Abstract 5515: ELVN-001, a highly selective ATP-competitive ABL1 tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia alone or in combination with asciminib

Abstract ELVN-001 is a potent, highly selective ABL1 Tyrosine Kinase Inhibitor (TKI) currently being evaluated in a Phase 1a/b clinical trial in patients with BCR-ABL1-driven chronic myelogenous leukemia (CML). Due to its unique binding mode, ELVN-001 retains activity against many of the TKI-associated ABL1 resistance mutations including T315I as well as most of the emergent resistance mutations associated with the allosteric inhibitors like asciminib. While the active-site TKI ponatinib is active against T315I, its poor kinome selectivity limits its clinical utility. In contrast, ELVN-001 is highly kinome-selective thereby avoiding off-target kinases, including KDR, c-KIT, FLT3, PDGFR and SRC, which underlie many of the adverse events associated with the approved active-site TKIs; notably myelosuppression, edema, pleural effusions, hypertension, and certain cardiovascular events. Accordingly, ELVN-001 has demonstrated early signs of efficacy with good tolerability in heavily pre-treated patients with CML. Asciminib represents an important alternative for patients who have become intolerant of active site TKIs or whose disease is relapsed or refractory to treatment. As asciminib inhibits ABL1 by engaging its myristoyl pocket, it is highly kinome-selective and thus demonstrates an improved clinical safety profile. Because asciminib binds outside the kinase domain, it is not sensitive to most mutations conferring resistance to active site TKIs including T315I although a 5-fold higher dose is required to effectively treat this mutation. ABL1 mutations conferring clinical resistance to asciminib (and likely other STAMP inhibitors) have been reported which largely reside within the non-catalytic myristoyl pocket. Importantly, ELVN-001 retains potency against a panel of clinically relevant asciminib resistance mutants in a Ba/F3 cell background. As ELVN-001 and asciminib target distinct non-overlapping regions in ABL1, we evaluated the potential advantage of combining these agents. The mechanistic and functional effects of these drugs both alone and in combination were assessed in cell models of CML including a model of T315I resistance. Results showed that while each compound exerted differentiated effects on the known BCR-ABL1 effector pathways, both exhibited potent antiproliferative and pro-apoptotic activity, especially in combination. Therefore, the combination of ELVN-001 and asciminib was evaluated in a mouse tumor xenograft model of CML. Results demonstrated that combining ELVN-001 and asciminib was not only well tolerated but elicited profound anti-tumor activity. Finally, ENU mutagenesis screens were conducted in a Ba/F3 BCR-ABL1 line with ELVN-001 and asciminib, alone and in combination. Results of these studies and their impact on the clinical utility of this combination will be discussed. Citation Format: Stefan David Gross, Christopher A. Eide, Michael R. Burkard, Anna Reister Schultz, Yiheng Zhang, Joseph E. Aslan, Owen J. McCarty, Monette A. Aujay, Samuel Kintz, Brian J. Druker, Joseph P. Lyssikatos. ELVN-001, a highly selective ATP-competitive ABL1 tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia alone or in combination with asciminib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5515.