Dynamic contrast-enhanced magnetic resonance imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma

作者：Hahn Olwen M; Yang Cheng; Medved Milica; Karczmar Gregory; Kistner Emily; Karrison Theodore; Manchen Elizabeth; Mitchell Myrosia; Ratain Mark J; Stadler Walter M^*

来源：Journal of Clinical Oncology, 2008, 26(28): 4572-4578.

DOI：10.1200/JCO.2007.15.5655

Purpose
Sorafenib is an antiangiogenic agent with activity in renal cancer. We conducted a randomized trial to investigate dynamic contrast magnetic resonance imaging (DCE-MRI) as a pharmacodynamic biomarker.
Patients and Methods
Patients were randomly assigned to placebo or 200 or 400 mg twice per day of sorafenib. DCE-MRI was performed at baseline and 4 weeks. DCE-MRI parameters, area under the contrast concentration versus time curve 90 seconds after contrast injection (IAUC(90)), and volume transfer constant of contrast agent (K-trans) were calculated for a metastatic site selected in a blinded manner. Primary end point was change in K-trans.
Results
Of the 56 assessable patients, 48 underwent two MRIs; 44 MRIs were assessable for study end points. Mean K-trans log ratios were 0.131 (standard deviation [SD], 0.315), -0.148 (SD, 0.382),-0.271 (SD, 0.499) in placebo, 200-and 400-mg cohorts, respectively (P = .0077 for trend) corresponding to changes of = 14%,-14%, and-24%. IAUC(90) log ratios were 0.041 (SD, 0.197), -0.040 (SD, 0.132), -0.356 (SD, 0.411), respectively (P = .0003 for trend), corresponding to changes of + 4%, -4%, and -30%. Using a log-rank test, IAUC(90) and K-trans changes were not associated with progression-free survival (PFS). Patients with high baseline K-trans had a better PFS (P = .027).
Conclusion
IAUC(90) and K-trans are pharmacodynamic biomarkers for sorafenib, but variability is high and magnitude of effect is less than previously reported. Changes in DCE-MRI parameters after 4 weeks of sorafenib are not predictive of PFS, suggesting that these biomarkers are not surrogate end points. The value of baseline K-trans as a prognostic or predictive biomarker requires additional study.

• 出版日期2008-10-1