Horizon Ii PDF

Cediranib Plus FOLFOX/CAPOXVersus Placebo Plus
FOLFOX/CAPOXin Patients With Previously Untreated

Metastatic Colorectal Cancer: ARandomized, Double-Blind,
Phase III Study (HORIZONII)
Paulo M. Hoff, Andreas Hochhaus, Bernhard C. Pestalozzi, Niall C. Tebbutt, Jin Li, Tae Won Kim,
Krassimir D. Koynov, Galina Kurteva, Tamas Pinte r, Ying Cheng, Brigitte van Eyll, Laura Pike,
Anitra Fielding, Jane D. Robertson, and Mark P. Saunders
See accompanying article on page 3588
Paulo M. Hoff, Instituto do Cncer do
Estado de Sao Paulo, Universidade de Sao
Paulo; Paulo M. Hoff, Centro de Oncologia,
Hospital Srio Libane s; Brigitte van Eyll,
Instituto do Cncer Arnaldo Vieira de
Carvalho, Sao Paulo, Brazil; Andreas Hoch-
haus, Klinik fu r Innere Medizin II, Univer-
sitatsklinikum Jena, Jena, Germany;
Bernhard C. Pestalozzi, University Hospital,
Zu rich, Switzerland; Niall C. Tebbutt, Austin
Health, Melbourne, Australia; Jin Li, Shang-
hai Cancer Hospital of Fudan University,
Shanghai; Ying Cheng, Jilin Provincial
Tumor Hospital, Jilin, China; Tae Won Kim,
Asan Medical Center, University of Ulsan,
Seoul, South Korea; Krassimir D. Koynov,
University Multiprole Hospital for Active
Treatment; Galina Kurteva, National Oncol-
ogy Medical Centre, Soa, Bulgaria; Tamas
Pinte r, Petz Aladr Hospital, Onkoradiologiai
Osztaly, Gyor, Hungary; Laura Pike, Anitra
Fielding, and Jane D. Robertson, AstraZen-
eca, Alderley Park, Maccleseld; and Mark
P. Saunders, Christie Hospital and Radium
Institute, Manchester, United Kingdom.
Submitted February 24, 2012; accepted
June 29, 2012; published online ahead of
print at www.jco.org on September 10,
2012.
Written on behalf of the HORIZON II
study group.
Supported by AstraZeneca, which also
provided support for medical writing by
Ben Clarke of Mudskipper Bioscience.
Presented as an oral presentation at the
35th European Society for Medical Oncol-
ogy Congress, Milan, Italy, October, 8-12,
2010.
Authors disclosures of potential conicts
of interest and author contributions are
found at the end of this article.
Clinical trial information: NCT00399035.
Corresponding author: Paulo M. Hoff, MD,
FACP, Instituto do Cncer do Estado de
Sao Paulo, Faculdade de Medicina da
Universidade de Sao Paulo, Av. Dr. Arnaldo
251, Sao Paulo, Brazil; e-mail:
paulo.hoff@icesp.org.br.
2012 by American Society of Clinical
Oncology
0732-183X/12/3029-3596/$20.00
DOI: 10.1200/JCO.2012.42.6031
A B S T R A C T
Purpose
Cediranib is a highly potent inhibitor of vascular endothelial growth factor (VEGF) signaling with activity
against all three VEGF receptors. HORIZON II [Cediranib (AZD2171, RECENTIN) in Addition to Chemo-
therapy Versus Placebo Plus Chemotherapy in Patients With Untreated Metastatic Colorectal Cancer]
assessed infusional uorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (FOLFOX/CAPOX)
with or without cediranib in patients with previously untreated metastatic colorectal cancer (mCRC).
