Abstract 374: OMX-0407 - A spectrum selective kinase inhibitor shows preclinical efficacy in RCC as well as sarcomas

Abstract OMX-0407 is an orally available spectrum-selective kinase inhibitor targeting key oncology-relevant tyrosine kinases and the salt-inducible kinase family. OMX-0407 offers a dual mode of action (MoA) in cancer by inducing cell cycle arrest in tumor cells and sensitizing the tumor environment to immune cell-mediated tumor cell killing. It is being developed as first-in-class treatment for solid tumor indications with high unmet medical need. Key oncogenic signaling pathways of tyrosine kinases drive cancer progression by regulating cell cycle and growth signaling cascades. Dysregulation of these kinases, such as platelet-derived growth factor receptors, Eph receptors, and Src family kinases, contributes to cancer progression and therapy resistance. OMX-0407 effectively disrupts these processes through potent inhibition of these kinases and their downstream signaling cascades. A comprehensive viability screen of over 380 human cancer cell lines revealed a selective anti-tumor activity across a subset of cancers, including in renal cell carcinomas (RCC) and sarcomas. Pharmacodynamics studies via phospho-proteomics, Simple-Western or functional kinase activity assays revealed that OMX-0407 induces a G1 cell cycle arrest, accompanied by dose-dependent downregulation of cell cycle-associated proteins and kinase signaling pathways. These effects have been confirmed across in vitro cell line studies, in vivo cell line-derived models or even patient-derived xenograft models. Besides its direct effect on tumor cells, OMX-0407 is repolarizing the tumor microenvironment by reducing immunosuppressive regulatory T cells in the tumor bed and shifting toward a pro-inflammatory state. This dual MoA contributes to the potent anti-tumor effects in various syngeneic animal studies. In a human patient-derived xenograft of epithelioid angiosarcoma (AS), derived from a 9-year-old patient, OMX-0407 demonstrated remarkable dose-dependent anti-tumor efficacy as a single agent. The strong anti-tumor efficacy, with tumor reduction in individual animals, was associated with dose-dependent downregulation of phosphoproteins and significant inactivation of key OMX-0407 regulated signaling pathways on kinase level. Clinical data from a patient, diagnosed with secondary radiation-induced AS, resistant to prior lines of chemotherapy, demonstrated that OMX-0407 was well tolerated and achieved a complete response at doses of up to 60 mg twice daily, which remains ongoing at 14 month. These findings support OMX-0407 as a promising first-in-class therapeutic candidate for the treatment of AS and RCC, with a dual mechanism combining direct anti-tumor effects with repolarization of an immunosuppressive tumor microenvironment. As of September 2024, Ph1b expansion cohorts of the first-in-human trial (NCT05826600) were initiated for patients with unresectable or metastatic AS or clear cell RCC. Citation Format: Ilona Petra Maser, Carolin Strobl, Bettina Bauer, Andreas Schirmer, Moritz Zulley, Carmen Amerhauser, Marisa Stebegg-Wagner, Tiantom Jarutat, Hannes Loferer, Stefan Bissinger. OMX-0407 - A spectrum selective kinase inhibitor shows preclinical efficacy in RCC as well as sarcomas [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 374.