VOLUME 27 NUMBER 20 JULY 10 2009

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Sorafenib for Treatment of Renal Cell Carcinoma: Final

From the From Institut Gustave
Roussy, Villejuif; Hopital Europeen
Georges Pompidou, Paris; Centre Leon
Berard, Lyon; Institut Claudius Regaud,
Toulouse; Centre Rene Gauducheau,
Saint-Herblain, France; Cambridge
Research Institute, Cambridge; Royal
Marsden Hospital, Surrey, United King-
dom; Military School of Medicine;
Centrum Onkologii, Warsaw, Poland;
Urologische Klinik und Poliklinik Klini-
kum der Universitat Grohadern
Ludwig-Maximilian-Universitat,
Munchen, Germany; University of
Chicago, Chicago, IL; Baylor Charles A.
Sammons Cancer Center, Dallas, TX;
Bayer HealthCare Pharmaceuticals,
Montville, NJ; and Cleveland Clinic
Taussig Cancer Center, Cleveland, OH.
Submitted August 22, 2008; accepted
February 13, 2009; published online
ahead of print at www.jco.org on May
18, 2009.
Written on behalf of the Treatment
Approaches in Renal Cancer Global
Evaluation Trial (TARGET) Study Group.
Authors disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Clinical Trials repository link available on
JCO.org.
Corresponding author: Bernard
Escudier, MD, Department of Medicine,
Institut Gustave Roussy, 39 Rue
Camille Desmoulins, 94805 Villejuif,
France; e-mail: escudier@igr.fr.
Efficacy and Safety Results of the Phase III Treatment
Approaches in Renal Cancer Global Evaluation Trial
Bernard Escudier, Tim Eisen, Walter M. Stadler, Cezary Szczylik, Stephane Oudard, Michael Staehler,
Sylvie Negrier, Christine Chevreau, Apurva A. Desai, Frederic Rolland, Tomasz Demkow,
Thomas E. Hutson, Martin Gore, Sibyl Anderson, Gloria Hofilena, Minghua Shan, Carol Pena,
Chetan Lathia, and Ronald M. Bukowski
A B S T R A C T
Purpose
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.
Patients and 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 Cooper-
ative 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.
Conclusion
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.
J Clin Oncol 27:3312-3318. 2009 by American Society of Clinical Oncology

The Acknowledgment and Appendix

are included in the full-text version
of this article; they are available
online at www.jco.org. They are
not included in the PDF version
(via Adobe Reader).
2009 by American Society of Clinical
Oncology
0732-183X/09/2720-3312/$20.00
DOI: 10.1200/JCO.2008.19.5511
INTRODUCTION
Renal cell carcinoma (RCC) comprises 5% of epi-
thelial cancers diagnosed in the United States each
year, with the majority being of clear cell histology.1,2
Approximately 20% to 30% of patients with RCC
have metastases at diagnosis, and 20% to 40% of
those with localized disease who undergo nephrec-
tomy subsequently develop metastases.3 Until re-
cently, therapeutic options for unresectable and/or
metastatic RCC were limited. RCC is generally resis-
tant to conventional chemotherapy, and only a
small percentage of patients with RCC benefit from
cytokine treatment.2,4,5
Clear cell RCC is characterized by inactiva-
tion of the Von Hippel-Lindau (VHL) pathway
with somatic mutations or methylation of the
VHL gene in the majority of patients. The result-
ant increased production of vascular endothelial
growth factor (VEGF)/platelet-derived growth fac-
tor (PDGF) is considered to be fundamental to the
highly angiogenic nature of RCC and critical to on-
cogenesis.6,7 Several inhibitors of VEGF and its cog-
nate receptor VEGF receptor (VEGFR) 2 have

