Fixed Dose of Cemiplimab in Patients with Advanced Malignancies Based on Population Pharmacokinetic Analysis

Anne J Paccaly, Michael R Migden, Kyriakos P Papadopoulos, Feng Yang, John D Davis, Ronda K Rippley, Israel Lowy, Matthew G Fury, Elizabeth Stankevich, Danny Rischin, Anne J Paccaly, Michael R Migden, Kyriakos P Papadopoulos, Feng Yang, John D Davis, Ronda K Rippley, Israel Lowy, Matthew G Fury, Elizabeth Stankevich, Danny Rischin

Abstract

Introduction: This study outlined cemiplimab intravenous (IV) dosing strategy to move from body weight (BW)-based 3 mg/kg every-2-week (Q2W) dosing in first-in-human study (study 1423; NCT02383212) to fixed 350 mg every-3-week (Q3W) dosing, utilizing population pharmacokinetics (PopPK) modeling and simulations, and supported by a limited dataset from a phase 2 study (study 1540; NCT02760498).

Methods: Cemiplimab concentration data from a total of 505 patients were pooled from study 1423 in advanced malignancies and study 1540 in advanced cutaneous squamous cell carcinoma (CSCC). All patients received weight-based cemiplimab dose (1, 3, 10 mg/kg Q2W or 3 mg/kg Q3W) except 4% who received 200 mg Q2W. A linear two-compartment PopPK model incorporating covariates that improved goodness-of-fit statistics was developed to compare cemiplimab exposure at 350 mg Q3W versus 3 mg/kg Q2W. Upon availability, observed cemiplimab concentration at 350 mg Q3W in study 1540 was then compared with the simulated values.

Results: Post hoc estimates of cemiplimab exposure and variability (505 patients; weight range 30.9-156 kg; median 76.1 kg) at steady state were found to be similar at 350 mg Q3W and 3 mg/kg Q2W. Effect of BW on cemiplimab exposure was described by exposure versus BW plots and at extreme BW. Overlay of individual observed cemiplimab concentrations in 51 patients with metastatic CSCC on simulated concentration-time profiles in 2000 patients at 350 mg Q3W confirmed cemiplimab exposure similarity and demonstrated the robustness of dose optimization based on PopPK modeling and simulations.

Conclusions: Cemiplimab 350 mg Q3W is being further investigated in multiple indications.

Keywords: Advanced malignancies; Cemiplimab; Cutaneous squamous cell carcinoma; Fixed dosing; Population pharmacokinetics; Weight-based dosing.

Figures

Fig. 1
Fig. 1
Simulated cemiplimab concentration–time profiles in patients with advanced malignancies (n = 2000). Plots show the median (black line) and 95% CI (gray area) of simulated cemiplimab concentration–time profiles from 2000 patients with advanced malignancies. CI confidence interval, Q2W every 2 weeks, Q3W every 3 weeks
Fig. 2
Fig. 2
Distribution of post hoc cemiplimab AUC6wk,ss estimates in patients with advanced malignancies (n = 505). Plot shows the median (dashed line) and density (shaded area) of cemiplimab AUC6wk,ss distributions. AUC6wk,ss area under cemiplimab concentration–time curve over 6 weeks at steady state, IV intravenous, Q2W every 2 weeks, Q3W every 3 weeks
Fig. 3
Fig. 3
Post hoc cemiplimab exposure estimates by baseline body weight (n = 505). AUC6wk area under cemiplimab concentration–time curve over 6 weeks, Ctrough,ss minimum concentration at steady state, Q2W every 2 weeks, Q3W every 3 weeks
Fig. 4
Fig. 4
Overlay of observed and simulated cemiplimab concentration–time profiles at 350 mg Q3W. Plot shows the median (black line) and 95% CI (gray area) of simulated cemiplimab concentration–time profiles in 2000 patients with advanced malignancies overlaid with observed data (dots) from patients with advanced CSCC in study 1540. Only individual PK data from patients who were compliant with the cemiplimab 350 mg Q3W dosing regimen are shown. Data from 51 out of 53 patients in study 1540 group 3 are presented in this figure; data from 2 patients who had received a lower first dose of cemiplimab (216 mg and 240 mg, respectively) were excluded. CI confidence interval, CSCC cutaneous squamous cell carcinoma, PK pharmacokinetics, Q3W every 3 weeks.

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Source: PubMed

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