Impact of Sequential Ramucirumab Plus Docetaxel After PD ‐1 Inhibitors on Anti‐ PD ‐1 Antibody‐Bound T‐Cell Dynamics and Clinical Outcomes

ABSTRACT Ramucirumab plus docetaxel (RAM+DOC) demonstrates clinical activity after programmed cell death‐1 (PD‐1) inhibitors in advanced non‐small cell lung cancer (NSCLC); however, the underlying mechanisms remain unclear. We aimed to evaluate clinical efficacy and explore immunologic dynamics and benefit‐associated biomarkers. Patients treated with RAM+DOC after PD‐1 inhibitors were enrolled in a multicenter prospective cohort. Anti‐PD‐1 antibody bound (IgG4 + ) T‐cell subsets were measured at baseline (T0) and after 2–3 cycles (T1), reflecting residual anti‐PD‐1 antibody binding on circulating T cells. T1/T0 ratios of immune subsets were calculated to assess dynamics. Landmark analyses at T1 evaluated associations with progression‐free survival (PFS) and overall survival (OS). Prognostic biomarkers were assessed at baseline. Among 27 evaluable patients, the objective response rate was 37.0%, median PFS 5.1 months, and OS 10.4 months. RAM + DOC responders had higher IgG4 + CD8 + T‐cell and lower IgG4 + Treg T1/T0 ratios (both p < 0.001). Higher IgG4 + CD8 + ratios were associated with longer landmark PFS ( p = 0.002) and OS ( p = 0.016) and were inversely correlated with IgG4 + Treg ratios ( p = 0.008). Among the baseline factors, high IgG4 + CD8 + Temra conferred survival benefits (OS, not reached vs. 8.2 months; p = 0.006), and low vascular endothelial growth factor (VEGF)‐C levels were associated with longer OS (not reached vs. 8.5 months, p = 0.044). Both variables remained independent prognostic factors of PFS and OS in multivariable analysis. Our findings suggest that sequential strategy administering RAM+DOC during persistent binding of anti–PD‐1 antibody to T cells may be beneficial. IgG4 + CD8 + Temra and VEGF‐C levels at RAM+DOC initiation may serve as biomarkers of survival benefit. Trial Registration: UMIN‐Clinical Trials Registry (UMIN000050478)