Surrogate markers of activity of AG-013736, a multi-target tyrosine kinase receptor inhibitor, in metastatic renal cell cancer (RCC)

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Abstract
3003 Background: Significant activity of AG-013736, an oral small molecule with potent inhibitory effects against the VEGF receptors 1 (VEGFR-1) and 2 (VEGFR-2) and PDGF receptor, is reported in a phase 2 study in metastatic RCC (Rini D. et al, ASCO 2005). Over the 52 enrolled patients (pts), best response assessed by RECIST criteria is 40% (21 partial responses. However, the frequency of stable disease and clinical improvement lead to define new parameters of therapeutic evaluation. The question was addressed in 13 patients treated in Salpêtrière Hospital, included in this phase 2 study. Ancillary studies were conducted to monitor (i) vascular tumour flow using qualitative and quantitative CT perfusion for visceral and non-visceral metastases (ii) biological effect of the anti-angiogenic therapy including soluble proteins involved in the angiogenic pathway. Methods: To calculate various tumours perfusion parameters, regional blood flow and volume, mean transit time, hepatic arterial fraction were determined with General Electric’s CT Perfusion Program. Serum were collected pre- and 1, 2, 4, 6-months post AG-013736 treatment initiation and analysed by ELISA tests for VEGFs, VEGFR-1, VEGFR-2. Results: Decreased tumour perfusion (TP) was observed in patients responding to therapy, including liver metastases. Furthermore, in 4 out of 6 patients with stable or progressive disease by RECIST, decreased TP was strongly correlated with clinical improvement. No relation was observed in this cohort between responders (RECIST criteria, n=7 pts), non-responders (n=6) and biological parameters (VEGFs, VEGFR-1, VEGFR-2). Conclusion: Conventional RECIST criteria were designed as a tool for evaluating cytoxic agents. New tools, such as the quantification of tumor blood flow, may yield additional information in the evaluation of anti-angiogenic therapy for solid tumours. Although this observation is based on the data from a small number of patients, this preliminary finding leads us to believe that TP is a useful parameter in evaluating disease status.

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