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

Abstract

The first-in-human, Phase 1 Study 101 showed antitumor activity and a tolerable safety profile of farletuzumab ecteribulin in Japanese patients with platinum-resistant ovarian and non-small cell lung cancer. A pharmacometric assessment evaluated farletuzumab ecteribulin pharmacokinetics and exposure-response (E-R) relationships for efficacy and safety to support dose optimization. Patients received 0.3-1.2 mg/kg of farletuzumab ecteribulin intravenously every 3 weeks. A pharmacokinetics (PK) model was developed and used for E-R analyses. Efficacy was assessed via tumor response and safety via known treatment-emergent adverse events (TEAEs) of farletuzumab ecteribulin, particularly pneumonitis/interstitial lung disease (ILD). Dosing scenarios were simulated to identify dosing that maximizes the probability of an objective response while minimizing the risk of ILD. The farletuzumab ecteribulin PK dataset included 1261 observations from 82 patients. The final model included an estimated population mean value for farletuzumab ecteribulin clearance of 0.0162 L/h. Body surface area (BSA) was a significant PK covariate and was included in the model. Body weight (BW) was associated with higher farletuzumab ecteribulin exposure. Using BW-based dosing, farletuzumab ecteribulin AUC (area under the serum concentration-time curve) was higher in patients with tumor response or stable disease versus patients with progressive disease and higher in patients with ILD and other TEAEs. Dosing simulations showed that BSA-based dosing (33 mg/m²) yielded similar tumor responses to BW-based dosing (0.9 mg/kg) and decreased ILD rates. This study showed that BW-based dosing resulted in higher risks 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.