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.

Aims. The exposure-response relationship of bevacizumab may be confounded by various factors, i.e. baseline characteristics, time-dependent target engagement and recursive relationships between exposure and response. This work aimed at investigating the exposure-response relationships of bevacizumab in mCRC patients while mitigating potential sources of bias. Methods. Bevacizumab pharmacokinetics was described using target-mediated drug disposition (TMDD) modeling. The relationships between target kinetics, and progression-free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both potential biases due to prognostic-driven and response-driven of the concentration-effect relationship were mitigated. These models were used to evaluate the effect of increased antigen target levels and clearance, as well as intensified dosing regimen, on survival. Results. Estimated target-mediated pharmacokinetic parameters in 130 assessed patients were: baseline target levels (R0=8.4 nM), steady-state dissociation constant (KSS=10 nM) and antibody-target complexes elimination constant (kint=0.52 day-1). Distribution of R0 was significantly associated with an increased baseline CEA and circulating VEGF levels, and the presence of extra-hepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increased R0 or CL values led to decreased bevacizumab unbound concentrations, increased R levels, and shortened PFS and OS, whereas increasing bevacizumab dose led to decreased R and longer survival. Conclusion. This study is the first to show the relationship between bevacizumab concentrations, target involvement and clinical efficacy by mitigating potential sources of bias. Most of target amount may be tumoral in mCRC. A more in-depth description of this relationship should be made in future studies.