Abstract 2055: Molecular profiling of the PI3Kδ inhibitor roginolisib in metastatic uveal melanoma and its correlation with clinical outcomes

Abstract Introduction: Uveal melanoma (UM) is a rare orphan disease with significant unmet clinical need. Unlike cutaneous melanoma, UM has a low tumor mutational burden and a highly immunosuppressive microenvironment, rendering it largely unresponsive to checkpoint inhibitor therapies. PI3Kδ is involved in the pathophysiology of the disease, by enhancing regulatory T cell activity and supporting tumor cell survival. Roginolisib, a PI3Kδ inhibitor, was evaluated in 23 UM patients at an 80 mg biological effective dose (BED). Here, we report data from a comprehensive translational analyses of genomic, transcriptomic, proteomic and cellular data from UM patients, supporting PI3Kδ as a suitable therapeutic target for UM patients. Methods: IOA-244-101 (NCT04328844) was conducted in patients with advanced cancer, which included metastatic uveal melanoma patients. Baseline and on-treatment blood and plasma samples were analyzed to evaluate circulating immune cells using mass cytometry, circulating tumor DNA (ctDNA) via whole exome sequencing, and circulating proteins through targeted proteomics. Additionally, biopsies at baseline and Day28 of treatment were analyzed for tumor transcriptomic and genomic profiles using whole transcriptome and whole exome sequencing. Results: Roginolisib treatment induced progressive decrease of circulating regulatory T cells and increased CD39+CD8T cells, accompanied by reduction of soluble PD1, CCL22 and increase of IL15 and IFNGR2. We identified a subpopulation of mUM patients that particularly benefited from roginolisib treatment. Patients with RECIST 1.1-defined stable disease (SD) at 16 weeks experienced significantly longer median overall survival (28.5 months) compared to those with progressive disease (PD) (10.9 months). SD patients had enhanced CD8+ T cell/Treg ratios and downregulation of PI3K/mTOR-associated proteins in plasma. Conversely, PD patients showed upregulation of these proteins after8 weeks of treatment , suggesting a potential resistance mechanism. Transcriptomic analysis of tumor biopsies revealed that SD patients had higher baseline expression of 325 genes, including 61 GPCR (G-protein coupled receptors), which were downregulated post-treatment. Longitudinal ctDNA profiling further demonstrated dynamic tumor evolution, with specific variants emerging or disappearing over time. Conclusion: These findings highlight the importance of immune modulation, PI3K/mTOR signaling, and GPCR gene expression in potentially driving treatment outcomes, and encourage further evaluation of Roginolisib in a Phase 2 randomized study. Citation Format: Alessio Bevilacqua, Tan Ziyang, Lakshmikanth Tadepally, Petter Brodin, Anna Maria Di Giacomo, Michele Maio, Jeff Evans, Armando Santoro, Tracey Hammett, Paramijt Kaur, Lars van der Veen, Michael Lahn, Giusy Di Conza. Molecular profiling of the PI3Kδ inhibitor roginolisib in metastatic uveal melanoma and its correlation with clinical outcomes [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 2055.