PII-088 - POPULATION PHARMACOKINETICS AND EXPOSURE-RESPONSE ANALYSIS FOR THE BIFUNCTIONAL PD-L1/TGF-βRII FUSION PROTEIN RETLIRAFUSP ALPHA TO SUPPORT A FLAT DOSE AS AN ALTERNATIVE REGIMEN

P. Chen¹, Y. Zhang², X. Gu¹, N. DJEBLI³; ¹Jiangsu Hengrui Pharmaceuticals, Shanghai, China, Jiangsu Hengrui Pharmaceuticals - Shanghai, China, ²Jiangsu Hengrui Pharmaceuticals, Shanghai, China, Jiangsu Hengrui Pharmaceuticals - Shanghai,, China, ³Luzsana / Hengrui, Luzsana Biotechnology (subsidiary of Jiangsu Hengrui Pharmaceutical), Basel, Switzerland.

Background: Retlirafusp alfa, a novel bifunctional PD-L1/TGF-βRII fusion protein, demonstrated a significantly longer overall survival (OS) for patients with gastric/gastroesophageal junction carcinoma (GC/GEJ) when combined with chemotherapy . The population pharmacokinetic (PopPK) modeling and explored exposure–response (ER) relationship are reported with a comparison of exposures from body weight (BW)-based versus flat dosing regimens.

Methods: Data from 4 studies, including 750 patients receiving either body weight‐based regimen or flat dosing, were used for PopPK modeling using a non-linear mixed-effects approach. The ER was performed using logistic regression (objective response rate [ORR] and safety endpoints), Kaplan-Meier together and time-to-event methodology (overall survival [OS] and progression-free survival [PFS]).

Results: A two‐compartment model with linear time-varying clearance (CL) was selected. The retained covariates on CL were: time-varying ALB and tumor size, baseline AST, BW, creatinine clearance, neutrophil count, and time-varying ADA titer . None of those translated into a clinically relevant impact. Moreover, the CL decay was higher in patients who responded to treatment than in non-responders. Exposure to Retlirafusp alfa (first administration) was not significantly associated with ORR or OS. The Cavg0-21d after the first dose was significantly associated to PFS. On top of drug exposure, the covariate analysis indicated that higher BW was associated with longer PFS, even though the exposures and BW were correlated (due to BW-adjusted dosing). There was no statistical relationship identified between Retlirafusp alfa exposures and any of the safety endpoints (G3+ AEs, Severe AEs, irAEs, imAEs and AEs of special interest). Moreover, similar distributions of exposures between flat dose regimen and weight-based dosing regimen were predicted.

Conclusion: The present PopPK/ER analysis did not identify any significant relationship between exposure and ORR, OS or any safety endpoint, while a significant relationship was observed between exposures and PFS, with BW as a covariate. Exposure-ORR/OS suggests that efficacy reached a plateau in the explored exposure range in the combination therapy for patients with GC/GEJ. Moreover, the flat dose seems to be a reasonable dosing alternative for Retlirafusp alfa.