Patients and Methods
Eligible patients were initially randomly assigned 1:1:1 to receive cediranib (20 or 30 mg per day)
or placebo plus FOLFOX/CAPOX. In an early analysis of this and two other cediranib studies
(HORIZON I [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With
Previously Treated Metastatic Colorectal Cancer] and HORIZON III [Cediranib Plus FOLFOX6
Versus Bevacizumab Plus FOLFOX6 in Patients With Untreated Metastatic Colorectal Cancer]),
the 20-mg dose met the predened criteria for continuation. Subsequent patients were randomly
assigned 2:1 to the cediranib 20 mg or placebo arms. Progression-free survival (PFS) and overall
survival (OS) were coprimary end points.
Results
In all, 860 patients received cediranib 20 mg (n 502) or placebo (n 358). The addition of
cediranib to FOLFOX/CAPOX resulted in PFS prolongation (hazard ratio [HR], 0.84; 95% CI, 0.73
to 0.98; P .0121; median PFS, 8.6 months for cediranib v 8.3 months for placebo) but had no
impact on OS (HR, 0.94; 95% CI, 0.79 to 1.12; P .5707; median OS, 19.7 months for cediranib
v 18.9 months for placebo). There were no signicant differences in the secondary end points of
objective response rate, duration of response, or liver resection rate. Median chemotherapy
dose-intensity was decreased by approximately 10% in patients treated with cediranib. Adverse
events (AEs) associated with cediranib were manageable.
Conclusion
Addition of cediranib 20 mg to FOLFOX/CAPOX resulted in a modest PFS prolongation, but no
signicant difference in OS. The cediranib AE prole was consistent with those from previous
studies. Because of the lack of improvement in OS, cediranib plus an oxaliplatin-based regimen
cannot be recommended as a treatment for patients with mCRC.
J Clin Oncol 30:3596-3603. 2012 by American Society of Clinical Oncology
INTRODUCTION
Oxaliplatin-based chemotherapy regimens (infu-
sional uorouracil [FU], leucovorin, and oxalip-
latin [FOLFOX]; capecitabine plus oxaliplatin
[CAPOX]) are commonly used as rst-line treat-
ment for metastatic colorectal cancer (mCRC);
however, for the 40% of patients with metastatic
disease at diagnosis, median survival is still less than
2 years. FOLFOXcomprises intravenous FU, leuco-
vorin, and oxaliplatin and is used in variations that
differ in the dose and delivery schedule of the com-
ponent drugs, such as FOLFOX4 [oxaliplatin 85
mg/m
2
intravenously on day 1, leucovorin 200
mg/m
2
per day by intravenous infusion on days 1
and 2, and FU 400 mg/m
2
intravenous bolus
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L R E P O R T
VOLUME 30 NUMBER 29 OCTOBER 10 2012
3596 2012 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at ASCO on October 19, 2012 from 158.232.242.13
Copyright 2012 American Society of Clinical Oncology. All rights reserved.
followed immediately by 600 mg/m
2
continuous intravenous infu-
sion over 22 hours on days 1 and 2, every 2 weeks], FOLFOX6
[oxaliplatin 100 mg/m
2
and leucovorin 400 mg/m
2
intravenously
on day 1, and FU 400 mg/m
2
intravenous bolus on day 1 followed
immediately by 2,400 mg/m
2
continuous intravenous infusion
over 46 hours every 2 weeks], and modied FOLFOX6 (mFOLFOX6)
[oxaliplatin85 mg/m
2
and leucovorin400 mg/m
2
intravenously on
day 1, and FU 400 mg/m
2
intravenous bolus on day 1 followed
immediately by 2,400 mg/m
2
over the next 46 hours every 2 weeks).
1,2
The CAPOXregimen is an
accepted alternative to FOLFOX and includes oral capecitabine as
the uoropyrimidine component in place of FU.
3,4
Targeting the vascular endothelial growth factor (VEGF) signal-
ing axis with bevacizumab, a humanized monoclonal antibody, has
resultedinimprovedprogression-freesurvival (PFS) but nodifference
in overall survival (OS) as rst-line treatment when combined with
oxaliplatin-based chemotherapy.
5
Indeed, no targeted agent has yet
demonstrated a statistically signicant increase in OS in this setting.
Cediranib is a once-daily oral tyrosine kinase inhibitor with
activity against all three VEGF receptors.
