Exposure–Response Modeling and Simulation of Progression‐Free Survival and Adverse Events of Sorafenib Treatment in Patients With Advanced Thyroid Cancer

• DOI: 10.1111/cts.12634
• Publication Date: 2019-03-28T13:42:54Z
• Authors: Joachim Grevel; Garrit Jentsch; Rupert Austin; Nicolaas H. Prins; John Lettieri; David Mitchell; Funan Huang; Marcia S. Brose; Martin Schlumberger; Gerold Meinhardt; Carol E. A. Peña; Bart A. Ploeger
• Keywords: Tolerability

Sorafenib is an oral multikinase inhibitor approved for the treatment of differentiated thyroid carcinoma (DTC), renal cell carcinoma, and hepatocellular carcinoma. In phase III DECISION trial in patients with DTC, sorafenib exposure incidence some adverse events (AEs) were higher than previous trials; therefore, we analyzed exposure-response relationships, including progression-free survival (PFS) selected AEs DTC. A novel, stratified prediction-corrected visual predictive check (pc-VPC) was developed to show robustness relationships. Time-to-event simulations confirmed benefit recommended dosing schedule 800 mg/day: initial doses mg/day associated highest PFS, whereas lower (600 or 400 mg/day) improved tolerability but reduced PFS. simulated dose-reduction strategy two cycles followed by dose reductions seemed likely maintain efficacy while possibly mitigating (e.g., diarrhea hand-foot skin reactions).