PURPOSE: There is an unmet need for noninvasive markers to measure the biological effects of targeted agents, particularly those inhibiting the vascular endothelial growth factor (VEGF) receptor (VEGFR) pathway, and identify patients most likely to benefit from treatment. In this study, we investigated potential blood-based biomarkers for SU11248 (sunitinib malate), a multitargeted tyrosine kinase inhibitor, in patients with metastatic imatinib-refractory gastrointestinal stromal tumors. EXPERIMENTAL DESIGN: Patients (n=73) enrolled in a phase I/II trial received SU11248 daily for 14 or 28 days followed by 14 days without treatment per cycle. Clinical benefit was defined as progression-free survival of >6 months. We assessed plasma markers, including VEGF and soluble VEGFR-2 (sVEGFR-2), and two cellular populations bearing VEGF receptors: monocytes and, in a subset of patients, mature circulating endothelial cells (CEC). RESULTS: Compared to patients with progressive disease, patients with clinical benefit had significantly greater increases in CECs (0.52 versus -0.01 CEC/microL/d, P=0.03) and smaller decreases in monocyte levels (47% versus 60%, P=0.007) during cycle 1. VEGF increased by 2.2-fold and sVEGFR-2 decreased 25% during the first 2 weeks of treatment. Neither plasma marker correlated with clinical outcome although a modest inverse correlation was observed between sVEGFR-2 changes and plasma drug levels. Monocytes, VEGF, and sVEGFR-2 all rebounded towards baseline off treatment. CONCLUSIONS: Monocytes, VEGF, and sVEGFR-2 were consistently modulated by treatment, suggesting that they may serve as pharmacodynamic markers for SU11248. Changes in CECs and monocytes, but not the plasma markers, differed between the patients with clinical benefit and those with progressive disease. These end points merit further investigation in future trials to determine their utility as markers of SU11248 activity and clinical benefit in gastrointestinal stromal tumors and other tumor types.
PURPOSE: There is an unmet need for noninvasive markers to measure the biological effects of targeted agents, particularly those inhibiting the vascular endothelial growth factor (VEGF) receptor (VEGFR) pathway, and identify patients most likely to benefit from treatment. In this study, we investigated potential blood-based biomarkers for SU11248 (sunitinib malate), a multitargeted tyrosine kinase inhibitor, in patients with metastatic imatinib-refractory gastrointestinal stromal tumors. EXPERIMENTAL DESIGN:Patients (n=73) enrolled in a phase I/II trial received SU11248 daily for 14 or 28 days followed by 14 days without treatment per cycle. Clinical benefit was defined as progression-free survival of >6 months. We assessed plasma markers, including VEGF and soluble VEGFR-2 (sVEGFR-2), and two cellular populations bearing VEGF receptors: monocytes and, in a subset of patients, mature circulating endothelial cells (CEC). RESULTS: Compared to patients with progressive disease, patients with clinical benefit had significantly greater increases in CECs (0.52 versus -0.01 CEC/microL/d, P=0.03) and smaller decreases in monocyte levels (47% versus 60%, P=0.007) during cycle 1. VEGF increased by 2.2-fold and sVEGFR-2 decreased 25% during the first 2 weeks of treatment. Neither plasma marker correlated with clinical outcome although a modest inverse correlation was observed between sVEGFR-2 changes and plasma drug levels. Monocytes, VEGF, and sVEGFR-2 all rebounded towards baseline off treatment. CONCLUSIONS: Monocytes, VEGF, and sVEGFR-2 were consistently modulated by treatment, suggesting that they may serve as pharmacodynamic markers for SU11248. Changes in CECs and monocytes, but not the plasma markers, differed between the patients with clinical benefit and those with progressive disease. These end points merit further investigation in future trials to determine their utility as markers of SU11248 activity and clinical benefit in gastrointestinal stromal tumors and other tumor types.
Authors: Tracy T Batchelor; Dan G Duda; Emmanuelle di Tomaso; Marek Ancukiewicz; Scott R Plotkin; Elizabeth Gerstner; April F Eichler; Jan Drappatz; Fred H Hochberg; Thomas Benner; David N Louis; Kenneth S Cohen; Houng Chea; Alexis Exarhopoulos; Jay S Loeffler; Marsha A Moses; Percy Ivy; A Gregory Sorensen; Patrick Y Wen; Rakesh K Jain Journal: J Clin Oncol Date: 2010-05-10 Impact factor: 44.544
Authors: John F de Groot; Yuji Piao; Hai Tran; Mark Gilbert; Hua-Kang Wu; Jun Liu; B Nebiyou Bekele; Tim Cloughesy; Minesh Mehta; H Ian Robins; Andrew Lassman; Lisa DeAngelis; Kevin Camphausen; Alice Chen; W K A Yung; Michael Prados; Patrick Y Wen; John V Heymach Journal: Clin Cancer Res Date: 2011-06-01 Impact factor: 12.531
Authors: Andreas Varkaris; Paul G Corn; Nila U Parikh; Eleni Efstathiou; Jian H Song; Yu-Chen Lee; Ana Aparicio; Anh G Hoang; Sanchaika Gaur; Lynnelle Thorpe; Sankar N Maity; Menashe Bar Eli; Bogdan A Czerniak; Yiping Shao; Mian Alauddin; Sue-Hwa Lin; Christopher J Logothetis; Gary E Gallick Journal: Clin Cancer Res Date: 2015-08-13 Impact factor: 12.531
Authors: Alison T Stopeck; Joseph M Unger; Lisa M Rimsza; William T Bellamy; Maria Iannone; Daniel O Persky; Michael Leblanc; Richard I Fisher; Thomas P Miller Journal: Leuk Lymphoma Date: 2009-05
Authors: L Vroling; J S W Lind; R R de Haas; H M W Verheul; V W M van Hinsbergh; H J Broxterman; E F Smit Journal: Br J Cancer Date: 2009-12-15 Impact factor: 7.640