Abstract LB295: ELV-3111, a type 1 pan-RAF inhibitor, that safely combines with MEK inhibitors for enhanced anti-tumor activity in NRAS and BRAF mutant cancers including the most common mechanisms of BRAF inhibitor clinical resistance

Abstract Tumors harboring RAS/RAF mutations represent a significant unmet medical need that is potentially addressable by targeted therapy. Currently approved RAF inhibitors target BRAFV600X mutant cancers via a type 1.5 binding mode (DFG-in, αC-helix out) that effectively inhibits monomeric BRAFV600X, while inducing RAF pathway activation in contexts where RAF signals as a dimer (wildtype, BRAF class II/III and RAS mutant settings). Their inability to inhibit dimeric RAF presents three significant challenges: (1) they are only active against BRAFV600X tumors (2) they induce toxicities due to pathway activation in normal tissues (3) tumors become readily resistant via mutations that convert BRAFV600X monomeric signaling to a dimeric one (e.g. KRAS or NRAS co-mutations). Combining type 1.5 RAF inhibitors with other targeted therapies, like MEK inhibitors or EGFR antagonistic antibodies, has improved both their efficacy and tolerability. Improved efficacy derives from enhanced pathway suppression in the tumor. Improved tolerability is thought to result from concurrent cancelling out of the RAF inhibitor-associated pathway activation and the reversal of the MEK inhibitor pathway suppression in normal tissues. To address the limited breadth of therapeutic utility of the 1.5 inhibitors, type 2 RAF inhibitors (DFG-out, αC-helix-in) such as naporafenib, have been evaluated clinically. These agents inhibit monomeric and dimeric RAF in all contexts with minimal pathway activation. Accordingly, these inhibitors address a much broader range of tumors harboring a diversity of mutations in RAS and RAF. However, the type 2 inhibitors have proven disappointing as single agents compelling their evaluation in combination with MEK inhibitors. While efficacy was markedly improved, the combination robustly suppresses the pathway in normal tissues leading to enhanced toxicity. To address the limitations of the type 1.5 and 2 RAF inhibitors, we discovered ELV-3111, the first type 1 RAF inhibitor with broad activity against RAS/RAF pathway alterations. ELV-3111 has exceptional drug-like properties and kinome selectivity. ELV-3111 inhibits BRAF class I/II/III, CRAF and NRAS mutant cancer cell lines both in vitro and in vivo. Further, unlike Type 2 RAF inhibitors, ELV-3111 induces robust MAPK hyperactivation in normal cells enabling better tolerated and more efficacious MEK inhibitor combinations. Finally, ELV-3111 effectively addresses the most common alterations driving resistance to the approved RAF inhibitors including BRAF alternative splice variants and co-occurring NRAS or KRAS mutations. Therefore, ELV-3111 represents a next generation RAF inhibitor with the breadth of utility of a type 2 inhibitor and the ability to safely combine with other targeted therapies like a Type 1.5 inhibitor. Citation Format: Stefan David Gross, Tara L. Peters, Michael R. Burkard, Dalton Dacus, Mathieu Desaunay, Poulikos I. Poulikakos, Samuel Kintz, Joseph P. Lyssikatos. ELV-3111, a type 1 pan-RAF inhibitor, that safely combines with MEK inhibitors for enhanced anti-tumor activity in NRAS and BRAF mutant cancers including the most common mechanisms of BRAF inhibitor clinical resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB295.