6,7
During early-phase
clinical evaluation, the combination of cediranib with mFOLFOX6
was tolerable
8
and demonstrated encouraging antitumor efcacy
in patients with mCRC.
9
The HORIZON II trial [Cediranib
(AZD2171, RECENTIN) in Addition to Chemotherapy Versus
Placebo Plus Chemotherapy inPatients With Untreated Metastatic
Colorectal Cancer] is one of two pivotal phase III studies of cedi-
ranib in rst-line mCRC; the other trial, HORIZON III [First
Line Metastatic Colorectal Cancer Therapy in Combination With
FOLFOX], compared the efcacy of cediranib plus FOLFOX6 ver-
sus bevacizumab plus FOLFOX6.
10,10a
This randomized, double-blind phase III study (ClinicalTrials
.gov identier NCT00399035) compared the efcacy and tolerability
of cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/
CAPOXin patients with previously untreated mCRC.
PATIENTS AND METHODS
Patients
Eligible patients were age 18 years with histologic/cytologic conr-
mation of metastatic (stage IV) CRC, a WHOperformance status (PS) of 0
or 1, and a life expectancy of 12 weeks. Patients must not have received
prior systemic therapy for mCRC; any adjuvant (or neoadjuvant) therapy
with oxaliplatin or FU must have been received more than 12 months or
more than 6 months, respectively, before study entry. Patients were ex-
cluded if they had an unresolved toxicity of Common Terminology Crite-
ria (CTC) grade 2 from previous anticancer therapy, or if they had
receivedprior anti-VEGFor antiVEGFreceptor therapy withmonoclonal
antibodies or small-molecule inhibitors.
Study Design
Patients randomly assigned to this double-blind, placebo-controlled
study were stratied according to chemotherapy regimen, WHO PS, and
Enrolled
(N = 1,254)
Random allocation
(n = 1,076)
Allocated to cediranib 20 mg (n = 502)
Did not receive cediranib (n = 2)
Did not receive chemotherapy (n = 2)
Allocated to placebo (n = 358)
Did not receive placebo (n = 0)
Did not receive chemotherapy (n = 0)
Receiving cediranib at data cut-off (n = 31)
Discontinued cediranib by data cut-off (n = 469)
) 3 1 1 = n ( t n e v e e s r e v d A
) 5 8 2 = n ( y c a c i f f e f o k c a L
) 1 = n ( p u - w o l l o f o t t s o L
Voluntary discontinuation (n = 51)
) 9 1 = n ( r e h t O
Receiving placebo at data cut-off (n = 16)
Discontinued placebo by data cut-off (n = 342)
) 0 5 = n ( t n e v e e s r e v d A
) 0 5 2 = n ( y c a c i f f e f o k c a L
) 2 = n ( p u - w o l l o f o t t s o L
) 2 1 = n ( r e h t O
) 2 0 5 = n ( d e z y l a n A
Excluded from ITT population (n = 0)
Excluded from safety set (n = 2)
Did not receive treatment (n = 2)
) 8 5 3 = n ( d e z y l a n A
Excluded from ITT population (n = 0)
Excluded from safety set (n = 0)
Not randomly allocated (n = 178)
Did not meet inclusion criteria (n = 168)
) 2 = n ( h t a e D
Lost to follow-up (n = 1)
Other reasons (n = 1)
Allocated to cediranib 30 mg
(n = 216)
Fig 1. CONSORT diagram. ITT,
intention-to-treat.
Cediranib Plus FOLFOX/CAPOX in Metastatic Colorectal Cancer
www.jco.org 2012 by American Society of Clinical Oncology 3597
baseline albuminand alkaline phosphatase values applied to centralized refer-
ence ranges.
