Abstract 3627: Volrustomig a novel PD-1/CTLA-4 bispecific antibody leads to robust increase in peripheral and intra-tumoral pharmacodynamic biomarkers in solid tumors from FTiH study

Abstract Background: Volrustomig (MEDI5752) is designed to fully inhibit PD-1 while preferentially inhibiting CTLA-4 on activated PD-1+ T cells. In a FTiH trial, volrustomig demonstrated meaningful clinical activity in patients with solid tumors (including 1L RCC and NSCLC), acceptable safety profile, sustained PD-1 receptor occupancy, and T cell proliferation at levels greater than seen with clinically tolerable doses of CTLA-4 inhibitors with co-administration of anti-PD(L)-1. We sought to further characterize volrustomig pharmacodynamic effect in the periphery and tumor to demonstrate its biological activity and inform dose optimization. Methods: Pre- and on-treatment blood samples from 86 patients enrolled in dose exploration were collected. Peripheral T cell profiling was assayed by flow cytometry, RNAseq, TCRSeq and serum proteomics. Paired tumor biopsies (N=17), pre- and at week 6 on-treatment, were analyzed for T cell infiltration and function using RNAseq and computational image analysis of immune cell marker density detected by histochemistry and multiplex immune fluorescence assays. Results: Volrustomig achieved dose-dependent peripheral pharmacodynamic changes of biomarkers specific to CTLA-4 blockade at ≥ 225mg. At C1D8 with doses ≥ 500mg, increases in CD4 T cell proliferation (ki67), activation (ICOS), and memory T cells (1516%, 321% and 88%, respectively) were seen, each greater than observed with historical controls of patients treated with tremelimumab 3mg/kg (T3) in combination with durvalumab. Similarly, CD8 proliferation and activation were also higher than T3 at C1D8 with 300% and 161% increase respectively. Additional CD4 and CD8 T cell proliferation and activation was observed at C2D8 supporting the benefit of repeat dosing. Higher peripheral T cell clonal expansion at doses ≥ 500mg was seen and associated with PFS and OS benefit. In patients with paired biopsies, volrustomig achieved robust T cell mediated anti-tumor activity including increases in T cell infiltration (CD8+, 2.3 fold, p=0.04), proliferation (CD8+ Ki67+, 2.1 fold, p=0.04) and, T cell cytotoxicity and activation (GrB+, 2.2 fold, p=0.01; T cell effector and IFNg gene signatures, > 2-fold, p< 0.01). Additionally, volrustomig increased CD8 proliferation in tumor compared to historical control durvalumab alone (>2-fold increase in 70% vs 50% patients). Conclusion: Voltrustomig demonstrated robust peripheral and intra-tumoral T cell activation and proliferation, broadening the pool of antigen experienced T cells, at levels greater than seen with dual checkpoint blockade currently used in the clinic. Citation Format: Ikbel Achour, Michael Kuziora, Florian Song, Steven Eck, Lina Meinecke, Jorge Blando, Jennifer Pearson, Megha Saraiya, Christian Eisen, Felix Segerer, Markus Schick, Nicolas Triltsch, Michael Surace, Gisele Silva Boos, Harald Hessel, Mai Bui, Katrin Pratsch, Alma Andoni, Shelby Denise Gainer, Dan Freeman, Deepa Subramaniam, Ben Tran. Volrustomig a novel PD-1/CTLA-4 bispecific antibody leads to robust increase in peripheral and intra-tumoral pharmacodynamic biomarkers in solid tumors from FTiH study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3627.