(T-093) Adjusted Ideal Body Weight Dosing Reduces Pharmacokinetic Variability of the PD-L1 Targeted Antibody-Drug Conjugate PDL1V (PF-08046054)

Enahoro Iboi – Pharmacometrics and System Pharmacology, Pfizer Inc., Bothell, Washington; Yen Lin Chia – Pharmacometrics and System Pharmacology, Pfizer Inc., South San Francisco, California; Faye Zhang – Oncology Clinical Pharmacology, Pfizer Inc., Bothell, Washington; John Harrold – Pharmacometrics and System Pharmacology, Pfizer Inc., South San Francisco, California; Andres Forero-Torres – Early-Stage Clinical Development Oncology, Pfizer Inc., Bothell, Washington; Manisha Lamba – Pharmacometrics and System Pharmacology, Pfizer Inc., Pearl River, New York; Amit Garg – Oncology Clinical Pharmacology, Pfizer Inc., South San Francisco, California; Flavia Storelli – Oncology Clinical Pharmacology, Pfizer Inc., Bothell, Washington

Purpose: PDL1V (PF-08046054) is a novel programmed cell death ligand 1 (PD-L1) directed vedotin antibody-drug conjugate designed to deliver the cytotoxic agent monomethyl auristatin E (MMAE) to tumor cells expressing the PD-L1 cell surface protein. Here, we developed a preliminary population pharmacokinetic (PK) model to characterize the PK of PDL1V antibody-conjugated MMAE (acMMAE) and evaluate the impact of baseline demographics, laboratory results and patient disease characteristics on PDL1V acMMAE PK. The impact of dosing based on adjusted ideal body weight (AiBW) versus total body weight on PK variability was also explored.

Methods: Preliminary data from a total of 162 patients with 3751 acMMAE plasma concentrations from phase 1 study (NCT05208762) (monotherapy dose escalation, optimization and expansion cohorts) were used to characterize the PK of acMMAE via nonlinear mixed effects modeling using NONMEM version 7.4.3. All patients were dosed based on their AiBW; 145 patients received 0.5-1.75 mg/kg AiBW on Days 1 and 8 every 3 weeks and 17 patients received 1.75 – 2.0 mg/kg AiBW on Days 1 and 15 every 4 weeks. The primary tumor types were head and neck squamous cell cancer (53.1%) and non-small cell lung cancer (42.6%); other tumor types were esophageal squamous cell carcinoma (1.2%) and triple negative breast cancer (3.1%). The impact of demographics, laboratory values, and patient disease characteristics on acMMAE PK were evaluated by visual examination followed, as applicable, by forward selection-backward elimination.

Results: PDL1V acMMAE plasma concentrations were well described by a 2-compartment model with first-order elimination. Among the covariates that were evaluated, increased AiBW was associated with higher acMMAE clearance (CL) and higher central volume of distribution. The AiBW exponent on acMMAE CL was 0.91 (i.e., CL increases almost dose proportionally with AiBW). Baseline tumor size and higher ECOG performance status were also associated with increased acMMAE CL with statistically significance but minimal effect. PK simulations showed that, in comparison with total body weight dosing, AiBW-dosing reduced overall variability in acMMAE exposure, lowered acMMAE exposure in high body weight patients and increased exposure for low body weight patients.

Conclusions: The significant impact of AiBW on PDL1V acMMAE clearance highlights the appropriateness of AiBW-based dosing in reducing PK variability and to mitigate the risk of over-dosing high body weight patients and underdosing lower weight patients and thus has the potential to widen the therapeutic window of PDL1V.

Citations: NA

Keywords: AiBW