11
The chemotherapy regimenfor each patient was selected by the
individual investigator; the regimenoptions were FOLFOX4, mFOLFOX6, or
CAPOX(oxaliplatin 130 mg/m
2
intravenously on day 1 and oral capecitabine
1,000 mg/m
2
twice per day on days 1 to 14 every 3 weeks). Patients were
initially randomly assigned 1:1:1 to receive once-per-day cediranib 30 mg,
cediranib 20 mg, or placebo in combination with FOLFOX/CAPOX. Recruit-
ment to all three arms continued until a planned end-of-phase (EoP) II
analysis, conducted by an independent data monitoring committee. The EoP
II analysis (February 2008) assessed all patients from the HORIZON II study
who had received treatment for 3 months, along with data from the
HORIZONI [CediranibPlus FOLFOX6 Versus BevacizumabPlus FOLFOX6
in Patients With Previously Treated Metastatic Colorectal Cancer] and III
studies, and concluded that the cediranib 20 mg dose met all of the predened
criteria for continuation. All study personnel other than the independent data
monitoring committee remained blinded to the data until the trial ended.
Following this analysis, recruitment to the cediranib 30 mg arm was discon-
tinued (patients receiving cediranib 30 mg were unblinded and given the
optiontocontinuewithopen-label cediranib20or 30mgplus chemotherapy),
and patients who enrolled subsequently were randomly assigned 2:1 to the
cediranib20mgor placeboarms. Followingreports of improvedPFSoutcome
for patients with mCRC who continued FOLFOX chemotherapy until pro-
gressionrather thanfor axednumber of cycles,
12,13
aprotocol amendment in
September 2007mandatedtreatment withblindedstudytreatment andchem-
otherapy (provided it remained well tolerated) until progression or any other
discontinuation criteria were met. The study was performed in accordance
with the Declaration of Helsinki, the International Conference on Harmoni-
zation/Good Clinical Practice, applicable regulatory requirements, and the
AstraZeneca policy on Bioethics.
14
Study Objectives
The primary objective was to compare the efcacy of cediranib 20 mg
when added to FOLFOX/CAPOX with that of FOLFOX/CAPOX alone by
assessment of the coprimary end points of PFS and OS. Secondary objectives
included assessments of objective response rate (ORR; ie, complete response
plus partial response), duration of response (DoR), rate of resection of liver
metastases, safety, and tolerability.
Assessments
Tumors were evaluated according to Response Evaluation Criteria in
Solid Tumors (RECIST) version 1.0
15
; tumor assessments were performed at
weeks 6, 12, 18, and 24, and then every 12 weeks in the absence of disease
progression. An independent central review of all available patient scans was
also performed. The severity of adverse events (AEs) was graded according to
the National Cancer Institute (NCI) CTCversion 3.0.
Statistical Methods
OS was dened as the time fromrandomassignment to death fromany
cause. PFS was dened as the time from random assignment to objective
progressionor deathfromany cause; patients whoremainedalive andwithout
a progressionevent at the time of analysis were censoredat the date of their last
evaluable objective tumor assessment. The study was powered to show supe-
riority for OS and aimed to recruit a total of 1,050 patients. To preserve the
overall type I error at 5%, OS was to be tested only if PFS was found to be
signicantly improved with cediranib treatment. Final PFS and OS analyses
were to be performed when approximately 510 deaths had occurred. At this
point, the analyses had 90% power (if the true hazard ratios [HRs] were 0.77
and0.74for thePFSandOSanalyses, respectively), assumingatwo-sided4.9%
signicance level. This signicance level was a consequence of an interim
analysis that was performed by using an OBrien-Fleming stopping boundary
once approximately 50% of the total events had occurred. OS and PFS were
analyzed by using a log-rank test stratied by WHO PS, chemotherapy regi-
men, a two-level liver function covariate (based on baseline albumin and
alkaline phosphatase levels), and study phase (ie, whether or not patients
contributed to the HORIZON program EoP II analysis). HRs and 95% CIs
were estimated from a Cox proportional hazards model adjusting for the
factors described earlier. Sensitivity analyses included an interval-censored
PFS analysis that used the approach outlined by Whitehead et al
16
and an
analysis of the tumor assessment data from the blinded, independent central
review. Efcacy analyses were performedonthe intention-to-treat population
for all patients randomly assigned to cediranib 20 mg or placebo.
