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Dynamic Contrast-Enhanced Magnetic Resonance Imaging Pharmacodynamic Biomarker Study of Sorafenib in Metastatic Renal Carcinoma

Olwen M. Hahn, Cheng Yang, Milica Medved, Gregory Karczmar, Emily Kistner, Theodore Karrison, Elizabeth Manchen, Myrosia Mitchell, Mark J. Ratain, Walter M. Stadler

From the University of Chicago, Chicago, IL

Corresponding author: Walter M. Stadler, MD, FACP, Sections of Hematology/Oncology and Urology, Departments of Medicine and Surgery, University of Chicago, 5841 S Maryland Ave, MC 2115, Chicago, IL 60637; e-mail: wstadler{at}medicine.bsd.uchicago.edu

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 (IAUC₉₀), 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%. IAUC₉₀ 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, IAUC₉₀ 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 IAUC₉₀ 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.

Supported by Bayer Pharmaceuticals Corporation and Grant No. 1R21 CA108184-01A2 from the National Institutes of Health.

Presented at 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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