PKPD-Modeling of Standard Uptake Value (SUV) in Gastro-Intestinal Stromal Tumors (GIST) patients treated with sunitinib
Emilie Schindler (1), Paul Westwood (1), Michael Amantea (2), Emma K. Hansson (1), Peter A. Milligan (2), Mats O. Karlsson (1), Lena E. Friberg (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; (2) Pfizer Global Research and Development
Objectives: A change in tumor glucose utilization, as determined by the maximal standardized uptake value (SUV), may be a significantly better predictor of early tumor response and clinical outcome compared with conventional tumor size measurements (RECIST) in patients treated with the multi-targeted tyrosine kinase inhibitor sunitinib [1]. The aim of this analysis was to characterize the time-course of SUV and investigate potential longitudinal relationships between sunitinib dose, AUC, biomarkers (VEGF, sVEGFR-2 and sKIT), and SUV in patients with gastro-intestinal stromal tumors (GIST).
Methods: SUV measurements ([18F]-fluorodeoxyglucose uptake determined by PET corrected for body weight, n=158) were available from 47 patients followed for a median time of 14 weeks of treatment with three different oral doses of sunitinib under three different treatment schedules. Dose, daily AUC and relative change in the three biomarkers from baseline over time, predicted by earlier developed models [2], were evaluated as drivers for the change in SUV in a longitudinal tumor growth inhibition model previously applied for tumor size (SLD, sum of longest diameters) [3].
Results: The longitudinal SUV data were well characterized by the tumor growth inhibition model with a fast initial decline in SUV, followed by a more static phase. Daily AUC was found to be the best predictor for SUV response and the model showed no additional improvement when also including model predicted sKIT, VEGF or sVEGFR-2 time courses as predictors.
Conclusions: The present results indicate that the daily AUC can potentially be used to predict early metabolic tumor response, as determined by SUV. In a previous analysis [3], sKIT was shown to be the best predictor of tumor size [4]. However, because of the rapid SUV response, it is not surprising that sKIT, with a turnover time of 14 weeks, didn't characterize the SUV data. It remains to be shown if SUV response is a better predictor of survival than response in SLD or angiogenic biomarkers.
Acknowledgements: This research was performed as part of the DDMoRe project.
References:
[1] Prior JO et al. J Clin Oncol (2009) 27 : 439-45
[2] Hansson E. et al. PAGE 18 (2009) Abstr 1521 [www.page-meeting.org/ ?abstract=1521]
[3] Claret et al. J Clin Oncol (2009) 27 : 4103-4108
[4] Hansson E. et al. PAGE 20 (2011) Abstr 2183 [www.page-meeting.org/?abstract=2183]
