Abstract
BackgroundSunitinib malate (SUTENT®) is an oral, multitargeted tyrosine kinase inhibitor, approved multinationally for the treatment of advanced RCC and of imatinib-resistant or – intolerant GIST. The purpose of this study was to explore potential biomarkers of sunitinib pharmacological activity via serial assessment of plasma levels of four soluble proteins from patients in a phase II study of advanced RCC: VEGF, soluble VEGFR-2 (sVEGFR-2), placenta growth factor (PlGF), and a novel soluble variant of VEGFR-3 (sVEGFR-3).MethodsSunitinib was administered at 50 mg/day on a 4/2 schedule (4 weeks on treatment, 2 weeks off treatment) to 63 patients with metastatic RCC after failure of first-line cytokine therapy. Predose plasma samples were collected on days 1 and 28 of each cycle and analyzed via ELISA.ResultsAt the end of cycle 1, VEGF and PlGF levels increased >3-fold (relative to baseline) in 24/54 (44%) and 22/55 (40%) cases, respectively (P < 0.001). sVEGFR-2 levels decreased ≥ 30% in 50/55 (91%) cases and ≥ 20% in all cases (P < 0.001) during cycle 1, while sVEGFR-3 levels were decreased ≥ 30% in 48 of 55 cases (87%), and ≥ 20% in all but 2 cases. These levels tended to return to near-baseline after 2 weeks off treatment, indicating that these effects were dependent on drug exposure. Overall, significantly larger changes in VEGF, sVEGFR-2, and sVEGFR-3 levels were observed in patients exhibiting objective tumor response compared with those exhibiting stable disease or disease progression (P < 0.05 for each analyte; analysis not done for PlGF).ConclusionSunitinib treatment in advanced RCC patients leads to modulation of plasma levels of circulating proteins involved in VEGF signaling, including soluble forms of two VEGF receptors. This panel of proteins may be of value as biomarkers of the pharmacological and clinical activity of sunitinib in RCC, and of angiogenic processes in cancer and other diseases.
Highlights
Sunitinib malate (SUTENT®) is an oral, multitargeted tyrosine kinase inhibitor, approved multinationally for the treatment of advanced renal cell carcinoma (RCC) and of imatinib-resistant or – intolerant gastrointestinal tumor (GIST)
Sunitinib malate (SUTENT®, SU11248; Pfizer Inc; New York, USA) is an oral multitargeted tyrosine kinase inhibitor with antiangiogenic and antitumor activity in clinical development for a variety of advanced solid malignancies. It is a potent and selective inhibitor of Class III and Class V split kinase domain receptor tyrosine kinases (RTKs), including VEGFR-1, -2, and -3; PDGFR-α and -β; stem cell factor receptor (KIT); Fms-like tyrosine kinase-3 receptor (FLT3); the RTK encoded by the ret proto-oncogene (RET); and the receptor for M-CSF (CSF-1R) [1,2,3,4,5,6,7,8] each of which have been implicated in tumor cell growth and survival either directly via tumor cell signaling, or, indirectly, via tumor-dependent angiogenesis [9,10,11,12,13]
Like RCC, metastatic neuroendocrine tumors (NET) and metastatic breast cancer (mBC) are highly vascular and characterized by high levels of VEGF/VEGFR [57,58,59], which may account for the similar observations in these analyses. These findings suggest that a panel of circulating proteins have utility as biomarkers of pharmacological and clinical activity. Each of these proteins has a known or presumed role in the regulation of angiogenic activity, and the modulation of plasma levels induced by sunitinib treatment is likely to be directly related, at least in part, to inhibition of VEGF signaling via receptor blockade
Summary
Sunitinib malate (SUTENT®) is an oral, multitargeted tyrosine kinase inhibitor, approved multinationally for the treatment of advanced RCC and of imatinib-resistant or – intolerant GIST. Sunitinib malate (SUTENT®, SU11248; Pfizer Inc; New York, USA) is an oral multitargeted tyrosine kinase inhibitor with antiangiogenic and antitumor activity in clinical development for a variety of advanced solid malignancies. In the second phase II study, in which 106 patients were treated with sunitinib (1 patient was excluded from the efficacy analysis), the overall investigator-assessed objective response rate was 44%; one patient (1%) achieved complete response and 45 patients (43%) a partial response [15] Based on these findings, sunitinib received accelerated approval in 2006 from the US FDA for the treatment of advanced RCC. The European Medicines Agency (EMEA) granted conditional approval for the treatment of advanced and/or metastatic RCC after failure of interferon alfa or interleukin-2 therapy
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