Abstract C064: Tumor Ecosystem and Microbiome Features Associated with Efficacy from Avelumab-based Multimodal Therapy in a Phase III Randomized Trial

Abstract Curative immune checkpoint blockade (ICB)-based multimodal therapy is now widely used across oncology; yet drivers of efficacy and resistance in most cancer types, including squamous cell carcinoma of the head and neck (SCCHN), are not well understood. To address this issue, we comprehensively characterized the tumor genome, microenvironment, microbiome, and TCR repertoire in a phase III international randomized trial to identify factors that shape outcomes to avelumab plus chemoradiotherapy versus chemoradiotherapy alone. Patients receiving avelumab whose tumors contained distinct immunologic and genetic features had superior outcomes compared to patients in the control arm that did not receive immunotherapy. In contrast, avelumab-treated patients with increased myeloid/neutrophil signatures had poorer outcomes compared to placebo. Strikingly, these tumors possessed telltale intratumoral bacteria, elevated tumor-associated neutrophils, high systemic neutrophil-to-lymphocyte ratio, suppressed levels of adaptive immunity, and were the least likely to respond to therapy. We use these findings to define tumor ecosystem classes that associate with response and resistance to combination chemoimmunotherapy. Importantly, our data demonstrate for the first time, the effects of intratumoral bacteria on ICB response within the context of a randomized trial. These discoveries enhance our understanding of combination immunotherapy response, provide a highly useful multi-omic resource, and identify unanticipated interactions between ICB and CRT that may guide future therapeutic strategies. Citation Format: Tyler Alban, Nadeem Riaz, Robert Haddad, Michelle Saul, Vladamir Makarov, Yingjie Zhu, Ezra Cohen, Robert Ferris, Peter Chang, Jin-Ching Lin, Amanda Pyrri, Prerana Parthasarathy, Ardijana Novaj, Mruniya Gawali, Jennifer Ko, Phineas Hamilton, Natalie Silver, Ivan Juric, Daniel Chawla, Ana Gradissimo, Daniel McGrail, Craig Davis, Nancy Lee, Timothy Chan. Tumor Ecosystem and Microbiome Features Associated with Efficacy from Avelumab-based Multimodal Therapy in a Phase III Randomized Trial [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C064.