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

Abstract

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.

Fig 1.

Schema of trial design. After a baseline dynamic contrast magnetic resonance imaging (DCE-MRI), patients were randomly assigned to placebo, sorafenib 200 mg twice per day, sorafenib 400 mg twice per day. After 4 weeks of therapy, patients underwent another DCE-MRI and were partially unblinded; patients initially on placebo were rerandomly assigned to a treatment arm.

Fig 2.

Sagittal image of a liver metastasis in a selected patient. Color map reflects the relative area under the contrast concentration versus time curve 90 seconds after contrast injection (IAUC₉₀) value in each voxel with yellow highest and violet as the lowest demonstrating heterogeneity of the parameter within the imaged region of interest. Negative voxels arise due to low signal and accompanying noise. (A) Baseline; (B) repeat image after 4 weeks of treatment.

Fig 3.

Log ratio of individual dynamic contrast magnetic resonance imaging (DCE-MRI) parameters (4 weeks/baseline) plotted by sorafenib dose (mg) demonstrating a decrease with dose. Mean log ratio and corresponding standard deviations (SD) in the placebo, 200-, and 400-mg cohorts are provided. (A) area under the contrast concentration versus time curve 90 seconds after contrast injection (IAUC₉₀); (B) volume transfer constant of contrast agent (K^trans); (C) blood plasma volume fraction (V_p).

Fig 4.

Kaplan-Meier estimates for progression-free survival (PFS) of patients with low and high baseline volume transfer constant of contrast agent (K^trans) and blood plasma volume fraction (V_p). (A) K^trans (cut point defined as the median baseline K_trans = 0.182). (B): V_p (cut point defined as the median baseline V_p = 0.072).