{
  "abstract": "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",
  "authors": [
    {
      "affiliations": [
        "University of Washington, Seattle, WA, USA"
      ],
      "name": "Rashmi Bhakuni"
    },
    {
      "affiliations": [
        "University of Washington, Seattle, WA, USA"
      ],
      "name": "Evan T Hall"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, Saint Louis, MO, USA"
      ],
      "name": "George Ansstas"
    },
    {
      "affiliations": [
        "University of Washington/Fred Hutch, Seattle, WA, USA"
      ],
      "name": "Shailender Bhatia"
    },
    {
      "affiliations": [
        "H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA"
      ],
      "name": "Andrew S Brohl"
    },
    {
      "affiliations": [
        "University of Pittsburgh Medical Center, Pittsburgh, PA, USA"
      ],
      "name": "Melissa A Burgess"
    },
    {
      "affiliations": [
        "Northwestern University, Chicago, IL, USA"
      ],
      "name": "Sunandana Chandra"
    },
    {
      "affiliations": [
        "Perlmutter Cancer Center at NYU Langone, New York, NY, USA"
      ],
      "name": "Maya Dimitrova"
    },
    {
      "affiliations": [
        "University of California Irvine, Irvine, CA, USA"
      ],
      "name": "Ling Gao"
    },
    {
      "affiliations": [
        "Yale University, New Haven, CT, USA"
      ],
      "name": "Jeffrey J Ishizuka"
    },
    {
      "affiliations": [
        "University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, USA"
      ],
      "name": "Gino K In"
    },
    {
      "affiliations": [
        "Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Evan J Lipson"
    },
    {
      "affiliations": [
        "University of Miami, Sylvester Cancer Center, Miami, FL, USA"
      ],
      "name": "Jose Lutzky"
    },
    {
      "affiliations": [
        "University of California Irvine, Irvine, CA, USA"
      ],
      "name": "Rupali Nabar"
    },
    {
      "affiliations": [
        "Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada"
      ],
      "name": "Sam Saibil"
    },
    {
      "affiliations": [
        "Dana-Farber Cancer Institute, Boston, MA, USA"
      ],
      "name": "Ann W Silk"
    },
    {
      "affiliations": [
        "University of Texas Southwestern, Dallas, TX, USA"
      ],
      "name": "Daniel Y Wang"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, Saint Louis, MO, USA"
      ],
      "name": "Alice Y Zhou"
    },
    {
      "affiliations": [
        "University of Washington/Fred Hutch, Seattle, WA, USA"
      ],
      "name": "Jina Yun"
    },
    {
      "affiliations": [
        "National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Isaac Brownell"
    },
    {
      "affiliations": [
        "Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Judy Murray"
    },
    {
      "affiliations": [
        "UPMC Hillman Cancer Center/University of Pittsburgh, Pittsburgh, PA, USA"
      ],
      "name": "Yvonne M Mowery"
    },
    {
      "affiliations": [
        "Fred Hutchinson Cancer Center, Seattle, WA, USA"
      ],
      "name": "Ted Gooley"
    },
    {
      "affiliations": [
        "Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health Bethesda, MD, USA"
      ],
      "name": "Steven Gore"
    },
    {
      "affiliations": [
        "Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, USA"
      ],
      "name": "Suzanne L Topalian"
    },
    {
      "affiliations": [
        "University of Washington, Seattle, WA, USA"
      ],
      "name": "Paul Nghiem"
    }
  ],
  "title": "599 The MATRiX trial: a multicenter, randomized, phase II study of ATR inhibition (via tuvusertib) with or without avelumab in patients with advanced anti-PD-(L)1-refractory merkel cell carcinoma",
  "uid": "ec295790-ef7a-5dcc-b5a8-4c91cb0ac2c5"
}