Pharmacokinetic and Exposure-Response Modeling Support Body Surface Area-Based Dosing of Farletuzumab Ecteribulin in Patients with Solid Tumors

Objectives: Farletuzumab ecteribulin (FZEC) is an ADC consisting of farletuzumab (an antibody that binds to folate receptor α) paired with eribulin mesylate (a microtubule dynamics inhibitor) conjugated via a cathepsin B-cleavable linker. A phase 1 dose-escalation and expansion study (Study 101) in patients with advanced solid tumors evaluated FZEC doses ranging from 0.3 mg/kg to 1.2 mg/kg IV every 3 weeks (Q3W) (Shimizu 2021). The dose expansion part of Study 101, which evaluated 0.9 mg/kg and 1.2 mg/kg Q3W, showed promising antitumor activity in patients with platinum-resistant ovarian cancer (PROC); however, pneumonitis/interstitial lung disease (ILD) was identified as a key risk and an observed adverse reaction for FZEC. In this work, pharmacokinetic (PK) and exposure-response (E-R) analyses for efficacy and safety were conducted and quantitatively compared to select a dose to minimize ILD while maintaining clinical benefit. Data in this work were previously presented in part at the 2022 ASCO Annual Meeting. Methods: Serum FZEC PK was characterized using a population PK approach, and serum FZEC exposure was considered for the E-R analyses. Exposure was predicted for different dosing scenarios: flat dosing, bodyweight (BW)-based dosing with or without a dose cap, adjusted ideal BW dosing, and body surface area (BSA)-based dosing. E-R analyses for efficacy (ie, ORR) and safety (ie, ILD) were conducted using logistic-regression analysis. Simulations (N=1000) were performed using a BW distribution from a previous phase 3 farletuzumab study in PROC (Vergote 2016) to predict the probability of ORR and ILD in patients treated with FZEC. Results: FZEC exposures were dose proportional, and the PK was described by a 2-compartment model with zero-order IV infusion and first-order elimination. Body weight was associated with higher FZEC exposure. Using BW-based dosing, FZEC AUC was higher in patients with tumor response or stable disease versus patients with progressive disease; and higher in patients with ILD. Dosing simulations showed BSA-based dosing (33 mg/m2 Q3W which results in equal AUC of 0.9 mg/kg Q3W dosing) yielded similar tumor responses to BW-based dosing (0.9 mg/kg) and decreased ILD risk. This study showed BW-based dosing resulted in higher risk of ILD events for patients with a high BW versus low BW, whereas BSA-based dosing is predicted to reduce this risk while maintaining clinical efficacy. Conclusions: Based on this assessment, BSA-based dosing is predicted to lower the exposure-dependent ILD risk in patients with higher BW while efficacy signal is maintained. BSA-based dosing is under evaluation in ongoing clinical trials.