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Copyright 2017 American Society of Clinical Oncology. All rights reserved.
 Final Efficacy and Safety Results of the Phase III TARGET Study
dramatic antitumor activity in RCC.8 Sorafenib tosylate (Nexavar;
Bayer HealthCare Pharmaceuticals Corporation, Montville, NJ; Onyx
Pharmaceuticals, Emeryville, CA) is an orally active multikinase in-
hibitor that blocks VEGFR-2, VEGFR-3, and PDGF receptor
(PDGFR-), as well as RAF-1, Flt-3, and c-KIT.9,10 In a phase II
randomized discontinuation trial, sorafenib improved progression-
free survival (PFS) of RCC patients.11
These findings prompted initiation of the phase III multicenter
Treatment Approaches in Renal Cancer Global Evaluation Trial
(TARGET), a randomized, double-blind, placebo-controlled study of
treatment with sorafenib in clear cell RCC patients who experienced
treatment failure with one prior systemic therapy.12 In January 2005, a
preplanned interim analysis conducted via independent assessment
reported that sorafenib-treated patients had PFS that was significantly
superior to that of patients randomly assigned to placebo (5.5 v 2.8
months, respectively; hazard ratio [HR] 0.44; 95% CI, 0.35 to 0.55;
P .000001). On the basis of this analysis, the data safety monitoring
board halted the trial, leading to cross over of patients still on placebo
to sorafenib and approval of sorafenib for the treatment of advanced
RCC by the US Food and Drug Administration and other regulatory
authorities. The initial preliminary survival data on cross over did not
meet the original planned statistical criteria (P .0094) for success on
interim analysis (HR 0.71, P .015). More mature survival data
from an analysis 16 months after cross over (September 2006), along
with data on VEGF as a predictive/prognostic molecular biomarker,
are now presented.
PATIENTS AND METHODS
Patients and Study Design
Study design and patient inclusion criteria for TARGET have been pre-
viously described.12 Patients were enrolled from November 2003 to March
2005. Briefly, this was a phase III, multicenter, randomized, double-blind,
placebo-controlled trial for patients with unresectable and/or metastatic RCC
who had undergone one prior systemic therapy. Other inclusion criteria in-
cluded low- or intermediate-risk Memorial Sloan-Kettering Cancer Center
(MSKCC) score5 and adequate organ function. Patients were stratified by
MSKCC score and country of enrollment and then randomly assigned to
receive either continuous treatment with sorafenib 400 mg twice a day
(n 451) or placebo (n 452). Treatment interruptions and two dose
modifications (first to 400 mg every day, then 400 mg every 2 days) were
permitted for therapy-related toxicities. Patients remained on study drug until
disease progression or discontinuation as a result of intolerable toxicity or
death, but those in the sorafenib group could continue open-label treatment
beyond the end point of radiologic progression at investigator discretion.
Cross Over
A planned analysis of PFS in January 2005 demonstrated an advantage in
the sorafenib group (HR 0.44; 95% CI, 0.35 to 0.55; P .001), leading to a
data monitoring committee recommendation to close the study and cross
patients on placebo over to sorafenib. Overall, 48% of the patients from the
placebo group crossed over to sorafenib.
Study End Points
Efficacy and safety end points. The original primary end point of
TARGET was overall survival (OS). Secondary end points included PFS (de-
fined as time from random assignment to disease progression based on radio-
logic or clinical assessment), response rate, and patient-reported outcomes. All
randomly assigned patients were included in the intent-to-treat (ITT) popu-
lation for the efficacy analyses, and at the time of cross over, three preplanned
efficacy analyses were specified: an initial OS analysis corresponding to start of
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cross over (pre cross-over analysis); a second OS analysis with a data cutoff
