{
  "abstract": "Background Immune-checkpoint-inhibitor (ICI) regimens have become standard-of-care (SOC) for first-line NSCLC. However, >60% patients develop ‘acquired resistance’ related to T-cell exhaustion and antigen-presenting-cell or APC pathway mutations, 1 which constitutes a severe unmet medical need with docetaxel remained as SOC. Plinabulin is a first-in-class differentiated tubulin binder in maturing dendritic cell (most potent APC) and T-cell activation.2 In a global phase 3 study (Dublin-3, n=559),3 plinabulin/docetaxel outperformed docetaxel in extending OS (HR 0.82, p=0.0399) and doubling 2- and 3-year survival rates, with additional benefits in PFS/ORR and >80% reduction in G4 neutropenia. Non-squamous patients (n=332) experienced better OS benefits (HR=0.72, p=0.0078).Methods This single-arm phase 2 303 study ( NCT05599789) enrolled 47 patients (30 non-squamous, 17 squamous) after immediate progression on ICI (n=6) or in combination with platinum doublets (n=41). Only patients with secondary resistance (prior ICI ≥6 months PFS) were enrolled. Participants received pembrolizumab 200mg, plinabulin 30mg/m2, and docetaxel 75mg/m2 on Day 1 in 21-day cycles. The primary endpoint was investigator-based ORR per RECIST1.1. The secondary endpoints included PFS/OS/DoR and safety. For immunophenotyping, whole blood was collected prior to drug administration on Cycle-1 Day 0 (C1D0) and Cycle-3 Day 0 (C3D0) and subjected to flow cytometry analysis.Results Median follow-up was 14.3 months at the data cut-off date of 31-Aug-2025 ( table 1). The median age was 67 including 80.9% male and 72.3% with smoking history. Confirmed ORR was 18.2% with 78.3% DCR (PR + SD 4 months). Median PFS (mPFS) was 7.0 months with 7.3-month mDoR. Median OS (mOS) had not been reached with 18-month OS rate of 80.0%. The safety of triplet is consistent with prior study with no new safety signal. Grade 3 TRAEs were reported in 51.1% patients; ≥5% included neutrophil decrease (17.0%), hypertension (12.8%), diarrhea (8.5%) and decreased white-blood-cell counts (6.4%). In 42 patients who completed blood sampling on C1D0 and C3D0, the proportions of CD4+ and CD8+ T cells remained stable (p>0.05) while Ki67+ CD8+ T cells were significantly increased (p=0.004). The frequencies of CD38+ HLA-DR+ CD4+ T cells and CD38+ HLA-DR+ CD8+ T cells were dramatically elevated (p<0.0001).Conclusions Plinabulin/docetaxel/pembrolizumab triplet combination in metastatic NSCLC with secondary resistance to ICI shows clinically meaningful efficacy with manageable side effects. Compared to historical data of docetaxel in similar population (~10% ORR and mPFS 3.7 months), 4 the triplet almost doubled ORR and PFS. Whole blood analysis indicated higher proportions of activated CD4+/CD8+ T-cells post treatment.Trial Registration NCT05599789References Memon D, Schoenfeld AJ, Ye D, et al. Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer. Cancer Cell. 2024;2:P209-224.E9.Lin SH, Subbiah V, Cohen EN, et al. Plinabulin Following Radiation Enhances Dendritic Cell Maturation and Checkpoint Inhibitor Retreatment of Relapsed/Refractory Cancers. Med, 2025; 100752 (online first).Han B, Feinstein T, Shi Y, et al. Plinabulin plus docetaxel versus docetaxel in patients with non-small-cell lung cancer after disease progression on platinum-based regimen (DUBLIN-3): a phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial. Lancet Respir Med. 2024;12:775–786.Ahn MJ, Tanaka K, Paz-Ares L, et al. TROPION-Lung01 Trial Investigators. Datopotamab deruxtecan versus docetaxel for previously treated advanced or metastatic non-small cell lung cancer: the randomized, open-label phase III TROPION-lung01 study. J Clin Oncol. 2025;43:260–272.Ethics Approval The study was approved by the Ethics Committee of Peking Union Medical College Hospital (Ethics Approval Number: I-22PJ575).Consent No sensitive or identifiable information was contained in the abstract.Abstract 1330 Table 1303 Study Phase 2 efficacy summary. A Phase 2 triplet study of plinabulin/docetaxel/pembrolizumab for metastatic NSCLC immediately after progression on immune-checkpoint-inhibitor alone or in combination: efficacy and biomarker analysis",
  "authors": [
    {
      "affiliations": [
        "Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Yan Xu"
    },
    {
      "affiliations": [
        "Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Minjiang Chen"
    },
    {
      "affiliations": [
        "Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Xiaoxing Gao"
    },
    {
      "affiliations": [
        "Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Huiyu Huang"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China"
      ],
      "name": "Yue Chang"
    },
    {
      "affiliations": [
        "Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Xiaoyan Liu"
    },
    {
      "affiliations": [
        "Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Wei Zhong"
    },
    {
      "affiliations": [
        "Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Jing Zhao"
    },
    {
      "affiliations": [
        "Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Ruili Pan"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China",
        "State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China",
        "Tsinghua University Medical College, Beijing, China"
      ],
      "name": "Taisheng Li"
    },
    {
      "affiliations": [
        "Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Mengzhao Wang"
    }
  ],
  "title": "1330 A phase 2 triplet study of plinabulin/docetaxel/pembrolizumab for metastatic NSCLC immediately after progression on immune-checkpoint-inhibitor alone or in combination: Efficacy and biomarker analysis",
  "uid": "907b3624-4c29-5988-9996-306a11207005"
}