Pharmacodynamic study of BAY 43-9006 in patients with metastatic renal cell carcinoma

Abstract

3005 Background: BAY 43-9006 (BAY) is a novel signal transduction inhibitor that prevents tumor cell proliferation and angiogenesis through blockade of the Raf/MEK/ERK pathway at the level of Raf kinase and the receptor tyrosine kinases VEGFR-2 and PDGFR-β. In preclinical models BAY administration is associated with decreased microvessel density and area in colon and breast cancer xenografts. We investigated alterations in tumor perfusion and vascular permeability associated with BAY using dynamic contrast-enhanced MRI (DCE-MRI). Methods: BAY was given from day 1 to 28 of a 28 day cycle at 400 mg bid. DCE-MRI was performed at baseline and after a median of 6.1 weeks (range 2.7–10.9 weeks). The rate constant for gadolinium transfer from the vasculature to the interstitium (Ktrans) and volume fraction of the tissue extracellular and extravascular space (Ve) were calculated for an index lesion for each patient and were normalized for the arterial input function. Response was assessed with CT scans after 12 weeks, then every 8 weeks for four months, then every 12 weeks using WHO criteria. Results: 17 renal cell carcinoma patients (pts) (median age 59, PS 0–1) have been enrolled on this pharmacodynamic study and 16 underwent baseline and follow-up MRIs. Data are available from both scans for 12 patients. 65% of patients had clear cell histology and had a median of 1 prior therapy (range 0–6). As in previous studies, BAY was well-tolerated at this dose and schedule. Responses using WHO criteria included 7 partial responses (ORR 41%), 7 minor responses (25–50% reduction), 2 stable disease and 1 progression prior to 12 weeks. Median time to progression has not been reached, but is at least 10.8 months. Among the 12 patients with data from both DCE-MRIs, Ktrans declined by 60.9% on average (95% CI 45.5–76.4%), and Ve declined by 23.4% (95% CI 4.8–41.9%). Both high Ktrans at baseline, and percent decline in Ktrans, correlated with time to progression. Conclusions: BAY 43–9006 is well-tolerated as a single-agent and is associated with significant alterations in measures of vascular permeability and tumor perfusion in patients with renal cell carcinoma. Preliminary evidence is adduced that therapeutic efficacy is a consequence of angiogenesis inhibition. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Bayer Bayer Bayer Bayer Bayer