date of 6 months after cross over; and a final primary OS analysis with a data
cutoff date originally planned to be when 540 events (deaths) had occurred,
which took place 16 months after cross over (Appendix Fig A1A and Appendix
Table A1, online only). Antitumor activity, safety, and the initial pre cross-
over survival have been previously described.12 Patient visits for safety moni-
toring were conducted every 3 weeks during the first 24 weeks of treatment and
every 4 weeks thereafter. A toxicity assessment was conducted 30 days after
discontinuation of study drug. After the conclusion of treatment with the
study drug, patients were contacted to determine survival status approxi-
mately every 3 months until death or loss to follow-up was documented.
VEGF analysis. Plasma samples were collected from patients at the
screening visit. Blood samples (10 mL) were drawn into a vacutainer contain-
ing potassium EDTA. Within 10 to 15 minutes after collecting, samples were
centrifuged at 4C to separate plasma. In the absence of a refrigerated centri-
fuge, samples were chilled on ice for 5 to 15 minutes and subsequently centri-
fuged at room temperature. Each plasma sample was frozen at 70C within
20 minutes of centrifugation. VEGF was determined by sandwich enzyme-
linked immunosorbent assay assay (code no. PDVE00; R&D Systems, Minne-
apolis, MN) according to the manufacturers protocol. Results are expressed as
the average of duplicate assays.
Statistical Analyses
Original sample size was calculated to detect a 0.77 HR in OS, assuming
an exponential survival distribution, a Lan-DeMets spending function for
constructing group sequential boundaries, an overall two-sided .04, and
power of 90%. For one interim and one final analysis to be performed, 540
events (deaths) were required.13 The original planned sample size was also
sufficient to detect a 0.67 HR in PFS using a single analysis, with an overall
two-sided .01 and a power of 90%. For the final OS analysis based on the
561 events (16 months after cross over, September 2006), a two-sided .037
was used. Survival analyses were stratified by country and MSKCC prognostic
risk category and conducted using the Kaplan-Meier method. Additional Cox
proportional hazard analyses using the prespecified stratification variables,
biomarker data (see next section), and treatment arm were also planned and
conducted. To account for a possible survival benefit after cross over, a pre-
specified ITT survival analysis uniformly censoring patients originally ran-
domly assigned to placebo at the time of cross over was also conducted.
VEGF Analysis
The relationship between VEGF, treatment arm, and PFS or OS was
examined using Cox proportional hazards regression models and Kaplan-
Meier analyses. Univariate analyses of baseline VEGF and outcome were
performed on placebo patients only. Multivariate models included baseline
VEGF as a continuous variable, Eastern Oncology Cooperative Group
(ECOG) performance status (PS; 0 v 1 or 2), and MSKCC score (low v
intermediate). To maximize the number of patients with noncensored data for
correlative analyses, tumor assessmentrelated data (progression) were evalu-
ated and determined by an investigator at the patients site as opposed to an
independent review committee. The PFS data were from the interim analysis
cutoff date (May 2005, before cross over), and the OS data were from the
16-month post cross-over cutoff data (September 2006), with placebo data
censored to June 2005 (before cross over; Appendix Figs A1A and A1B). The
significance of the relationships between demographic variables and VEGF
was evaluated using an analysis of variance F test.
RESULTS
Patient Characteristics and Disposition
A total of 903 patients were enrolled onto TARGET; 451 and
452 patients were randomly assigned to receive sorafenib or pla-
cebo, respectively (Appendix Fig A1B). Demographic and baseline
characteristics of the ITT population have previously been de-
scribed.12 A total of 216 patients randomly assigned to placebo (48%)
2009 by American Society of Clinical Oncology 3313
 Escudier et al

crossed over to treatment with sorafenib; 93 patients were receiving 84 in treatment), and 155 patients (34%) in the placebo group were
double-blind treatment at the time of cross over, one was receiving ongoing in the study (88 in post-treatment follow-up and 67 in treat-
open-label treatment, 121 were in long-term post-treatment follow- ment; Appendix Figs A1A and A1B).
up, and one patient had no status information (Appendix Fig A1B).
The majority of patients were male (75% to 76%), had a median age of
Exposure to Study Medication: ITT
59 years, and had received prior interleukin-2/interferon alfa therapy
Patients who were randomly assigned to placebo received treat-
(81% to 82%). The only significant differences between patients ran-
ment for a median of 12.0 weeks before cross over and 40.2 weeks after
domly assigned to placebo (n 452) and who crossed over (n 216)
cross over. In the final OS analysis (16 months after cross over), the
and those who did not cross over (n 236) were that a smaller
median administered dose of sorafenib was similar between sorafenib
proportion of the former had an ECOG PS 1 (37% v 67%, respec-
patients and placebo-assigned patients who had crossed over (790 mg;
tively) and a greater proportion of those who crossed over had a low
range, 213 to 1,707 mg v 778 mg; range, 229 to 1,444 mg, respectively).
MSKCC risk (62% v 36%, respectively; Table 1).
Fifty percent (n 225) of sorafenib-assigned and 40% (n 182) of
Of the 903 randomly assigned patients, 700 (78%) entered post-
placebo-assigned patients received 90% of planned dosing. Dose
treatment follow-up at any time during the trial (337 [75%] from the
reductions or interruptions were infrequent in both groups, with only
sorafenib group and 363 [80%] from the placebo group). The most
28% (n 126) and 22% (n 100) of patients in the groups originally
frequent reasons for discontinuation in the sorafenib and placebo
randomly assigned to sorafenib and placebo having two or more of
groups were death (229 v 248 patients, respectively), loss to follow-up
such events, respectively. Eighty-five percent of patients (n 385) in
(eight v 13 patients, respectively), and withdrawal of consent (six v five
the sorafenib-assigned group and 90% of patients (n 407) in the
patients, respectively). At the time of final survival analysis (16 months
placebo-assigned group had no dose delays. It is of note that 285
after cross over, September 2006), 170 patients (38%) in the sorafenib
patients (63%) randomly assigned to sorafenib and 104 cross-over
group were ongoing in the study (86 in post-treatment follow-up and
patients (48%) continued sorafenib therapy after Response Evalua-
tion Criteria in Solid Tumors (RECIST) defined disease progression
per investigator-assessed clinical benefit for a mean of 24.9 weeks
(median, 14.9 weeks) and 16.8 weeks (median, 10.6 weeks), respec-
Table 1. Baseline Patient Characteristics for Patients Randomly
Assigned to Placebo tively. Sorafenib therapy accounted for 61% of the treatment received
Patients Assigned to Placebo (n 452) throughout the entire study for the placebo-assigned group.
Baseline Cross Over No Cross Over
Demographics and (n 216) (n 236)
Clinical Characteristics PFS and OS
at Cross Over No. % No. % In January 2005, a preplanned interim PFS analysis, conducted
Sex via independent assessment, reported that patients treated with sor-
Male 161 75 179 76 afenib had PFS that was significantly superior to that of patients
Female 55 25 57 24 randomly assigned to placebo (median PFS, 5.5 v 2.8 months, respec-
Age, years
tively; HR 0.44; 95% CI, 0.35 to 0.55; P .000001).12 On the basis of
Median 59.0 59.0
Mean 58.5 58.3
these data, the protocol for TARGET was amended to permit patients
SD 10.2 8.8 randomly assigned to placebo to cross over to sorafenib treatment.
65 152 70 176 75 The first preplanned survival analysis for TARGET was performed in
65 64 30 60 25 May 2005, when 48% of patients initially randomly assigned to pla-
ECOG performance cebo crossed over to treatment with sorafenib. At that time, 220 deaths
status
had occurred, including 97 in the sorafenib group (22%) and 123 in
0 134 62 77 33
1 78 36 157 66
the placebo arm (27%). Although treatment with sorafenib was asso-
2 2 1 2 1 ciated with an improved OS (not available v 14.7 months for placebo;
Missing 2 1 0 0 HR 0.71; 95% CI, 0.54 to 0.94; P .015; for interim analy-
MSKCC category sis .0094), these data did not reach the OBrien-Fleming boundary
Low 134 62 85 36 for statistical significance (Table 2 and Appendix Table A1). A second
Intermediate 82 38 150 64
survival analysis was performed 6 months after cross over (November
Missing 0 0 1 1
Prior IL-2/IFN
2005) when 367 deaths had occurred (sorafenib 171; pla-
Yes 178 82 191 81 cebo 196). In this analysis, patients initially randomly assigned to
No 38 18 45 19 sorafenib had superior OS versus those initially assigned to placebo
Prior adjuvant IL-2/IFN (19.3 v 15.9 months, respectively; HR 0.77; 95% CI, 0.63 to 0.95;
Yes 38 18 40 17 P .015), although once again, the findings did not meet the prespeci-
No 178 82 196 83 fied boundary for statistical significance. A total of 561 deaths (sor-
Prior palliative IL-2/IFN
afenib 278; placebo 283) were reported at the final data cutoff
Yes 143 66 154 65
No 73 34 82 35
point 16 months after cross over (September 2006). In the final anal-
ysis of the ITT population, survival in the sorafenib group was not
Abbreviations: SD, standard deviation; ECOG, Eastern Cooperative Oncology
Group; MSKCC, Memorial Sloan-Kettering Cancer Center; IL-2, interleukin-2;
superior to placebo (17.8 v 15.2 months, respectively; HR 0.88; 95%
IFN, interferon. CI, 0.74 to 1.04; P .146; Fig 1A). To determine whether cross over
had an impact on OS, an analysis with censoring of placebo-assigned

