Early pembrolizumab plasma levels as a prognostic biomarker in real-world NSCLC patients.

BACKGROUND: Pembrolizumab is a standard first-line treatment for metastatic non-small cell lung cancer (NSCLC). Although approved dosing regimens achieve near-maximal PD-1 receptor occupancy in clinical trials, variability in pembrolizumab exposure in real-world scenario may influence outcomes. We evaluated the prognostic relevance of pembrolizumab plasma levels after the first treatment cycle (C1 trough) in metastatic NSCLC clinical practice.

METHODS: We analyzed 133 patients with metastatic NSCLC from 12 centers in Spain, who received first-line pembrolizumab as monotherapy (IO) or combined with chemotherapy (ChIO). Plasma C1 trough concentrations were measured by ELISA (High-Low cutoff; 10 µg/mL). High tumor burden was defined by SLD ≥ 5 cm, T‑parameter ≥ 3, or ≥ 4 metastatic sites. PBMCs from 82 patients were analyzed by flow cytometry to assess free PD-1 on T cells.

RESULTS: Low pembrolizumab C1 trough levels were significantly associated with inferior outcomes (PFS HR 2.08, p < 0.001; OS HR 3.06, p < 0.001). Female sex and fixed dosing were linked to higher exposure, largely explained by lower body weight and higher relative dose per kilogram. High tumor burden (p = 0.006) and low albumin (r = 0.29, p = 0.038) were associated to lower levels of pembrolizumab. Pembrolizumab C1 trough levels negatively correlated with PD-1 availability on CD4+ (r = -0.422, p < 0.001) and CD8+ T cells (r = -0.250, p = 0.023). In multivariate analysis, pembrolizumab C1 trough, ECOG status, and PD-L1 tumor proportion score positivity independently predicted survival.

CONCLUSIONS: Low pembrolizumab exposure after the first cycle is associated with poor survival and incomplete PD-1 blockade. C1 trough assessment may serve as a prognostic biomarker to guide individualized dosing and optimize outcomes.