PI-105 - POPULATION PHARMACOKINETICS OF FS-1502, AN HER2 ANTIBODY-DRUG CONJUGATE (ADC), IN PATIENTS WITH HER2 EXPRESSED ADVANCED MALIGNANT SOLID TUMORS.

Y. Sun¹, C. Li², L. Diao¹; ¹Fosun Pharma, Shanghai, China, ²Fosun Pharma, Cary, NC, USA.

Background: FS-1502 is an HER2 ADC bearing a novel cleavable linker and payload of monomethyl auristatin F (MMAF) and currently being investigated in patients with HER2 expressed advanced solid tumors. A population pharmacokinetic (PPK) model was developed to characterize the PK of FS-1502 and MMAF.

Methods: The PPK model was built with PK data from 74 Chinese patients receiving 0.1–3.0 mg/kg FS-1502 every 3 and 4 weeks from a Phase Ia trial. The structural model consisted of compartment models for intact ADC and MMAF. The input rate of MMAF was modeled by a drug antibody ratio (DAR) term that declined exponentially over time1. Covariates including age, body weight (BW), albumin, liver enzymes, creatinine clearance, tumor burden, HER2, ECOG, metastasis status, anti-drug antibody, etc., were tested.

Results: PK is nonlinear below 1 mg/kg. The nonlinear and time dependent FS-1502 PK were described by a two-compartment model with linear and time dependent Michaelis-Menten (MM) eliminations. Following RP2D 2.3 mg/kg q3w, 17% decrease in CL was predicted at Cycle 3 over Cycle 1. The population predicted parameters are: linear clearance (CLl) 0.0184 L/h, central volume (V1) 3.33 L, peripheral volume (V2) 0.751 L, inter-compartmental clearance (Q) 0.0568 L/h, maximum MM elimination rate (Vmax) 211 ug/h, MM constant (Km) 3670 ug/L, and first-order rate for decrease of Vmax (Kdes) 0.00022 1/h. Inter-individual variability were modest. Final model included BW on CLl, and albumin on V1 with exponents of 0.863 and -3.67. BW and albumin had minimum impact on steady-state AUC and Cmax of FS-1502 but a significant effect on Ctrough. MMAF PK was described by one-compartment model with first-order elimination.

Conclusion: The PPK model of FS-1502 described the PK data well and supports weight-based dosing of FS-1502.

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