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 Final Efficacy and Safety Results of the Phase III TARGET Study

Table 2. Results of OS Analyses of TARGET Trial

Median OS (months)

OS Analysis and Date Description No. of Events Sorafenib Placebo HR 95% CI P

First interim OS analysis
(May 2005) Before cross over 220 Not yet reached 14.7 0.71 0.54 to 0.94 .015
Second interim OS analysis
(November 2005) 6 months after cross over 367 19.3 15.9 0.77 0.63 to 0.95 .015
Final OS analysis (September
2006) 16 months after cross over 561 17.8 15.2 0.88 0.74 to 1.04 .146
Placebo-censored secondary OS OS data were censored in cross-over patients
analysis (September 2006*) randomly assigned to placebo known to be
alive to minimize postcross-over effect 424 17.8 14.3 0.78 0.62 to 0.97 .029

Abbreviations: TARGET, Treatment Approaches in Renal Cancer Global Evaluation Trial; OS, overall survival; HR, hazard ratio.
*Placebo data are from June 2005.
Statistically significant.

patients who crossed over to sorafenib at the start of cross over was Safety
conducted. In this case, treatment with sorafenib was associated with Overall, sorafenib was well tolerated, and most events were grade
an improved survival compared with placebo (17.8 v 14.3 months, 1 or 2, reversible, and clinically manageable. Treatment-related ad-
respectively; HR 0.78; 95% CI, 0.62 to 0.97; P .0287; Fig 1B). verse events (AEs) for all patients randomly assigned to sorafenib or

A B C
Intent-to-Treat Placebo Patients Censored Placebo Patients Only

Progression-Free Survival (%)

100 Sorafenib (n = 451) 17.8 months 100 Sorafenib (n = 451) 17.8 months 100 VEGF 131 pg/mL (n = 176) 3.3 months
Placebo (n = 452) 15.2 months Placebo (n = 452) 14.3 months VEGF > 131 pg/mL (n = 172) 2.7 months
Overall Survival (%)

Overall Survival (%)

HR = 0.88 (95% CI, 0.74 to 1.04) HR = 0.78 (95% CI, 0.62 to 0.97) HR = 1.44 (95% CI, 1.13 to 1.85)
75 75 75

50 50 50

25 25 25

P = .146 P = .0287 P < .01

0 4 8 12 16 20 24 28 32 36 40 0 4 8 12 16 20 24 28 32 36 40 0 2 4 6 8 10 12 14 16 18 20

Time Since Random Time Since Random Time Since Random

Assignment (months) Assignment (months) Assignment (months)

D E
Low-baseline VEGF ( 131 pg/mL) High-baseline VEGF (> 131 pg/mL)
Progression-Free Survival (%)

Progression-Free Survival (%)

100 Sorafenib (n = 180) 5.5 months 100 Sorafenib (n = 184) 5.5 months
Placebo (n = 176) 3.3 months Placebo (n = 172) 2.7 months
HR = 0.64 (95% CI, 0.49 to 0.83) HR = 0.48 (95% CI, 0.38 to 0.62)
75 75

50 50

25 25

P < .01 P < .01

0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20

Time Since Random Time Since Random

Assignment (months) Assignment (months)

Fig 1. Final overall survival (OS) and progression-free survival (PFS) data. (A) Kaplan-Meier analysis of final OS for the intent-to-treat (ITT) population. (B) Kaplan-Meier
analysis of final OS for the ITT population with placebo patients censored. (C) Kaplan-Meier analysis of PFS in placebo patients only by baseline vascular endothelial
growth factor (VEGF) levels. (D and E) Kaplan-Meier analyses of PFS by baseline VEGF levels. HR, hazard ratio.

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 Escudier et al

Table 3. Overall and Grade 3 or 4 Treatment-Related Adverse Events for All Patients Randomly Assigned to Sorafenib or Placebo and for Placebo Patients
Who Crossed Over to Sorafenib
Sorafenib (n 452) Placebo (n 451) Cross Over to Placebo (n 216)

All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4
Treatment-Related Adverse
Events No. of Patients % No. of Patients % No. of Patients % No. of Patients % No. of Patients % No. of Patients %
Any treatment-related adverse
event 392 87 132 29 242 54 29 7 173 80 63 29
Diarrhea 216 48 14 3 49 11 4 1 103 48 10 5
Fatigue 133 29 14 3 74 16 5 1 53 25 10 5
Nausea 85 19 1 1 56 12 1 1 30 14 3 1
Hypertension 78 17 15 4 5 1 0 0 28 13 8 4
Anorexia 63 14 2 1 31 7 4 1 34 16 1 1
Dry skin 58 13 0 0 12 3 0 0 18 8 0 0
Vomiting 54 12 3 1 26 6 1 1 19 9 2 1
Weight loss 38 8 5 1 6 1 0 0 23 11 3 1
Constipation 33 7 0 0 16 4 0 0 15 7 0 0
Headache 29 6 0 0 16 4 0 0 9 4 0 0
Joint pain 25 6 1 1 10 2 0 0 3 1 0 0
Mucositis (oral) 23 5 0 0 8 2 0 0 21 10 1 1
Abdominal pain 23 5 1 1 14 3 1 1 6 3 0 0
Muscle pain 23 5 0 0 7 2 0 0 5 2 0 0
Hand-foot skin reaction 151 33 29 6 37 8 2 1 80 37 14 7
Rash/desquamation 187 41 6 1 59 13 1 1 63 29 8 4
Alopecia 140 31 0 0 19 4 0 0 73 34 0 0
Pruritus 77 17 1 1 20 4 0 0 24 11 0 0
Dermatologic/other 53 12 0 0 9 2 0 0 21 10 1 1

Five percent or more of patients in any group.

placebo and for patients who crossed over from placebo to sorafenib Patients with a higher MSKCC score (poorer prognosis) or
are listed in Table 3. Grade 3 and 4 treatment-related AEs were un- higher ECOG PS (poorer performance) had significantly higher base-
common in both the sorafenib-assigned and cross-over groups; diar- line VEGF levels than those with low MSKCC (P .0001) or ECOG
rhea, fatigue, hypertension, hand-foot skin reaction, and rash/ scores (P .0001; Table 4), lending further support for the association
desquamation were reported in more than 2% of patients. of high VEGF levels with poor prognosis in RCC patients. Sex (male v
Twenty-two patients (4.9%) randomly assigned to sorafenib
reported cardiac ischemic/infarct AEs, with six events reported as
related to study drug. Dose interruption was required in six pa-
Table 4. Baseline VEGF Levels and Demographic Variables
tients receiving sorafenib, and one participant reported dose re-
duction. One cardiac ischemic event in the sorafenib group led to Baseline VEGF
(pg/mL)
permanent discontinuation of study drug. Of note, the sorafenib Demographic
arm had a longer follow-up time and inclusion of postprogression Variable No. of Patients Mean Median P

patients. Three cross-over patients (1.4%) and two patients on Sex .76
placebo (0.4%) reported cardiac ischemia/infarct events. CNS Male 509 206 126
Female 199 212 137
ischemia was reported by seven sorafenib patients (1.5%), com-
Age, years .29
pared with three patients (0.7%) in the placebo group and none in 65 496 214 137
the cross-over group. 65 212 193 122
MSKCC score .0001
Low 362 159 102
VEGF As a Prognostic Factor for PFS and OS in RCC Intermediate 346 258 161
Previous studies have suggested that VEGF levels may be a ECOG PS .0001
prognostic factor in RCC.14 These findings, in combination with 0 347 176 108
the inhibition of VEGFR-2 by sorafenib, led to the hypothesis that 1 354 233 143
patients with elevated baseline VEGF levels may derive enhanced 2 7 526 161
Stage at study entry .39
benefit from sorafenib treatment. Therefore, we examined VEGF
III 21 251 110
levels in the present study. Assessable baseline VEGF data were IV 687 206 132
available for 712 patients. In univariate analyses of VEGF (as a
Abbreviations: VEGF, vascular endothelial growth factor; MSKCC, Memorial
continuous variable) versus outcome in placebo patients, VEGF Sloan-Kettering Cancer Center; ECOG, Eastern Cooperative Oncology Group;
levels correlated inversely with PFS (P .0013; Fig 1C) and OS PS, performance status.
(P .0009; data not shown).

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 Final Efficacy and Safety Results of the Phase III TARGET Study
female; P .7595), age ( v 65 years; P .2904), and stage at study
entry (stage III v IV; P .3879) did not have significant association
with baseline VEGF levels (Table 4).
To determine whether VEGF offers additional prognostic infor-
mation independently of ECOG PS and MSKCC score, multivariate
analyses were performed (Table 5). Results of these analyses indicate
that both MSKCC score and baseline VEGF are independent prognos-
tic factors for PFS when analyzed for patients on placebo only
(MSKCC, P .0012; VEGF, P .0231), but not in patients treated
with sorafenib (MSKCC, P .0657; VEGF, P .6252). For the
analysis of OS, MSKCC score, ECOG PS, and baseline VEGF were
all independently prognostic in both placebo patients (MSKCC,
P .0001; ECOG, P .0018; VEGF, P .0416) and sorafenib-treated
patients (MSKCC, P .0001; ECOG, P .0248; VEGF, P .0145;
Table 5).
Initial analysis of baseline VEGF and sorafenib antitumor
activity (in terms of PFS) using the median value (131 pg/mL) to
define high- versus low-VEGF groups suggested that both groups
benefit from sorafenib treatment (Figs 1D and 1E). However, the
high-VEGF group trended toward deriving more benefit from sor-
afenib (HR 0.48; 95% CI, 0.38 to 0.62) than the low-VEGF group
(HR 0.64; 95% CI, 0.49 to 0.83; P for interaction between VEGF and
treatment arm .096). In an attempt to optimize this difference,
further exploratory analyses using the 25th and 75th percentiles to
define low versus high VEGF were performed using half of the data set
(for hypothesis generation, chosen randomly). The difference in ben-
efit between the high- and low-VEGF groups was most pronounced
using the 75th percentile (254 pg/mL; HR 0.27; 95% CI, 0.15 to
0.460 for high VEGF v 0.58; 95% CI, 0.43 to 0.78 for low VEGF; P for
interaction .020), with the high-VEGF group deriving more benefit
from sorafenib (Appendix Table A2, online only). This finding was
supported by analyzing the second half of the data (confirmatory data
set; P .023; Appendix Table A2), again suggesting that, although
both high- and low-VEGF groups benefit from sorafenib (in terms of
PFS), the high-VEGF group may benefit more.
DISCUSSION
The TARGET trial demonstrated that treatment with sorafenib
doubled PFS versus placebo in patients with previously treated
advanced RCC. The final survival analyses were confounded by the
crossing over of study participants from placebo to sorafenib. This
Table 5. Multivariate Analysis of ECOG PS, MSKCC Score, and Baseline VEGF as Independent Prognostic Factors for PFS and OS in RCC
PFS
Placebo Sorafenib
Parameter Parameter
Variable P Estimate SE P Estimate
ECOG PS .23 0.15984 0.13378 .71 0.0509
MSKCC score .0012 0.44099 0.13589 .066 0.26177
Baseline VEGF .023 0.0005666 0.0002493 .63 0.0001435
Abbreviations: ECOG, Eastern Cooperative Oncology Group; PS, performance status; MSKCC, Memorial Sloan-Kettering Cancer Center; VEGF, vascular endothelial
growth factor; PFS, progression-free survival; OS, overall survival; RCC, renal cell carcinoma.
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likely contributed to the lack of observed survival advantage in the
final analysis. In a preplanned secondary analysis in which patients
crossing over from placebo to sorafenib were censored, treatment
with sorafenib led to a survival advantage over placebo, further
suggesting that the primary end point was confounded by the
cross over.
Sorafenib was well tolerated, and most AEs were grade 1 or 2,
easily managed, and consistent with prior reports. The observed car-
diovascular events are more notable than in the original report and are
similar to what has been reported with other VEGF pathway directed
agents. Although these events were confounded by the longer treat-
ment time on sorafenib than placebo, they illustrate the potential
vascular toxicity of these agents. Whether more aggressive blood pres-
sure management, as has been suggested with increasing experience
with VEGF pathway directed agents, will ameliorate this toxicity re-
mains to be determined.
Increased tumor VEGF activity is frequently observed in patients
with RCC.7 Previous studies have shown that serum VEGF is corre-
lated with tumor grade, stage, and recurrence after definitive local
resection.14 Serum VEGF has also been associated with poorer out-
come with sunitinib therapy.15 The findings of the current study
support a prognostic role for VEGF in the largest RCC population
tested to date. The prognostic value of VEGF is preserved in multivar-
iate analyses including MSKCC score and ECOG PS, suggesting that
VEGF reflects an aggressive tumor biology not captured by these
scoring scales. In addition, although patients with either high or low
baseline VEGF benefit from sorafenib (in terms of PFS), the data
presented here suggest that patients with high VEGF levels, who are at
an initial disadvantage with poorer prognosis, may benefit more.
Updated results from TARGET, including data from pre cross-
over, 6-month post cross-over, and 16-month post cross-over cut-
off dates, demonstrated that sorafenib provided significant clinical
benefit for patients with RCC. Although final OS analyses were con-
founded by participants who had crossed over from placebo to sor-
afenib, censoring these patients at cross over revealed a significant
improvement in OS for patients randomly assigned to sorafenib.
These data confirm the findings of the planned interim analysis of
TARGET; sorafenib is efficacious for the treatment of advanced RCC.
These data are also in accordance with data recently reported with
sunitinib, suggesting that tyrosine kinase inhibitors improve OS in
RCC, although cross over and sequential treatments decrease the
magnitude of the difference.
OS
Placebo Sorafenib
Parameter Parameter
SE P Estimate SE P Estimate SE
0.13691 .0018 0.6746 0.21667 .025 0.30932 0.13782
0.14222 .0001 1.01794 0.23268 .0001 0.73377 0.14185
0.0002937 .042 0.0007215 0.000354 .015 0.0006643 0.0002718
2009 by American Society of Clinical Oncology 3317
 Escudier et al

