{
  "abstract": "Purpose Liver metastases (LMs) confer resistance to immune checkpoint blockade in advanced non-squamous non‐small cell lung cancer (ns‐NSCLC), likely through an immunosuppressive tumor microenvironment (TME). We hypothesized that vascular endothelial growth factor (VEGF)-A blockade, by remodeling the immunosuppressive TME, could restore the benefit of chemoimmunotherapy in LM+ patients. Here, we report the first comparative analysis of chemoimmunotherapy with and without bevacizumab specifically in this population.Experimental design Data were analyzed from the phase III IMpower130 and IMpower150 trials in treatment‐naïve, EGFR/ALK-wild‐type patients with ns‐NSCLC. Treatment arms included chemotherapy (CT), CT plus atezolizumab (CT+immunotherapy (IT)), CT plus bevacizumab (CT+antiangiogenic (AA)), and CT+IT+ AA, with LM as a stratification factor. Survival outcomes were assessed by Kaplan-Meier estimates and multivariate Cox regression analyses. Bulk and single‐cell RNA sequencing data were used to characterize the LM TME.Results Among 1,713 patients, 236 (13.8%) presented with LMs. In IMpower130, LM+ patients derived no overall survival (OS) benefit from CT plus IT (CT+IT) compared with CT alone (HR for OS: 1.05; 95% CI 0.63 to 1.73). In contrast, in IMpower150, the addition of bevacizumab to CT+IT (CT+IT+ AA) significantly improved progression-free survival (PFS; HR: 0.49) and OS (HR: 0.52) in LM+ patients—an effect not observed in patients without LM. Baseline transcriptomic exploratory analyses from IMpower150 revealed a myeloid-enriched, lymphocyte-depleted TME. Single-cell RNA sequencing further demonstrated VEGF-A/VEGFR-1/2 crosstalk between macrophages and endothelial cells, as well as an autocrine VEGF-A/VEGFR-1 loop within macrophages.Conclusion The addition of bevacizumab to chemoimmunotherapy was associated with improved survival in ns‐NSCLC specifically in patients with LMs. These hypothesis-generating findings suggest that the benefit may stem from disruption of VEGF-A-driven immunosuppressive signaling in the liver, but require prospective confirmation.",
  "authors": [
    {
      "affiliations": [
        "Laboratoire d’Immunomonitoring, INSERM U1363, Gustave Roussy, Villejuif, France",
        "Medical Oncology Department, Hôpital Européen Georges Pompidou, Paris, France",
        "Drug Development Department, Gustave Roussy, Villejuif, Paris"
      ],
      "name": "Matthieu Roulleaux-Dugage"
    },
    {
      "affiliations": [
        "Translational Cancer Genomics team, INSERM U981, Gustave Roussy, Villejuif, Île-de-France, France"
      ],
      "name": "Andrey Yurchenko"
    },
    {
      "affiliations": [
        "Translational Cancer Genomics team, INSERM U981, Gustave Roussy, Villejuif, Île-de-France, France"
      ],
      "name": "Sergey Nikolaev"
    },
    {
      "affiliations": [
        "Computational Sciences Center of Excellence, Genentech, South San Francisco, California, USA"
      ],
      "name": "Barzin Nabet"
    },
    {
      "affiliations": [
        "INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Villejuif, France"
      ],
      "name": "Stéphanie Corgnac"
    },
    {
      "affiliations": [
        "INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Villejuif, France"
      ],
      "name": "Céline Anquetil"
    },
    {
      "affiliations": [
        "Genentech, South San Francisco, California, USA"
      ],
      "name": "Minu K Srivastava"
    },
    {
      "affiliations": [
        "Genentech, South San Francisco, California, USA",
        "Rancho BioSciences LLC, San Diego, California, USA"
      ],
      "name": "Velimir Gayevskiy"
    },
    {
      "affiliations": [
        "Roche Products, Welwyn Garden City, Hertfordshire, UK"
      ],
      "name": "Virginia McNally"
    },
    {
      "affiliations": [
        "Medical Oncology Department, Hospital Clinic de Barcelona, Barcelona, Spain",
        "Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, Barcelona, Spain"
      ],
      "name": "Laura Mezquita"
    },
    {
      "affiliations": [
        "Inserm U1363, Laboratory of Molecular Radiotherapy and Therapeutic Innovation, Gustave Roussy, Villejuif, France"
      ],
      "name": "Jean-Luc Perfettini"
    },
    {
      "affiliations": [
        "Laboratoire de Recherche Translationnelle en Immunothérapies (LRTI), INSERM U1015, Gustave Roussy, Villejuif, Île-de-France, France"
      ],
      "name": "Severine Mouraud"
    },
    {
      "affiliations": [
        "Drug Development Department, Gustave Roussy, Villejuif, Paris"
      ],
      "name": "Christophe Massard"
    },
    {
      "affiliations": [
        "Medical Oncology Department, Gustave Roussy, Villejuif, Île-de-France, France"
      ],
      "name": "Benjamin Besse"
    },
    {
      "affiliations": [
        "Drug Development Department, Gustave Roussy, Villejuif, Paris",
        "Medical Oncology Department, Gustave Roussy, Villejuif, Île-de-France, France"
      ],
      "name": "Yohann Loriot"
    },
    {
      "affiliations": [
        "Drug Development Department, Gustave Roussy, Villejuif, Paris",
        "Laboratoire de Recherche Translationnelle en Immunothérapies (LRTI), INSERM U1015, Gustave Roussy, Villejuif, Île-de-France, France"
      ],
      "name": "Aurelien Marabelle"
    },
    {
      "affiliations": [
        "Laboratoire d’Immunomonitoring, INSERM U1363, Gustave Roussy, Villejuif, France"
      ],
      "name": "Nathalie Chaput"
    },
    {
      "affiliations": [
        "Medical Oncology Department, Hôpital Européen Georges Pompidou, Paris, France"
      ],
      "name": "Edouard Auclin"
    }
  ],
  "title": "VEGF-A blockade overcomes liver metastases resistance to chemoimmunotherapy in patients with advanced non-squamous NSCLC",
  "uid": "1426e052-e84e-5046-b800-fe1ad1a63a98"
}