy, September 13-16, 2018, Miami, FL; and at the Society of Hematologic Oncology Sixth Annual Meeting, September 12-15, 2018, Houston, TX.
