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.