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Background Merkel cell carcinoma (MCC) is a rare neuroendocrine skin cancer driven by UV-induced mutations or the Merkel cell polyomavirus. It is aggressive, with a high Ki-67 proliferative index. Despite an ~55% response rate to PD-1 pathway inhibitors, most patients develop primary or acquired resistance. ATR (ataxia telangiectasia and Rad3-related) kinase, a critical cell cycle checkpoint regulator, ensures genome fidelity in cancer cells experiencing high replication stress. Recent preclinical 1 2 and clinical3–6 data suggest that ATR inhibition can enhance anti-tumor immunity and synergize with anti-PD-(L)1 therapy. Our preclinical findings suggest transcriptional induction of NF-κB-associated proinflammatory mechanisms with ATR inhibition. The potent, selective, oral ATR inhibitor tuvusertib has shown antitumor activity in phase I trials.6 We hypothesize that tuvusertib with anti-PD-(L)1 therapy, may induce tumor regression in advanced anti-PD-(L)1-refractory MCC.Methods The multicenter, randomized, phase II MATRiX trial tests the safety and efficacy of tuvusertib ± avelumab in patients with metastatic MCC refractory to PD-(L)1 blockade ( figure 1). Patients with progressive disease per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) within 120 days of their last anti-PD-(L)1 therapy are eligible. Subjects in Arm 1 or 2 receive tuvusertib 180 mg QD on days 1-14 of each 21-day cycle (figure 2). Subjects in Arm 2 also receive avelumab 1600 mg IV on day 1 of each cycle. Imaging at week 9 and every 12 weeks thereafter is assessed per RECIST v1.1. The primary endpoint is progression-free survival (PFS). With a targeted enrollment of 50 patients, this trial has 83% power (one-sided level of 10%) to detect a hazard ratio of 2.0 for PFS using a stratified (primary vs. acquired resistance) log-rank test. Binary outcomes will be compared via a Mantel-Haenszel test. Tumor, blood, and stool specimens will be profiled for multi-omic signatures of immune-mediated therapeutic outcomes.Results Between June 2024 and June 2025, 24 subjects were enrolled across 15 centers. Arm 1 (tuvusertib monotherapy) enrolled 10 patients and was closed for lack of efficacy on 5/12/2025, as per the pre-defined statistical plan; 5 crossed over to Arm 2. All additional new patients will be enrolled on Arm 2, with a target of 25 subjects.Conclusions There is a need for additional therapeutic approaches for immunotherapy-refractory MCC, as demonstrated by robust enrollment on this trial. This orthogonal approach to solid tumor immunotherapy, relevant to more common immunogenic cancers, may guide future combination strategies to better harness anti-tumor immunity.Acknowledgements NCI Experimental Therapeutics Clinical Trials Network, protocol writing, and regulatory teams. Patients, families, and partnering teams for their commitment to advancing our understanding of this disease. EDDOP Leadership Award-P30 Administrative Supplement, the Mark Foundation for Cancer Research, the Kelsey Dickson Team Science Courage Research Team Award, and the MCC Patient Gift Fund. This study is financially supported by EMD Serono (CrossRef Funder ID: 10.13039/100004755), which provides avelumab and tuvusertib.Trial Registration NCT05947500References Vendetti FP, Karukonda P, Clump DA, et al. ATR kinase inhibitor AZD6738 potentiates CD8+ T cell-dependent antitumor activity following radiation. J Clin Invest. 2018;128(9):3926–3940.Hardaker EL, Sanseviero E, Karmokar A, et al. The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment. Nat Commun. 2024;15(1):1700.Thomas A, Takahashi N, Rajapakse VN, et al. Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress. Cancer Cell. 2021;39(4):566-579.e7.Kim R, Kwon M, An M, et al. Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced/metastatic melanoma who have failed prior anti-PD-1 therapy. Ann Oncol. 2022;33(2):193–203.Besse B, Pons-Tostivint E, Park K, et al. Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial. Nat Med. 2024;30(3):716–729.Yap TA, Tolcher AW, Plummer R, et al. First-in-human study of the ataxia telangiectasia and Rad3-related (ATR) inhibitor tuvusertib (M1774) as monotherapy in patients with solid tumors. Clin Cancer Res. 2024;30(10):2057-2067.Ethics Approval The study is reviewed by NCI’s Central Institutional Review Board; approval number is 10592.Abstract 599 Figure 1An overview of the multicenter, NCI-sponsored Phase II study designed to test the efficacy of tuvusertib, with or without avelumab, to address anti-PD-(L)1 resistance in advanced, refractory MCC; NCT05947500Abstract 599 Figure 2Timeline of treatment regimen and biospecimen acquisition for patients randomized to arm 1 and 2