Modeling Sunitinib and Biomarker Response as potential Predictors of Time to Progression in Patients with Metastatic Colorectal Cancer
Friederike Kanefendt (1), Andreas Lindauer (1), Martina Kinzig (2), Max Scheulen (3), Dirk Strumberg (4), Richard Fischer (5), Fritz Sörgel (2), Klaus Mross (6), Ulrich Jaehde(1)
(1)Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Germany; (2)IBMP - Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany; (3)University Hospital of Essen, Department of Internal Medicine and Tumor Research, Germany; (4)Marienhospital Herne, Department of Hematology and Oncology, Germany; (5)University Hospital of Freiburg, Department of Gastroenterology, Germany; (6)Tumor Biology Center Freiburg, Department of Medical Oncology, Germany
Objectives: Sunitinib is a multi-tyrosine kinase inhibitor inhibiting angiogenesis which is essential for tumor growth. The concentrations of several circulating proteins are influenced by sunitinib and may serve as biomarkers in PK/PD models to predict tumor response. The aim of this investigation was the development of PK/PD models to describe the anti-angiogenic response to sunitinib and to identify potential predictors for the time to progression (TTP) in patients with metastatic colorectal cancer (mCRC).
Methods: 21 patients receiving a daily dose of 37.5 mg sunitinib on a 4-weeks on/2-weeks off treatment schedule in addition to FOLFIRI participated in this study. Blood samples were drawn at baseline and every two weeks for two therapy cycles. Sunitinib and the active metabolite SU12662 (the sum is referred to as ‘active drug') concentrations were measured using LS-MS/MS. Both circulating biomarkers, sVEGFR-2 and sVEGFR-3, were determined by validated immunoassays. Furthermore, TTP defined as day from first study medication to first assessment of progression was selected as clinical endpoint. If no information was available data were censored to the last date the patient was confirmed to be progression-free. A sequential PK/PD analysis was performed using NONMEM (version 7.1.2). Potential predictors for TTP were analyzed using Cox regression and a model-based approach.
Results: Biomarker concentration-time courses could be well described by an indirect response model. Minimum concentrations relative to baseline were estimated as 0.63 and 0.59 for sVEGFR-2 and sVEGFR-3, respectively. Concentrations of both biomarkers were highly correlated, however did not predict TTP in this data set. Higher exposure to unbound active drug was instead identified as positive predictor for TTP (HR: 0.49 (95% CI: 0.27-0.88), p=0.013).
Conclusions: The concentration-time profile of both active drug and biomarkers could be well described by the PK/PD model. The extent of biomarker response was comparable with healthy volunteers [1] but did not predict tumor response in patients with mCRC. In contrast, TTP was correlated to active drug pharmacokinetics . However, more patients have to be studied to confirm this relationship.
References:
[1] Lindauer A. et al. Pharmacokinetic/pharmacodynamic modeling of biomarker response to sunitinib in healthy volunteers. Clin Pharmacol Ther 2010; 87:601-8.