RESULTS
Patients
Overall, 1,076 patients were randomly assigned to receive cedi-
ranib 30 mg (n 216), cediranib 20 mg (n 502), or placebo
(n358), incombinationwithFOLFOX/CAPOX(Fig 1). Of the 860
patients randomly assigned to the cediranib 20 mg or placebo arms,
225 (26.2%) received FOLFOX4, 147 (17.1%) received mFOLFOX6,
and 488 (56.7%) received CAPOX. Demographic and baseline char-
acteristics were generally well balanced between treatment groups
(Table 1). At data cutoff (March21, 2010), 720progressionevents and
523 death events had occurred.
Efcacy
For the coprimary end point of PFS, a statistically signicant
improvement was observed for patients treated with cediranib 20 mg
Table 1. Demographic and Baseline Characteristics
Characteristic
Cediranib
(20 mg)
(n 502)
Placebo
(n 358)
No. % No. %
Age, years
Median 58.0 59.0
Range 2-83 22-82
Sex
Male 299 59.6 212 59.2
Female 203 40.4 146 40.8
Race/ethnicity
White 320 63.7 254 70.9
Black 7 1.4 5 1.4
Asian 166 33.1 88 24.6
Other 9 1.8 11 3.1
WHO performance status
0 288 57.4 209 58.4
1 214 42.6 149 41.6
Type of cancer
Colon 288 57.4 232 64.8
Rectal 214 42.6 126 35.2
Baseline liver covariate
ALP 320 U/L and albumin 3.5 g/dL 397 79.1 274 76.5
Other combinations of ALP and albumin 105 20.9 84 23.5
Initial diagnosis to random assignment, months
6 326 64.9 245 68.4
6 to 12 22 4.4 12 3.4
12 to 24 57 11.4 37 10.3
24 to 36 48 9.6 28 7.8
36 49 9.8 36 10.1
Prior therapies
Radiotherapy 69 13.7 40 11.2
Adjuvant chemotherapy 104 20.7 80 22.3
Abbreviation: ALP, alkaline phosphatase.
Because patients who were randomly assigned to the cediranib 30 mg arm

had their treatment unblinded, a blinded randomized comparison of data from
all three arms was not possible; therefore, only data from the 20 mg and
placebo arms are presented.
Hoff et al
3598 2012 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
compared with placebo (HR, 0.84; 95% CI, 0.73 to 0.98; P .0121).
Median PFS was 8.6 months in the cediranib 20 mg arm and 8.3
months in the placebo arm(Fig 2A). The Kaplan-Meier curves reect
adherence to the visit schedule, with progression events generally
detected at these times. The proportions of patients alive and
progression free at 6 and 12 months after randomassignment were
69% and 25%, respectively, in the cediranib arm and 62% and
19%, respectively, in the placebo arm. The statistically signicant
improvement in PFS for patients treated with cediranib was con-
rmed by the independent central review (HR, 0.86; 95% CI, 0.73
to 1.02; P .0307). Furthermore, the results from all other sensi-
tivity analyses performed were statistically signicant and support-
ive of the primary analysis.
