Abstract 5422: Exploring the feasibility of longer dosing intervals in a population with relapsed/refractory classic Hodgkin's lymphoma based on population pharmacokinetics modeling analysis
Authors: Chen Benchao , Dong Yongcheng , Xiao Jin , Wang Max , Xia Dennis , Xia Michelle , Li Baiyong 
Published: June 2022

Abstract
Background: Penpulimab is a humanized IgG1 monoclonal antibody that blocks PD-1 binding to PD-L1. During the dose-escalation phase, no dose-limiting toxicity event was observed, and the maximum administered dose(MAD) was 10 mg/kg Q2W. The RO% of all dose groups (1.0, 3.0 and 10.0 mg/kg Q2W) reached 80%~100%. Penpulimab was administered in a fixed dosing regimen (200 mg Q2W) in a phase II study (AK105-201) demonstrating efficacy and safety in R/R cHL patients. Longer dosing intervals may offer greater flexibility and convenience to both patients and healthcare professionals. So we explored the feasibility of a longer dosing regimen (200 mg Q3W and 400 mg Q6W).
Methods: A penpulimab population PK (PPK) model was established based on PK data from a total of 332 subjects from six clinical studies. The following PK parameters were determined and used in subsequent analyses: Cmin,ss, Cmax,ss, AUCss. Exposure-response (ER) evaluation was conducted using univariate logistic regression. The efficacy endpoints included complete response (CR), overall response rate (ORR) and disease control rate (DCR) in AK105-201 study. Safety endpoints included grade ≥ 3 treatment-related adverse event (TRAE), grade ≥ 3 immune-related adverse events (irAE), or AE leading to suspension in all the six clinical studies. PK simulation was conducted using the PPK model among different regimens (200 mg Q3W and 400 mg Q6W vs. 200 mg Q2w regimen), and in comparison with Cmin,ss of 3 μg/mL (6 x concentration for 80% RO in vitro).
Result: The final PPK structural model for penpulimab was a two-compartment model with first-order elimination. Body weight correlated with volume of distribution but the effect is not considered clinically significant, supporting fixed dose in subsequent studies. Relatively flat ER relationships were observed betwedn the efficacy endpoints (CR, ORR and DCR) and PK exposure (simulated Cmax,ss, Cmin,ss, AUCss) in R/R cHL patients. No apparent correlation was observed between PK exposure and safety response in patients with different types of cancer. The PK simulation showed that the steady-state concentration-time curves for 200 mg Q2W or 3 mg/kg Q2W administration were generally consistent. Compared to the 200 mg Q2W regimen, the mean Cmin,ss of 200 mg Q3W and 400 mg Q6W regimens were approximately 36.5% and 55.5% lower, respectively. But in both cases, the Cmin,ss of 97.5% of the population were higher than 3 μg/mL, suggesting sufficient receptor occupancy. The Cmax,ss and AUCss under the 400 mg Q6W regimen were lower than MAD(10 mg/kg Q2W).
Conclusions: The conducted analyses support fixed dosing and showed relatively flat exposure-efficacy and exposure-safety relationships. PK simulations suggest that both 200 mg Q3W or 400 mg Q6w could offer similar efficacy and safety as compared to 200 mg Q2W, while allow greater flexibility and convenience.
Citation Format: Benchao Chen, Yongcheng Dong, Jin Xiao, Max Wang, Dennis Xia, Michelle Xia, Baiyong Li. Exploring the feasibility of longer dosing intervals in a population with relapsed/refractory classic Hodgkin's lymphoma based on population pharmacokinetics modeling analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5422.