Model-based ‘learn and confirm approach’ demonstrates similarity of cemiplimab exposure in pediatric and adult populations
Authors: Jayachandran Priya , Veyrat-Follet Christine , Nguyen Jenny-Hoa , Harnisch Lutz , Masinde Sheila , Papachristos Apostolos , Paccaly Anne , Visich Jennifer , Davis John , Chittenden Jason 
Published: February 2025

Objectives: Cemiplimab (Libtayo) is an immune checkpoint inhibitor approved in adults for treatment of cutaneous squamous cell carcinoma, basal cell carcinoma, and non-small cell lung cancer [1]. Cemiplimab was studied in pediatric populations with recurrent or refractory solid or CNS tumors, newly diagnosed diffuse intrinsic pontine glioma or high-grade glioma (HGG) or recurrent HGG at weight-based doses approximating adult exposure at the approved effective dose, 350mg IV Q3W. This analysis aimed to develop a population PK model of cemiplimab using pediatric and adult data and to determine model predicted exposure metrics in simulated pediatric subjects at 3 and 4.5mg/kg IV Q2W compared to adult subjects at 350mg IV Q3W.Methods: Adult data (N&#3f1227) from Phase 1 (NCT02383212), 2 (NCT02760498, NCT03132636) and 3 (NCT03088540) studies were pooled with pediatric data (N&#3f55) from a Phase 1/2 (NCT03690869) study. A 2‐compartment linear PK model with time-varying clearance (CL) parameterized by a sigmoid Emax function built using adult data was updated with pediatric data (NONMEM v7.5). Allometric exponents fixed to 0.75 and 1 for clearance and volume parameters, respectively, accounted for body size differences. Baseline and time-varying covariates were assessed by stepwise covariate modeling. Two pediatric age groups were simulated: 0 to < 12 years old split by weight brackets ( < 25kg, ≥25kg) receiving 3 and 4.5mg/kg IV Q2W, and 12 to < 18 years old receiving 3mg/kg IV Q2W. Simulations with the final model (N&#3f300/group) assumed similar covariate distributions for adult and pediatric subjects as observed in the adult and pediatric studies, respectively. Simulated exposure metrics after first dose and at steady-state for pediatrics were compared with adults receiving 350 mg IV Q3W.Results: The final PK model with fixed allometric exponents described adult and pediatric data well. VPCs showed good predictive performance over the range of body weights. The covariate analysis identified baseline albumin and ALT, sex, tumor type, and time-varying albumin and weight on CL and baseline albumin on central volume as statistically significant covariates. Only baseline weight and albumin had a significant impact on the geometric mean ratios of post-hoc model predictions of AUC0−6wk. The predicted median pediatric Ctrough,ss for all groups did not fall below the observed adult target Ctrough,ss (58.7mg/L [2]). Compared to the observed adult target Cmax,ss (166mg/L [2]), the predicted median pediatric Cmax,ss was similar for subjects dosed at 3mg/kg IV Q2W and higher for subjects dosed at 4.5mg/kg IV Q2W, but within acceptable safety limits.Conclusions: The model-based analysis confirmed matching pediatric and adult exposure for the pediatric dosing regimens. Overall, predicted exposure distributions overlapped between age and weight groups for all pediatric subjects, and achieved exposures in the range previously observed for adults.Citations: [1] Regeneron Pharmaceuticals, Inc. LIBTAYO® [cemiplimab-rwlc] injection full US prescribing information. Available from https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761097s007lbl.pdf. Accessed May 14, 2024[2] Paccaly, A.J., Migden, M.R., Papadopoulos, K.P. et al. Fixed Dose of Cemiplimab in Patients with Advanced Malignancies Based on Population Pharmacokinetic Analysis. Adv Ther 38, 2365–2378 (2021). https://doi.org/10.1007/s12325-021-01638-5