A subgroup analysis revealed that PFS was, in general, similar
across the patient subgroups explored, withthe exceptionof WHOPS
and prior adjuvant chemotherapy (Fig 2B). For patients with a base-
line WHO PS of 0, the treatment effect of cediranib versus placebo
appeared to be greater than the overall effect, whereas patients with a
baseline PS score of 1 did not seem to benet from the addition of
cediranib. However, the global interaction test, which assessed the
strength of evidence for consistency over all subgroups, was not sig-
nicant (P .3140); thus, the strength of evidence was not sufcient
A
B
0
HR = 0.84; 95% CI, 0.73 to 0.98; P = .0121
FOLFOX/CAPOX + cediranib 20 mg (n = 502)
FOLFOX/CAPOX + placebo (n = 358)
P
r
o
g
r
e
s
s
i
o
n
-
F
r
e
e
S
u
r
v
i
v
a
l

(
p
r
o
b
a
b
i
l
i
t
y
)
Time Since Random Allocation (months)
Hazard ratio (FOLFOX/CAPOX + cediranib /
FOLFOX/CAPOX + placebo)
1.0
0.8
0.6
Full analysis set
FOLFOX4
mFOLFOX6
CAPOX
In HORIZON EoPII analysis
Not in HORIZON EoPII analysis
WHO performance status 0
WHO performance status 1
Favorable liver function
Poor liver function
LDH 1.5 x ULN
LDH > 1.5 x ULN
VEGF < 98 pg/mL
VEGF 98 pg/mL
Age < 65 years
Age 65 years
Male
Female
Treated in China
Not treated in China
Treated in East Asia
Not treated in East Asia
Prior adjuvant chemotherapy
No prior adjuvant chemotherapy
0.4
0.2
6 3 12 9 18 15 33 30 27 24 21
No. at risk*
FOLFOX/CAPOX 502 411 311 204 111 74 47 16 9 5 2 1
+ cediranib 20 mg
FOLFOX/CAPOX 358 283 203 111 60 35 23 13 9 4 1 0
+ placebo
8.3 m 8.6 m
0.75 0.5 1.25 1.0
Hazard ratio < 1 favors cediranib
Fig 2. (A) Kaplan-Meier curves of
progression-free survival for patients who
received cediranib 20 mg plus infusional
uorouracil, leucovorin, and oxaliplatin/cape-
citabine plus oxaliplatin (FOLFOX/CAPOX) or
placebo plus FOLFOX/CAPOX. (B) Subgroup
analysis of progression-freesurvival. EoP, end-
of-phase [analysis]; FOLFOX4, oxaliplatin 85
mg/m
2
intravenously on day 1, leucovorin 200
mg/m
2
per day by intravenous infusion on
days 1 and 2, and uorouracil 400 mg/m
2
intravenous bolus followed immediately by
600 mg/m
2
over 22 hours on days 1 and 2 every 2 weeks;
HR, hazardratio; LDH, lactatedehydrogenase;
mFOLFOX6, oxaliplatin 85 mg/m
2
intrave-
nously on day 1, leucovorin 400 mg/m
2
intravenously on day 1, and uorouracil 400
mg/m
2
intravenously on day 1, followed by
continuous infusion of 2,400 mg/m
2
over the
next 46 hours every 2 weeks; ULN, upper
limit of normal. NOTE. 98 pg/mL was used as
the cutoff to dene low and high vascular
endothelial growth factor (VEGF) subgroups
because it was the overall median base-
line value across HORIZON II [Cediranib
(AZD2171, RECENTIN) in Addition to Chemo-
therapy Versus Placebo Plus Chemotherapy
in Patients With Untreated Metastatic Colo-
rectal Cancer] and HORIZON III (Cediranib
Plus FOLFOX6 Versus Bevacizumab Plus
FOLFOX6 in Patients With Untreated Meta-
static Colorectal Cancer). (*) No. of patients at
risk denotes No. of patients event free at the
beginning of the period.
toshowa denitive benet inany subgroupof patients. The treatment
effect was larger in patients who had received prior adjuvant therapy
before entering the study, although this was a small subgroup of
patients, and the CIs around the HR were wide. Further analysis
revealed that, in general, these patients were initially diagnosed a long
time before study entry, which is suggestive of a better prognosis and
thus consistent with the trend observed for WHOPS.
For the coprimary end point of OS, there was no statistically
signicant difference between the cediranib 20 mg and placebo
groups (HR, 0.94; 95%CI, 0.79 to 1.12; P.5707). The medianOS
was 19.7 and 18.9 months in the cediranib and placebo groups,
respectively (Fig 3). Furthermore, OS was generally consistent
across the patient subgroups explored (data not shown). Following
the discontinuation of randomly assigned treatment, there were no
major imbalances between study arms in second-line cancer ther-
apies received, with irinotecan-based chemotherapies being ad-
ministered most commonly.
