Model‐informed dose selection for an investigational human epidermal growth factor receptor 2 antibody–drug conjugate FS‐1502 in patients with human epidermal growth factor receptor 2‐expressing advanced malignant solid tumours

Aims The dose‐escalation phase (phase Ia study) of a novel human epidermal growth factor receptor 2 (HER2) antibody–drug conjugate (ADC) FS‐1502 included a dose range from 0.1 to 3.5 mg/kg in HER2‐expressing advanced malignant solid tumours. However, the defined maximum tolerated dose was not reached. This model‐informed approach integrated population pharmacokinetic (PopPK) modelling and exposure–response (E‐R) analysis to facilitate dose selection for phase II. Methods The PopPK model was constructed using PK data from 109 Chinese patients who received doses of 0.1–3.5 mg/kg FS‐1502 every 3 (Q3W) or 4 weeks during a phase I dose‐escalation and dose expansion trial. The structural model consisted of compartment models for FS‐1502 and unconjugated monomethyl auristatin F. E‐R was explored for the percentage change in tumour size, overall response rate and treatment‐related adverse events. Results A semi‐mechanistic 2‐analyte PopPK model was developed. The FS‐1502 PK data were best described by a 2‐compartment PK model with parallel linear and nonlinear Michaelis–Menten eliminations. The PK of unconjugated monomethyl auristatin F was described by a 2‐compartment model with first‐order elimination. E‐R analysis supported the clinically meaningful efficacy of FS‐1502 at 2.3 mg/kg and above. However, 2.3 mg/kg Q3W was considered to have a better benefit–risk balance due to a lower incidence of safety events without a significant reduction in efficacy compared to 3.0 mg/kg Q3W. Conclusion This PopPK and E‐R analysis guided the recommended phase II dose selection of 2.3 mg/kg Q3W and supported body weight‐based dosing for an investigational HER2 ADC FS‐1502.