Abstract 6830: JZP815, a potent and selective pan-RAF inhibitor, is effective against a spectrum of mutant KRAS and NRAS solid tumor cancers, as monotherapy and in combination, generating a gene expression profile of MAPK inhibition

Abstract Activation of the mitogen-activated protein kinase (MAPK) pathway by oncogenic mutations in RAS and RAF are frequent drivers of human cancer. Targeting specific components of the MAPK pathway is a precise and rational route to deliver benefits to cancer patients. RAS and RAF proteins are core pathway components that interact directly to mediate MAPK signaling. Direct and indirect inhibition of this key MAPK pathway intersection is critical in driving responses in patients with RAS and RAF mutations. JZP815 (flezurafenib) is an oral pan-RAF inhibitor under development by Jazz Pharmaceuticals. We examined in vitro and in vivo effects of JZP815 pan-RAF inhibition as a single agent and in combination, in multiple RAS and RAF mutant cell and tumor model systems, and those arising from KRAS G12C inhibitor therapy. Lastly, we established a pharmacodynamic (PD) profile indicating JZP815 MAPK pathway engagement. Specifically, in vitro studies in a broad KRAS and NRAS mutant tumor cell line dataset revealed a complex and extensive potency profile of JZP815. Mutant NRAS lines demonstrated significant anti-proliferative response, whereas KRAS mutant lines showed a more diverse response profile. JZP815 inhibited cell proliferation in KRAS mutant cell lines with acquired resistance mutations known to arise in patients after KRAS inhibitor therapy, including acquired KRAS and BRAF mutations. JZP815, in combination with a MEK inhibitor, generated synergistic antiproliferative activity in mutant NRAS melanoma cells lines. In vivo CDX and PDX models showed JZP815 activity against KRAS, NRAS, and BRAF mutant (class 1, 2, 3) xenografts. In BRAF class 1 melanoma PDX models, JZP815 monotherapy generated a more robust antitumor effect compared to 2nd-generation RAF inhibitors. JZP815 demonstrated activity alone and in combination with SOC agents in CRC PDX models, derived from patients who had progressed on KRAS G12C inhibitors. Using bioinformatic analysis, PD profiles were generated that indicated direct impact of JZP815 in MAPK signaling on xenograft tumors bearing KRAS mutations. Whole transcriptome profiling of a KRAS G13D mutant tumor model showed JZP815 suppressed a clinically relevant transcriptional biomarker of MAPK pathway inhibition (MPAS). In addition, the suppression of MPAS gene signature was associated with JZP815 exposure. These PD data support dose- and time-dependent MAPK pathway and target engagement by JZP815 in preclinical models. In summary, JZP815, a potent selective pan-RAF inhibitor, is active against a variety of KRAS, NRAS, and BRAF mutants, and KRAS inhibitor generated mutants, as a single agent and in combination. JZP815 elicits a clinically verified PD profile that could be used to confirm target engagement in patients. JZP815 is currently in phase 1 testing (NCT05557045). Citation Format: Robert Hauptschein, Ankur Karmokar, Emanuele Loro, Yang Yuan, Graham Brock, Robin C. Humphreys, Alexey Sorokin, Preeti Kanikarla, Scott Kopetz. JZP815, a potent and selective pan-RAF inhibitor, is effective against a spectrum of mutant KRAS and NRAS solid tumor cancers, as monotherapy and in combination, generating a gene expression profile of MAPK inhibition [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 6830.