Blood-based biomarkers of SU11248 activity and clinical outcome in patients with metastatic imatinib-resistant gastrointestinal stromal tumor.
OBJECTIVE
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.


METHODS
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.
Norden-Zfoni
Anat
A
Children's Hospital Boston, Boston, Massachusetts, USA.
Desai
Jayesh
J
Manola
Judith
J
Beaudry
Paul
P
Force
Jeremy
J
Maki
Robert
R
Folkman
Judah
J
Bello
Carlo
C
Baum
Charles
C
DePrimo
Sam E
SE
Shalinsky
David R
DR
Demetri
Goerge D
GD
Heymach
John V
JV
D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D015415:Biomarkers / Q000097:blood; D042783:Endothelial Cells; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000097:blood* / Q000188:drug therapy*; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D009000:Monocytes; D010879:Piperazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood*
D000970:Antineoplastic Agents; D001549:Benzamides; D015415:Biomarkers; D007211:Indoles; D010879:Piperazines; D011743:Pyrimidines; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000068877:Imatinib Mesylate; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib