Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial.
OBJECTIVE
Mature survival data and evaluation of vascular endothelial growth factor (VEGF) as a prognostic biomarker from the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) study in patients with renal cell carcinoma (RCC) are reported.


METHODS
Nine hundred three previously treated patients were randomly assigned to receive sorafenib versus placebo. On demonstration of progression-free survival (PFS) benefit with sorafenib, patients assigned to placebo were offered sorafenib. Overall survival (OS) was determined at two planned interim analyses and one final analysis, with a secondary OS analysis conducted by censoring placebo patients who crossed over to sorafenib. The relationships between baseline VEGF level and prognosis and efficacy were evaluated.


RESULTS
The final OS of patients receiving sorafenib was comparable with that of patients receiving placebo (17.8 v 15.2 months, respectively; hazard ratio [HR] = 0.88; P = .146); however, when post-cross-over placebo survival data were censored, the difference became significant (17.8 v 14.3 months, respectively; HR = 0.78; P = .029). Adverse events at 16 months after cross over were similar to those previously reported. Baseline VEGF levels correlated with Eastern Cooperative Oncology Group performance status (P < .0001), Memorial Sloan-Kettering Cancer Center score (P < .0001), and PFS and OS in univariate (PFS, P = .0013; OS, P = .0009) and multivariate (PFS, P = .0231; OS, P = .0416) analyses of placebo patients and with short OS by multivariate analysis of patients receiving sorafenib (P = .0145). Both high-VEGF (P < .01) and low-VEGF (P < .01) groups benefited from sorafenib.


CONCLUSIONS
Although an OS benefit was not seen on a primary intent-to-treat analysis, results of a secondary OS analysis censoring placebo patients demonstrated a survival advantage for those receiving sorafenib, suggesting an important cross-over effect. VEGF levels are prognostic for PFS and OS in RCC. The results of TARGET establish the efficacy and safety of sorafenib in advanced RCC.
Escudier
Bernard
B
Institut Gustave Roussy, Villejuif, France. escudier@igr.fr
Eisen
Tim
T
Stadler
Walter M
WM
Szczylik
Cezary
C
Oudard
Stéphane
S
Staehler
Michael
M
Negrier
Sylvie
S
Chevreau
Christine
C
Desai
Apurva A
AA
Rolland
Frédéric
F
Demkow
Tomasz
T
Hutson
Thomas E
TE
Gore
Martin
M
Anderson
Sibyl
S
Hofilena
Gloria
G
Shan
Minghua
M
Pena
Carol
C
Lathia
Chetan
C
Bukowski
Ronald M
RM
D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000009:adverse effects / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy*; D018592:Cross-Over Studies; D003967:Diarrhea / Q000139:chemically induced; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009325:Nausea / Q000139:chemically induced; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011379:Prognosis; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D000077157:Sorafenib; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000077157:Sorafenib