First Results of Asciminib As Initial Therapy with Addition of Lower Dose Tyrosine Kinase Inhibitors for Patients with Chronic Myeloid Leukemia Who Do Not Achieve a Deep Molecular Remission (ALERT CML) from the H Jean Khoury Cure CML Consortium (HJKC3)

Background: Although tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of patients (pts) with CML, further improvements are needed in efficacy, reduction in AEs, and functional cure. Less than 50% of pts achieve a sustained MR4.5 (sine qua non for treatment discontinuation) by 10 years and approximately 40% need change of therapy within 5 years because of lack of efficacy or unacceptable toxicity. Asciminib is a potent allosteric inhibitor of BCR::ABL1, effective in vitro against BCR::ABL1 mutations that confer resistance to ATP-competitive tyrosine kinase inhibitors (TKIs). Asciminib may be combined with ATP-competitive TKIs to prevent emergence of resistant clones, potentially increasing the depth of molecular response in pts without deep molecular response (DMR) with single-agent treatment. In a phase I study of asciminib, 65% of pts with chronic phase (CML-CP) resistant to or intolerant of ≥2 prior TKIs achieved a major molecular response. Asciminib is approved for CML-CP patients with more than 2 prior TKIs and recently had positive Ph3 study in newly diagnosed CML when compared to standard of care TKIs. We hypothesized that asciminib in pts with newly diagnosed CML-CP might lead to more DMR and less toxicity and that addition of low dose TKI in patients without DMR with asciminib may result in increased rates of DMR.

Aims: The primary study endpoint is the rate of MR4.5 at 12 months among pts with newly diagnosed CML-CP.

Methods: This is an ongoing multicenter phase 2, single-arm, open-label, study of asciminib in patients with newly diagnosed CML-CP (NCT05143840) within the HJKC3 (Protocol Number HJKC3-0004). Patients received asciminib 40 mg orally twice daily (later amended to 80 mg once daily). Peripheral blood BCR::ABL1 by RQ-PCR was monitored in a central lab. Patients not achieving MR4.5 after 24 months of single agent asciminib will be offered the addition of low dose TKI (LowTKI; imatinib 300 mg, dasatinib 50 mg or nilotinib 300 mg daily) with the goal to attain MR4.5. Patient reported outcomes were collected at multiple timepoints.

Results: As of 7/1/24, 43 pts have enrolled on the study. The median age is 51 yrs (range 25-79); 32.6% are female. Sokal score was low/intermediate/high/unknown in 10/11/1/9 pts respectively. With a median follow up of 13.6 weeks (0-93.6), 38 (88.4%) pts remain on study. Of the 31 pts evaluable at 3 months, 74.2%, 35.5%, 6.5% and 3.2% achieved MR2, MR3, MR4 and MR4.5, respectively. Of the 20 pts evaluable at 6 months, 85.0%, 60.0%, 25.0%, and 15.0% achieved MR2, MR3, MR4 and MR4.5, respectively. Of the 11 pts evaluable at 12 months, 90.9%, 81.8%, 63.6%, and 36.4% achieved MR2, MR3, MR4 and MR4.5, respectively. Grade 1/2 anemia, neutropenia and thrombocytopenia occurred in 9%, 12% and 12% of pts, respectively. No grade 3/4 hematological toxicity has been observed. The most common grade 1/2 non-hematological toxicities were fatigue (19%), nausea (14%), arthralgia (14%), AST increase (12%), and lipase increase (7%). Grade 3/4 toxicities reported were CPK increase (5%), lipase increase (5%), abdominal pain (2%), ALT increase (2%), arthralgia (2%), headache (2%), and rhabdomyolysis (2%). Four pts have discontinued treatment for treatment failure (1), grade 3 CPK increase (1), grade 3 arthralgia (1) and grade 2 dizziness (1). No patient has met criteria for addition of LowTKI.

Summary and Conclusion: In the frontline setting, asciminib monotherapy led to rapid early and deep responses in pts with CML-CP with a favorable safety profile. Updated data will be presented at the meeting.

Cortes:Biopath Holdings: Consultancy, Research Funding; Rigel: Consultancy; Nerviano: Consultancy; Takeda: Consultancy; Abbvie: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding. Mauro:Pfizer: Consultancy, Honoraria; Sun Pharma/SPARC: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Tantravahi:Incyte: Consultancy, Honoraria; Partnership for Health Analytic Research LLC: Consultancy, Honoraria; CTI Biopharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria, Research Funding. Yang:Puretech: Research Funding; Pfizer: Research Funding; Novartis: Consultancy, Research Funding. Gao:Pfizer: Current equity holder in publicly-traded company; Roche: Current equity holder in publicly-traded company; Novartis: Research Funding; Takeda: Research Funding. Flynn:Inhibikase: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. Radich:ThermoFisher: Honoraria. Atallah:Novartis Pharmaceuticals Corporation: Honoraria.

Asciminib as frontline therapy. This is not an approved indication for asciminib at the time of this submission.