Abstract B024: The clinical benefit from treatment of advanced MSS mCRC with the adenosine 2a/2b antagonist etrumadenant is associated with adenosine-mediated T-cell exclusion and enhancement of the effectiveness of immunotherapy

Abstract Background: Microsatellite stable (MSS) metastatic colorectal cancers (mCRCs) are refractory to checkpoint inhibitors. mCRCs express elevated levels of the adenosine-generating enzyme CD73, which contributes to reduced effector T cell-mediated anti-tumor immunity. Etrumadenant (etruma; AB928) is an orally bioavailable, selective adenosine 2a/2b receptor antagonist designed to reverse adenosine-mediated immunosuppression. Etruma, in combination with zimberelimab (Z) (an anti-PD-1 antibody) and FOLFOX/bevacizumab (bev) (EZFB regimen) demonstrated a significant overall survival (OS) benefit over regorafenib (rego) in third-line, MSS, chemo-resistant mCRC in the ARC-9 Ph2 study (NCT04660812). Here we assessed the predictive value of CD73 expression and the contributions of T cell number, spatial distribution, and PD-L1 expression to clinical benefit for patients treated with EZFB. Methods: Baseline tumor biomarker analyses were performed on 92 patients for CD73 by immunohistochemistry (IHC), 91 patients for whole transcriptome analysis, and 88 patients for whole exome sequencing. A custom multiplex immunofluorescence (mIF) panel was developed to quantify panCK, CD73, CD3, CD8, GZMB, and FAP proteins. Digital pathology was employed to assess the number and spatial distribution of cells expressing these six markers in tumor tissues. Results: EZFB dramatically improved OS as compared to rego with mOS of 19.7 vs 10.3 months in the biomarker evaluable population of ARC-9. In EZFB-treated patients, 46 out of 61 patients (75%) with CD73+ tumors exhibited significantly extended OS when compared to patients with CD73- tumors (20 vs 11.9 months). CD73+ tumors showed a significantly greater number of CD3+ and activated CD8+ GZMB+ T cells and were enriched for a T cell activation gene expression signature. Strikingly, spatial analysis revealed these T cells to be excluded into tumor-associated stroma. Proximity analysis highlighted a scarcity of tumor-infiltrating T cells in the vicinity of CD73+ cancer cells indicative of a focal, adenosine-rich, immunosuppressive microenvironment. Additional stratification of tumors by PD-L1 expression revealed significantly more tumor-excluded CD3+ and CD8+ GZMB+ T cells in CD73+ PD-L1high tumors than CD73- PD-L1high cases, suggesting a link between T cell exclusion and adenosine. With a median follow up of 20.4 months, EZFB-treated patients with CD73+ PD-L1high tumors derived a significant improvement in 20-month landmark OS of 75% (95% CI; 50, 89), compared to patients with CD73+ PD-L1low, 39% (95% CI; 13, 64) and CD73-, 21% (95% CI; 4, 47) tumors. Conclusion: The majority of ARC-9 patients were shown to have CD73+, T cell excluded tumors and experienced robust clinical benefit on EZFB regardless of CD73 or PD-L1 status. Patients with CD73+ PD-L1high tumors derived the greatest benefit, supporting the hypothesis that clinical efficacy on this regimen is fundamentally underpinned by reversal of T cell exclusion and reinvigoration of T cell mediated anti-tumor immunity in the late-line, MSS chemo-resistant mCRC. Citation Format: Jiyun Kim, Emily Brown, Shravani Shitole, Madhura Joglekar, Haben Ghermazien, Jose Aquino, Tingting Zhao, Jennifer Scott, Soonweng Cho, Angelo Kaplan, Omar Kabbarah. The clinical benefit from treatment of advanced MSS mCRC with the adenosine 2a/2b antagonist etrumadenant is associated with adenosine-mediated T-cell exclusion and enhancement of the effectiveness of immunotherapy [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 B024.