TheORR(completeresponseplus partial response) was 50.6%in
the cediranib20mg groupand49.7%inthe placebogroup. There was
no difference in response rate between the two treatment arms (odds
ratio, 1.02; 95%CI, 0.77 to 1.34; P .9043; Table 2).
For the patients who responded, the median DoRs were 8.5 and
6.9 months in the cediranib and placebo arms, respectively. An anal-
ysis of the expected DoR was performed based on the approach de-
scribed by Ellis et al
17
which did not demonstrate a statistically
signicant result at the 5%level (P .0753).
Exposure to Cediranib and Chemotherapy
Reductions in the dose of randomly assigned treatment were
carried out for 17% of patients in the cediranib arm compared with
7% of patients in the placebo arm, whereas 47.8% of patients in the
cediranib and 31.3% of patients in the placebo arms experienced a
pause in randomly assigned treatment. During the rst 6 months of
treatment, mediandose intensities for FU, capecitabine, and oxalipla-
tin were all reduced by approximately 10% in the cediranib arm
compared with the placebo arm(Fig 4).
The proportion of patients receiving the planned number of
chemotherapy treatment cycles during the rst 6 months (FOLFOX,
12 cycles; CAPOX, eight cycles) was lower in the cediranib arm
(36.6%; n 183 of 500) compared with the placebo arm (41.9%;
0
HR 0.94, CI, 0.79 to 1.12; P = .5707
FOLFOX/CAPOX + cediranib 20 mg (n = 502)
FOLFOX/CAPOX + placebo (n = 358)
O
v
e
r
a
l
l

S
u
r
v
i
v
a
l
(
p
r
o
b
a
b
i
l
i
t
y
)
Time Since Random Allocation (months)
1.0
0.8
0.6
0.4
0.2
6 3 12 9 18 15 33 30 39 36 27 24 21
No. at risk
FOLFOX/CAPOX 502 472 434 393 342 300 262 168 88 59 32 13 9 2
+ cediranib 20 mg
FOLFOX/CAPOX 358 335 309 283 246 209 180 127 84 55 28 11 3 1
+ placebo
18.9 m 19.7 m
Fig 3. Kaplan-Meier curves of overall
survival for patients who received cedi-
ranib 20 mg plus infusional uorouracil,
leucovorin, and oxaliplatin/capecitabine plus
oxaliplatin (FOLFOX/CAPOX) or placebo plus
FOLFOX/CAPOX. HR, hazard ratio.
Table 2. Best Objective Response by RECIST
Response
Cediranib (20 mg)
(n 502)
Placebo
(n 358)
No. % No. %
Responders 254 50.6 178 49.7
Complete response 10 2.0 7 2.0
Partial response 244 48.6 171 47.8
Stable disease 179 35.7 119 33.2
Progressive disease 43 8.6 49 13.7
Nonevaluable 26 5.2 12 3.4
Abbreviation: RECIST, Response Evaluation Criteria in Solid Tumors.
FOLFOX/CAPOX + cediranib
FOLFOX/CAPOX + placebo
P
r
o
p
o
r
t
i
o
n

o
f

E
x
p
e
c
t
e
d

D
o
s
e

(
%
)
100
80
60
40
20
20
FU/
capecitabine
03 months
Oxaliplatin
03 months
FU/
capecitabine
36 months
Oxaliplatin
36 months
Fig 4. Median chemotherapy dose-intensity during the rst 6 months. FOLFOX/
CAPOX, infusional uorouracil, leucovorin, and oxaliplatin/capecitabine plus ox-
aliplatin; FU, uorouracil.
Hoff et al
n 150 of 358). During the course of the study, patients treated with
cediranib received fewer cycles of FOLFOX4 (median cycles of all
components: nine v 11), mFOLFOX6 (10 v 11), and CAPOX (six v
seven) compared with patients treated with placebo.
