Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma.
OBJECTIVE
Renal cell carcinoma (RCC) is characterized by loss of von Hippel Lindau tumor suppressor gene activity, resulting in high expression of pro-angiogenic growth factors: vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). SU11248 (sunitinib malate), a small molecule inhibitor with high binding affinity for VEGF and PDGF receptors, was tested for clinical activity in patients with metastatic RCC.


METHODS
Patients with metastatic RCC and progression on first-line cytokine therapy were enrolled onto a multicenter phase II trial. SU11248 monotherapy was administered in repeated 6-week cycles of daily oral therapy for 4 weeks, followed by 2 weeks off. Overall response rate was the primary end point, and time to progression and safety were secondary end points. Results Twenty-five (40%) of 63 patients treated with SU11248 achieved partial responses; 17 additional patients (27%) demonstrated stable disease lasting > or = 3 months. Median time to progression in the 63 patients was 8.7 months. Dosing was generally tolerated with manageable toxicities.


CONCLUSIONS
SU11248, a multitargeted receptor tyrosine kinase inhibitor of VEGF and PDGF receptors, demonstrates antitumor activity in metastatic RCC as second-line therapy, a setting where no effective systemic therapy is presently recognized. The genetics of RCC and these promising clinical results support the hypothesis that VEGF and PDGF receptor-mediated signaling is an effective therapeutic target in RCC.
Motzer
Robert J
RJ
Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. motzerr@mskcc.org
Michaelson
M Dror
MD
Redman
Bruce G
BG
Hudes
Gary R
GR
Wilding
George
G
Figlin
Robert A
RA
Ginsberg
Michelle S
MS
Kim
Sindy T
ST
Baum
Charles M
CM
DePrimo
Samuel E
SE
Li
Jim Z
JZ
Bello
Carlo L
CL
Theuer
Charles P
CP
George
Daniel J
DJ
Rini
Brian I
BI
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011758:Pyrroles / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D011788:Quality of Life; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000097:blood; D000077210:Sunitinib
D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib