Abstract 5546: Rilvegostomig elicits greater immune activation and tumor inhibition than clinically approved anti-PD-1 monotherapy in models of HNSCC

Abstract Background: Rilvegostomig (AZD2936) is a monovalent, bispecific humanized IgG1 monoclonal antibody that targets human TIGIT and PD-1, engineered with a triple-mutation in its fragment crystallizable (Fc)-domain to prevent Fc-effector functionality. Rilvegostomig has shown promising anti-tumor activity in NSCLC patients in a Phase I/II clinical trial (NCT04995523) and is currently being investigated in multiple Phase III trials. Here, we report the enhanced anti-tumor activity of rilvegostomig compared to a clinically approved anti-PD-1 (αPD1) mAb in ex vivo and in vivo models of head and neck squamous cell carcinoma (HNSCC). Methods: Primary HNSCC explants, derived from freshly resected patient tumors, were cultured ex vivo in a 3D platform for therapeutic agent testing. Ex vivo immune activity was assessed via IFN-γ quantification. Baseline tumor features—characterized by IHC, flow cytometry, scRNA-seq, and multiplex imaging—were used to stratify patient response and identify candidate biomarkers. A CD34+ humanized mouse model of HNSCC was developed to enable long-term engraftment of functional multi-lineage hematopoietic cells and used to investigate efficacy and effects of IO therapeutics on different components of the immune system. Results: We investigated a cohort of 42 newly diagnosed HNSCC patient resected tumor samples. These samples represent the incidence of HNSCC by anatomical sites and share similar cohort attributes as those enrolled in KEYNOTE-689. Patient-derived tumor explants maintain tumor architecture and intact tumor microenvironment (TME), including tumor cells, immune cells, stroma cells, and extracellular matrix. αPD1 monotherapy elicited immune activity in 9.5% of HNSCC samples tested in our ex vivo platform, consistent with clinical observation of major pathological response in KEYNOTE-689. In contrast, rilvegostomig induced a significantly higher rate of ex vivo immune activity (28.6%). Rilvegostomig’s activity was observed in samples derived from multiple anatomical sites, showing the highest response rate in oral cavity samples. Moreover, our analyses identified key baseline correlates that distinguish rilvegostomig activity from αPD1. Lastly, using a CD34-engrafted humanized mouse model of oral cavity HNSCC, we compared the therapeutic efficacy of αPD-1 monotherapy with rilvegostomig. In contrast to αPD-1, which produced modest effects on tumor growth, rilvegostomig induced significant tumor growth inhibition. Conclusions: Rilvegostomig elicits greater immune cell activation and broader activity in samples derived from different anatomical sites of HNSCC compared to αPD1 monotherapy in a 3D ex vivo platform and a humanized mouse model of HNSCC. These results underscore rilvegostomig's potential as a promising treatment for newly diagnosed HNSCC and support its investigation in clinical trials. Citation Format: Jun Ren, Ngan Mitchell, Marie Boutet, Vladimir Roudko, Jeremy Ratiu, Jorge Blando, Sophia Varriano, Elizabeth Galery, Rebecca Halpin, Trevor Connor, Kanam Malhotra, Bartholomew Starich, Jessica Wagner, Yi Luan, Anna Huntley, Joseph Boland, Maurizio Scaltriti, Mark Cobbold, Simon Hollingsworth, Scott Hammond, Doug Palmer, Paul Chariou, Kristen Pollizzi, Daniela Dinulescu, . Rilvegostomig elicits greater immune activation and tumor inhibition than clinically approved anti-PD-1 monotherapy in models of HNSCC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5546.