Introduction. Pembrolizumab is an anti-programmed-death 1 (PD-1) monoclonal antibody used in non-small cell lung cancer (NSCLC) for which dose-concentration-response relationship remains unclear. Our aim was to assess this relationship using joint population target-mediated drug disposition (TMDD) and parametric survival modeling. Methods. This prospective observational monocentric study (RICEPS, NCT04804137) included 19 NSCLC patients who received 200 mg pembrolizumab infusions every 3 weeks. Blood samples were collected at each visit before infusion. Pembrolizumab pharmacokinetics and hazard function for progression were described using one compartment TMDD Wagner model and a log-logistic model, respectively. The association of body surface area (BSA), baseline white blood cell count (WBC) and programmed-Death Ligand 1 tumor expression ratio (PDL1R) with pharmacokinetic parameters and progression-free survival PFS was assessed. Results. Pembrolizumab volume of distribution (V=5.3 L/m2) increased with BSA (p=0.025) while estimated baseline target level (R0=0.22 nM.G-1.L) increased with WBC (p=0.033). Other parameters of the model were clearance (CL=0.19 L/day), target elimination rate (kdeg=0.17 day-1) and pembrolizumab-target steady-state dissociation constant (KSS=4.9 nM). Hazard to progress was halved for concentration and target occupancy of C50=8 mg/L and R50=0.10 nM, respectively. Discussion. This study is the first that investigated the relationship between pembrolizumab pharmacokinetics, target occupancy and PFS. We observed target-mediated nonlinear pharmacokinetics and an association between increased pembrolizumab concentrations and improved clinical efficacy. These results do not support the use of flat dose, but rather suggest a benefit of individual dosing optimization.