Pharmacodynamic study using FLT PET/CT in patients with renal cell cancer and other solid malignancies treated with sunitinib malate.
OBJECTIVE
To characterize proliferative changes in tumors during the sunitinib malate exposure/withdrawal using 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) positron emission tomography (PET)/computed tomography (CT) imaging.


METHODS
Patients with advanced solid malignancies and no prior anti-VEGF exposure were enrolled. All patients had metastatic lesions amenable to FLT PET/CT imaging. Sunitinib was initiated at the standard dose of 50 mg p.o. daily either on a 4/2 or 2/1 schedule. FLT PET/CT scans were obtained at baseline, during sunitinib exposure, and after sunitinib withdrawal within cycle #1 of therapy. VEGF levels and sunitinib pharmacokinetic (PK) data were assessed at the same time points.


RESULTS
Sixteen patients (8 patients on 4/2 schedule and 8 patients on 2/1 schedule) completed all three planned FLT PET/CT scans and were evaluable for pharmacodynamic imaging evaluation. During sunitinib withdrawal (change from scans 2 to 3), median FLT PET standardized uptake value (SUV(mean)) increased +15% (range: -14% to 277%; P = 0.047) for the 4/2 schedule and +19% (range: -5.3% to 200%; P = 0.047) for the 2/1 schedule. Sunitinib PK and VEGF ligand levels increased during sunitinib exposure and returned toward baseline during the treatment withdrawal.


CONCLUSIONS
The increase of cellular proliferation during sunitinib withdrawal in patients with renal cell carcinoma and other solid malignancies is consistent with a VEGF receptor (VEGFR) tyrosine kinase inhibitor (TKI) withdrawal flare. Univariate and multivariate analysis suggest that plasma VEGF is associated with this flare, with an exploratory analysis implying that patients who experience less clinical benefit have a larger withdrawal flare. This might suggest that patients with a robust compensatory response to VEGFR TKI therapy experience early "angiogenic escape."
University of Wisconsin Carbone Cancer Center, Wisconsin Institutes for Medical Research, Room 7051, 1111 Highland Avenue, Madison, WI 53705, USA. gxl@medicine.wisc.edu
Glenn
G
Liu
Robert
R
Jeraj
Matt
M
Vanderhoek
Scott
S
Perlman
Jill
J
Kolesar
Michael
M
Harrison
Urban
U
Simoncic
Jens
J
Eickhoff
Lakeesha
L
Carmichael
Bo
B
Chao
Rebecca
R
Marnocha
Percy
P
Ivy
George
G
Wilding
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D015224:Dideoxynucleosides / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007668:Kidney / Q000000981:diagnostic imaging / Q000187:drug effects; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging / Q000379:methods; D015999:Multivariate Analysis; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D049268:Positron-Emission Tomography; D011758:Pyrroles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077210:Sunitinib; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D020533:Angiogenesis Inhibitors; D015224:Dideoxynucleosides; D005462:Fluorine Radioisotopes; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C002854:alovudine; D000077210:Sunitinib