{
  "abstract": "Background There are limited treatment options for patients with metastatic non-small cell lung cancer (NSCLC) who develop tumor progression after prior use of immune checkpoint inhibitor (ICI). The co-blockade of the PD1/PD-L1 axis and TIGIT has been shown to be synergistic in preclinical studies and the effect may be potentiated by reducing the immunosuppressive effects of extracellular adenosine. We evaluated the combination of zimberelimab (anti-PD1) with domvanalimab (Fc-silent anti-TIGIT) and etrumadenant (adenosine receptor antagonist) in patients with previously treated NSCLC.Methods This is an open-label, single-arm phase II clinical trial enrolling patients with NSCLC with PD-L1 tumor proportion score (22C3-IHC assay) ≥ 1% who have received prior ICI in the metastatic setting. A maximum of 2 prior lines of therapy were allowed. Patients received zimberelimab 360mg IV q3 weeks, domvanalimab 15mg/kg IV q3 weeks and etrumadenant 150mg PO daily. The primary endpoint was objective response rate (ORR).Results A total of 30 patients were enrolled between October 2021 and April 2025, including 15 with PD-L1 1-49% and 15 with PD-L1 ≥ 50%. The median age was 68 years (range 48-86), most patients were male (67%), white (70%), had adenocarcinoma (53%) and one prior line of therapy (67%). The ORR was 10% for all patients, 0% for those with PDL1 1-49% and 20% for those with PD-L1 ≥ 50%, with disease control rates of 40% and 80% respectively. Progression free survival was 1.3 months (95% confidence interval [CI] 1.0-2.9) for PD-L1 1-49%, 4.8 months (95% CI 1.6-7.3) for PD-L1 ≥ 50%, and 2.5 months (95% CI 1.4-4.8) for all patients, with overall survival (OS) of 6.5 months (95% CI 2.4-9.3), 16.0 months (95% CI 3.2-NE), and 8.5 months (95% CI 4.7-14.0), respectively. The most common treatment-emergent adverse events (TEAEs) were lymphopenia (56%), anemia (53%), hypertension (43%) and anorexia (40%). The most common G3-4 TEAEs were lymphopenia and hypertension (17%). One patient had G5 complications from a CT-guided biopsy of the lung lesion, leading to hematoma and empyema.Conclusions The combination of zimberelimab, domvanalimab and etrumadenant did not meet the target ORR of 23% to warrant further expansion. Nevertheless, the combination was well tolerated and the high median OS in those with PD-L1 ≥ 50 suggests that selected patients benefited from the treatment. Biomarker analyses are planned.Trial Registration NCT04791839Ethics Approval The study was conducted in accordance with the International Conference on Harmonization Good Clinical Practice (ICH GCP) and approved by the Washington University Human Research Protection Office (IRB ID #: 202104122). All participants signed informed consent before taking part on the study.",
  "authors": [
    {
      "affiliations": [
        "Washington University in St. Louis, St. Louis, MO, USA"
      ],
      "name": "Anjali Rohatgi"
    },
    {
      "affiliations": [
        "Washington University in St. Louis, St. Louis, MO, USA"
      ],
      "name": "Waqar N Saiama"
    },
    {
      "affiliations": [
        "Washington University in St. Louis, St. Louis, MO, USA"
      ],
      "name": "Ningying Wu"
    },
    {
      "affiliations": [
        "Washington University in St. Louis, St. Louis, MO, USA"
      ],
      "name": "Haobin Chen"
    },
    {
      "affiliations": [
        "Washington University in St. Louis, St. Louis, MO, USA"
      ],
      "name": "Maria Q Baggstrom"
    },
    {
      "affiliations": [
        "Washington University in St. Louis, St. Louis, MO, USA"
      ],
      "name": "Brett H Herzog"
    },
    {
      "affiliations": [
        "Swedish Hospital, Seattle, WA, USA"
      ],
      "name": "Siddhartha Devarakonda"
    },
    {
      "affiliations": [
        "Washington University in St. Louis, St. Louis, MO, USA"
      ],
      "name": "Gina M Vellequette"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, St. Louis, MO, USA"
      ],
      "name": "Ramaswamy Govindan"
    },
    {
      "affiliations": [
        "Washington University in St. Louis, St. Louis, MO, USA"
      ],
      "name": "Daniel Morgensztern"
    }
  ],
  "title": "648 A pilot study to evaluate the combination of zimberelimab, domvanalimab and etrumadenant in patients with previously treated non-small cell lung cancer (NSCLC)",
  "uid": "e194d2f3-a3b8-520a-8926-80f2e7749c75"
}