Onyx, Genentech, Wyeth, Novartis Research Funding: Tim Eisen, Bayer

AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) indicated a financial or other interest that is relevant to the subject
matter under consideration in this article. Certain relationships marked
with a U are those for which no compensation was received; those
relationships marked with a C were compensated. For a detailed
description of the disclosure categories, or for more information about
ASCOs conflict of interest policy, please refer to the Author Disclosure
Declaration and the Disclosures of Potential Conflicts of Interest section in
Information for Contributors.
Employment or Leadership Position: Sibyl Anderson, Bayer
HealthCare (C); Gloria Hofilena, Bayer HealthCare (C); Minghua
Shan, Bayer HealthCare (C); Carol Pena, Bayer HealthCare (C);
Chetan Lathia, Bayer HealthCare (C) Consultant or Advisory Role:
Bernard Escudier, Bayer HealthCare (C), Pfizer (C), Roche (C); Tim
Eisen, Bayer HealthCare (C), Pfizer (C), Wyeth (C); Walter M. Stadler,
Onyx (C), Bayer HealthCare (C), Pfizer (C), Genentech (C), Novartis
(C), Wyeth (C); Cezary Szczylik, Bayer HealthCare (C); Michael
Staehler, Bayer HealthCare (C); Thomas E. Hutson, Bayer HealthCare
(C), Pfizer (C), Wyeth (C); Martin Gore, Bayer HealthCare (C); Carol
Pena, Bayer HealthCare (C); Ronald M. Bukowski, Pfizer (C), Bayer
HealthCare (C), Wyeth (C), Novartis (C), Genentech (C), Antigenics
(C), Regeneron (C) Stock Ownership: Walter M. Stadler, Abbott; Sibyl
Anderson, Bayer HealthCare; Gloria Hofilena, Bayer HealthCare;
Minghua Shan, Bayer HealthCare; Carol Pena, Bayer Healthcare; Chetan
Lathia, Bayer HealthCare Honoraria: Bernard Escudier, Bayer
HealthCare, Roche, Pfizer, Genentech, Novartis; Tim Eisen, Bayer
HealthCare, Pfizer, Wyeth; Cezary Szczylik, Bayer HealthCare; Michael
Staehler, Bayer HealthCare; Sylvie Negrier, Bayer HealthCare, Wyeth,
Pfizer; Thomas E. Hutson, Bayer HealthCare, Pfizer, Wyeth; Martin
Gore, Bayer HealthCare; Ronald M. Bukowski, Pfizer, Bayer HealthCare,
HealthCare, Pfizer; Walter M. Stadler, Bayer HealthCare, Pfizer,
Genentech, Novartis, Exilixis, Amgen, Bristol-Meyers Squibb,
AstraZeneca, Imclone Systems; Michael Staehler, Bayer HealthCare;
Sylvie Negrier, Wyeth; Thomas E. Hutson, Bayer HealthCare, Pfizer,
Wyeth; Martin Gore, Bayer HealthCare; Ronald M. Bukowski, Pfizer,
Bayer HealthCare, Novartis, Wyeth Expert Testimony: Walter M.
Stadler, Novartis (C); Cezary Szczylik, Bayer HealthCare (C) Other
Remuneration: Tim Eisen, Bayer HealthCare; Cezary Szczylik,
Bayer HealthCare
AUTHOR CONTRIBUTIONS
Conception and design: Bernard Escudier, Tim Eisen, Walter M. Stadler,
Sylvie Negrier, Christine Chevreau, Martin Gore, Gloria Hofilena,
Minghua Shan, Chetan Lathia, Ronald M. Bukowski
Provision of study materials or patients: Walter M. Stadler, Cezary
Szczylik, Stephane Oudard, Michael Staehler, Sylvie Negrier, Christine
Chevreau, Apurva A. Desai, Frederic Rolland, Tomasz Demkow, Thomas
E. Hutson, Martin Gore, Ronald M. Bukowski
Collection and assembly of data: Stephane Oudard, Frederic Rolland,
Martin Gore, Sibyl Anderson, Gloria Hofilena, Carol Pena, Chetan
Lathia, Ronald M. Bukowski
Data analysis and interpretation: Walter M. Stadler, Cezary Szczylik,
Apurva A. Desai, Thomas E. Hutson, Sibyl Anderson, Gloria Hofilena,
Minghua Shan, Carol Pena, Chetan Lathia, Ronald M. Bukowski
Manuscript writing: Walter M. Stadler, Thomas E. Hutson, Sibyl
Anderson, Carol Pena, Ronald M. Bukowski
Final approval of manuscript: Walter M. Stadler, Cezary Szczylik,
Stephane Oudard, Sylvie Negrier, Christine Chevreau, Apurva A. Desai,
Frederic Rolland, Thomas E. Hutson, Martin Gore, Gloria Hofilena,
Minghua Shan, Carol Pena, Chetan Lathia, Ronald M. Bukowski

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