{
  "abstract": "Background Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used medications in non-small cell lung cancer (NSCLC). We comprehensively evaluated the effect of NSAID exposure patterns on immunotherapy outcomes, prostaglandin E2 (PGE2) and immune cells.Methods This multicenter study employed both prospective and retrospective approaches for patient enrollment. Patients were included if they had advanced NSCLC, and were first-time users of immune checkpoint inhibitor (ICI). Endpoints included progression-free survival (PFS) and overall survival (OS). Serum and tumor tissue were collected in the prospective subset for PGE2 and immune cell assay.Results A total of 1,748 patients were included, with 232 patients prospectively enrolled. After multivariable adjustment, NSAID use was independently associated with improved PFS (HR 0.72, 95% CI 0.58 to 0.91, p=0.0053) and OS (HR=0.76, 95% CI 0.58 to 0.98, p=0.0364). Benefit was observed for both before-ICI (HR 0.75, 95 % CI 0.57 to 0.99, p=0.0383) and after-ICI initiation (HR 0.63, 95% CI 0.43 to 0.92, p=0.0159). For aspirin, low-dose aspirin users had better PFS than non-users (HR 0.69, 95% CI 0.51 to 0.94, p=0.0191), especially when used at least 30 days (HR=0.69, 95% CI 0.48 to 0.99, p=0.0464). Among non-selective NSAIDs, only after-ICI initiation improved OS (HR=0.49, 95% CI 0.24 to 0.99, p=0.0458). Any-grade (57.8% vs 53.4%) and grade ≥3 adverse events (9.2% vs 9.8%) were comparable among NSAID users and non-users. Serum sample indicated that aspirin was associated with less PGE2, which was related to better outcomes. On immune cells, RNA-seq revealed a correlation between the cyclooxygenase-2 pathway and neutrophils. Biosample analysis further demonstrated that aspirin use was associated with decreased neutrophils in both circulation and tumor.Conclusions Long-term low-dose aspirin enhanced immunotherapy efficacy in patients with advanced NSCLC. PGE2 and neutrophils represented potential biomarkers guiding NSAID-immunotherapy integration.Trial registration number NCT05754983.",
  "authors": [
    {
      "affiliations": [
        "Department of Medical Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China"
      ],
      "name": "Yanlin Li"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China"
      ],
      "name": "Xiaohui Jia"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China"
      ],
      "name": "Mengjie Liu"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China"
      ],
      "name": "Zehui Zhu"
    },
    {
      "affiliations": [
        "Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, China"
      ],
      "name": "Hui Qiao"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Qinghai University Affiliated Hospital, Xining, China"
      ],
      "name": "Jun Jiang"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Fifth People’s Hospital of Qinghai Province, Xining, China"
      ],
      "name": "Miao Li"
    },
    {
      "affiliations": [
        "Department of Oncology, Xi’an International Medical Center Hospital, Xi’an, China"
      ],
      "name": "Weihu Xia"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China"
      ],
      "name": "Longwen Xu"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China"
      ],
      "name": "Enyong Zhang"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China"
      ],
      "name": "Wenjuan Wang"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Norinco General Hospital, Xi’an, China"
      ],
      "name": "Juan Liu"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Shaanxi Provincial Cancer Hospital, Xi’an, China"
      ],
      "name": "Rui Xu"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Qinghai Provincial People’s Hospital, Xining, China"
      ],
      "name": "Yujuan Qi"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China"
      ],
      "name": "Guoqing Jing"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China"
      ],
      "name": "Yixue Bai"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China"
      ],
      "name": "Min Jiao"
    },
    {
      "affiliations": [
        "Department of Clinical Science, University of Liverpool, Liverpool, UK"
      ],
      "name": "Senyi Hu"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Xi'an No.3 Hospital, Xi'an, China"
      ],
      "name": "Zhiyan Liu"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China",
        "Phase I Clinical Trial Ward, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China",
        "Bioinspired Engineering and Biomechanics Center, Xi'an Jiaotong University, Xi'an, China",
        "Key Laboratory of Surgical Critical Care and Life Support, Xi'an Jiaotong University, Xi'an, China"
      ],
      "name": "Hui Guo"
    },
    {
      "affiliations": [
        "Phase I Clinical Trial Ward, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China"
      ],
      "name": "Lili Jiang"
    }
  ],
  "title": "Impact of NSAID type, initiation timing, duration and dose on clinical outcomes of immunotherapy in NSCLC: a multicenter two-cohort study",
  "uid": "b3e67939-0680-5c7c-8242-ed1f4388b3bf"
}