Circulating proteins as potential biomarkers of sunitinib and interferon-α efficacy in treatment-naïve patients with metastatic renal cell carcinoma.
OBJECTIVE
We investigated potential biomarkers of efficacy in a phase III trial of sunitinib versus interferon-alpha (IFN-α), first-line in metastatic renal cell carcinoma (mRCC), by analyzing plasma levels of vascular endothelial growth factor (VEGF)-A, VEGF-C, soluble VEGF receptor-3 (sVEGFR-3) and interleukin (IL)-8.


METHODS
Seven hundred and fifty mRCC patients were randomized to oral sunitinib 50 mg/day in repeated cycles of a 4-week on/2-week off schedule or IFN-α 9 million units subcutaneously thrice weekly. Plasma samples collected from a subset of 63 patients on days 1 and 28 of cycles 1-4 and at end of treatment were analyzed by ELISA.


RESULTS
Baseline characteristics of biomarker-evaluated patients in sunitinib (N = 33) and IFN-α (N = 30) arms were comparable to their respective intent-to-treat populations. By univariate Cox regression analysis, low baseline soluble protein levels were associated with lower risk of progression/death (all P < 0.05): in both treatment arms, baseline VEGF-A and IL-8 were associated with overall survival (OS) and baseline VEGF-C with progression-free survival (PFS); in the sunitinib arm, baseline VEGF-A was associated with PFS and baseline sVEGFR-3 with PFS and OS; in the IFN-α arm, baseline IL-8 was associated with PFS. In multivariate analysis, baseline sVEGFR-3 and IL-8 remained independent predictors of OS in the sunitinib arm, while no independent predictors of outcome remained in the IFN-α arm. Pharmacodynamic changes were not associated with PFS or OS for any plasma protein investigated.


CONCLUSIONS
Our findings suggest that, in mRCC, baseline VEGF-A and IL-8 may have prognostic value, while baseline sVEGFR-3 may predict sunitinib efficacy.
Pfizer Oncology, 10646 Science Center Drive, La Jolla, San Diego, CA, 92121, USA.
Charles S
CS
Harmon
Samuel E
SE
DePrimo
Robert A
RA
Figlin
Gary R
GR
Hudes
Thomas E
TE
Hutson
M Dror
MD
Michaelson
Sylvie
S
Négrier
Sindy T
ST
Kim
Xin
X
Huang
J Andrew
JA
Williams
Tim
T
Eisen
Robert J
RJ
Motzer
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D016898:Interferon-alpha / Q000627:therapeutic use*; D016209:Interleukin-8 / Q000097:blood*; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000097:blood*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007211:Indoles; D016898:Interferon-alpha; D016209:Interleukin-8; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D040321:Vascular Endothelial Growth Factor Receptor-3; D000077210:Sunitinib