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

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).