{
  "abstract": "Background Compared with conventional chemotherapy, pembrolizumab-based chemoimmunotherapy (Pembro) and nivolumab plus ipilimumab with or without two cycles of platinum-doublet chemotherapy (Nivo+Ipi) improve survival in advanced non-small cell lung cancer (NSCLC). However, biomarkers for selecting optimal immunotherapy remain unclear. This study aimed to assess whether programmed cell death-ligand 1 (PD-L1) expression on tumor and immune cells (ICs) can guide first-line immunotherapy in advanced NSCLC.Methods This multicenter, observational study retrospectively reviewed patients with NSCLC treated with first-line Pembro or Nivo+Ipi who had evaluable PD-L1 expression on tumor (Tumor Proportion Score (TPS), 22C3) and ICs score (SP142). In addition, whole-exome and RNA sequencing were performed on treatment-naïve NSCLCs with available PD-L1 expression status by both assays.Results Between 2019 and 2023, 198 patients were included (Pembro/Nivo+Ipi: 137/61). In the Pembro cohort, patients with high TPS (≥ 50%) had significantly longer progression-free survival (PFS) than those with low TPS (< 50%) (median PFS (mPFS, months): 8.1 vs 7.1; p=0.02), while IC score was not predictive. In the Nivo+Ipi cohort, high IC score (≥1) was associated with longer PFS than low IC score (0) (mPFS: 7.7 vs 2.8; p=0.04), while TPS showed no impact. Among patients with low TPS/high IC scores, Nivo+Ipi achieved longer PFS than Pembro (mPFS: 12.4 vs 6.6; restricted mean survival time (RMST) Nivo+Ipi/RMSTPembro (24 months)=1.5; p=0.049). Multiomics analysis using 152 NSCLC samples showed that tumors with low TPS/high IC scores exhibited an activated tumor immune microenvironment comparable to that of tumors with high TPS. However, these tumors had significantly highest tumor mutation burden (TMB) and regulatory T cell (Treg) fraction among the PD-L1 phenotypes (median TMB (mut/Mb): 1.6 in tumors with low TPS/low IC score, 18.2 in low TPS/high IC score, and 1.9 in high TPS/any IC score; median Treg fraction (×10−2]: 0.0, 0.2, and 0.0, respectively), supporting a potential benefit of cytotoxic T-lymphocyte-associated antigen 4 blockade in addition to programmed cell death protein 1 (PD-1)/PD-L1 inhibition in this subgroup.Conclusions Patients with NSCLC and low TPS/high IC scores may benefit more from Nivo+Ipi than from Pembro due to distinct genomic and immunological features, including high TMB and T reg fraction.",
  "authors": [
    {
      "affiliations": [
        "Department of Thoracic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan",
        "Department of Respiratory Medicine, Chiba University, Chiba, Chiba, Japan",
        "Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan"
      ],
      "name": "Jun Miyakoshi"
    },
    {
      "affiliations": [
        "Department of Thoracic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan",
        "Department of Experimental Therapeutics, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan"
      ],
      "name": "Tatsuya Yoshida"
    },
    {
      "affiliations": [
        "Department of Experimental Therapeutics, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan",
        "Department of Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo, Japan"
      ],
      "name": "Yuji Uehara"
    },
    {
      "affiliations": [
        "Department of Respiratory Medicine, Kansai Medical University Hospital, Hirakata, Japan"
      ],
      "name": "Yuki Takeyasu"
    },
    {
      "affiliations": [
        "Department of Respiratory Medicine, Kitasato University Hospital, Sagamihara, Kanagawa, Japan"
      ],
      "name": "Masayuki Shirasawa"
    },
    {
      "affiliations": [
        "Division of Cancer Immunology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan"
      ],
      "name": "Akito Fukuda"
    },
    {
      "affiliations": [
        "Department of Diagnostic Pathology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan"
      ],
      "name": "Jumpei Kashima"
    },
    {
      "affiliations": [
        "Division of Cancer Immunology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan"
      ],
      "name": "Shogo Kumagai"
    },
    {
      "affiliations": [
        "Department of Thoracic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan"
      ],
      "name": "Hidehito Horinouchi"
    },
    {
      "affiliations": [
        "Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan"
      ],
      "name": "Hanako Ono"
    },
    {
      "affiliations": [
        "Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan"
      ],
      "name": "Kouya Shiraishi"
    },
    {
      "affiliations": [
        "Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan"
      ],
      "name": "Takashi Kohno"
    },
    {
      "affiliations": [
        "Department of Chemotherapy and Palliative Care, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan"
      ],
      "name": "Shunsuke Kondo"
    },
    {
      "affiliations": [
        "Department of Thoracic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan"
      ],
      "name": "Yasushi Goto"
    },
    {
      "affiliations": [
        "Department of Experimental Therapeutics, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan"
      ],
      "name": "Noboru Yamamoto"
    },
    {
      "affiliations": [
        "Department of Diagnostic Pathology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan"
      ],
      "name": "Yasushi Yatabe"
    },
    {
      "affiliations": [
        "Department of Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo, Japan"
      ],
      "name": "Yukio Hosomi"
    },
    {
      "affiliations": [
        "Department of Respiratory Medicine, Kansai Medical University Hospital, Hirakata, Japan"
      ],
      "name": "Takayasu Kurata"
    },
    {
      "affiliations": [
        "Department of Respiratory Medicine, Kitasato University Hospital, Sagamihara, Kanagawa, Japan"
      ],
      "name": "Katsuhiko Naoki"
    },
    {
      "affiliations": [
        "Department of Respiratory Medicine, Chiba University, Chiba, Chiba, Japan"
      ],
      "name": "Takuji Suzuki"
    },
    {
      "affiliations": [
        "Department of Thoracic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan"
      ],
      "name": "Yuichiro Ohe"
    }
  ],
  "title": "PD-L1 phenotype classification based on expression in tumor and immune cells as a potential biomarker for optimizing anti-PD-1/CTLA-4 immunotherapies in NSCLC",
  "uid": "e80e0177-3018-5cb4-bdc2-be928d009a17"
}