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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