DCE-MRI tracks inhibition of tyrosine kinase in human trial

CONTEXT: Growth factor receptor tyrosine kinase (TK) expression is implicated in many kinds of cancer. As a result, TK inhibitors (TKIs) are thought to have considerable potential as cancer therapy. TKI therapy involves disrupting cellular signaling processes that cannot easily be assessed by conventional imaging techniques. Pfizer investigators are evaluating clinical applications of dynamic contrast-enhanced MRI (DCE-MRI) as a way to evaluate tumor response to a vascular endothelial growth factor (VEGF) TKI inhibitor, AG-013736. Results of a phase I human trial using DCE-MRI as a marker of response were reported at the ISMRM conference in Kyoto.

RESULTS: Thirty-six patients with various types of solid tumors received AG-031736, an inhibitor of the VEGF receptor, platelet-derived growth factor receptor, and c-KIT receptor. The study's primary objective was to determine the maximum tolerated dose of AG-013736. However, use of DCE-MRI afforded the opportunity to evaluate KTRANS and initial area under the curve (IAUC), both quantitative indicators of solid-tumor-related angiogenesis. Changes in the two parameters of treatment response indicated that the TKI was inhibiting angiogenesis necessary for tumor viability. Although evidence of tumor size change was not apparent, DCE-MRI provided evidence of an acute vascular response within two days of the first dose of AG-031736. At higher drug exposures, both KTRANS and IAUC decreased at least 50% from baseline, meeting the definition of a significant tumor vascular response.

IMAGE: KTRANS and initial area under the curve (IAUC) measures of dynamic flow plotted on the chart show that AG-013736 was shutting down the blood supply of various solid tumors as early as two days after the initiation of treatment.

IMPLICATIONS: The unexpected evidence of clinical efficacy in this phase I trial provided impetus for phase II evaluation of AG-013736.

"The exciting thing in this clinical trial-and you don't expect to see this in a phase I trial-was the amount of clinical activity. We saw stable disease and partial responses," said Dr. Teresa McShane of Pfizer Global Research and Development.

Additional research will determine whether early results from DCE-MRI can predict the drug's clinical benefit.