Treatment to Progression
Although the proportion of patients treated to progression with
cediranib was high (72%), the proportion treated to progression with
cediranibplus the uoropyrimidine component of chemotherapy (ie,
FU for FOLFOX patients or capecitabine for CAPOX patients) was
lower (42%) and less than the proportion of patients treated to pro-
gression with placebo plus the uoropyrimidine component (58%).
More patients in both arms received treatment to progression with
randomly assigned treatment plus capecitabine (48%in the cediranib
arm and 68% in the placebo arm) than randomly assigned treatment
plus FU (33% in the cediranib arm and 45% in the placebo arm),
althoughadifference betweenthe twoarms was observedregardless of
the uoropyrimidine component used.
Safety and Tolerability
The most common AEs experienced in both treatment arms
were diarrhea, nausea, and vomiting (Table 3). The overall incidence
of grade 3AEs was higher inthe cediranibarmthanthe placeboarm
(77.8%v 62.0%, respectively). In addition, the proportion of patients
in the cediranib arm who experienced serious adverse events (SAEs;
40.8%) was higher thaninthe placeboarm(29.3%), withdiarrheaand
dehydration being most common.
There was also a higher incidence of AEs leading to discontinua-
tion of randomly assigned treatment in the cediranib arm compared
with the placebo arm (22.8% v 16.2%). The most common AEs
leading to discontinuation of cediranib were diarrhea (n 15; 3.0%)
and hypertension (n 10; 2.0%). The incidence of AEs with the
outcome of death was similar in both arms (2.8% v 3.4% in the
cediranib and placebo arms, respectively). The only fatal AEs to occur
in more than one patient were pneumonia (cediranib, n 3 [0.6%];
placebo, n 2 [0.6%]) and septic shock (cediranib, n 2 [0.4%];
placebo, n 1 [0.3%]).
DISCUSSION
This phase III study of previously untreated patients with mCRCmet
the coprimary end point of PFS prolongation with cediranib plus
FOLFOX/CAPOX treatment compared with FOLFOX/CAPOX
alone; however, no benet was observed in the cediranib arm for the
coprimary end point of OS (postprogression therapy was balanced
across groups, both in terms of number of patients and type of treat-
ment, suggesting that this was not a major inuence on the different
outcomes for PFS and OS; 1.3% [cediranib] v 3.1% [placebo] of
patients who progressed, but without a death event, received bevaci-
zumab as second-line treatment). Although the PFS results observed
here are modest, they are similar to those reported in a phase III trial
5
assessing the efcacy of bevacizumab as rst-line treatment for pa-
tients with mCRC(bevacizumab plus FOLFOX4/CAPOXversus pla-
cebo plus FOLFOX4/CAPOX: HR, 0.83; 97.5% CI, 0.72 to 0.95;
P .002). The results are also consistent with a phase III trial of
rst-line panitumumab in a subset of patients with mCRCwith wild-
type KRAS (panitumumab plus FOLFOX4 v placebo plus FOLFOX4:
HR, 0.80; 95% CI, 0.66 to 0.97; P .02).
18
Furthermore, similar
median PFS durations were reported in phase III trials of vatalanib
19
and cetuximab,
20
both in combination with FOLFOX4, in patients
with previously untreated mCRC, although a signicant improve-
ment in PFS was not reported in either study. The absence of an OS
benet has been observed previously in phase III studies assessing the
addition of VEGF-targeted agents to FOLFOX/CAPOX in this set-
ting.
5,18,19
These consistent ndings raise the intriguing hypothesis
that an oxaliplatin-based regimen may not be the optimum regimen
for incorporation of VEGF-targeted therapies.
The results from the chemotherapy alone arm were as expected
on the basis of previous randomized trials with these regimens.
3,21
In
addition, both the PFS benet and OS results were consistent across
the three available chemotherapy regimens. The results of the pre-
dened subgroup analyses were generally consistent with the primary
analysis, andnosignicant differences were observedbetweenthe two
treatment arms in ORR or DoR. The ORR observed for cediranib-
treated patients in this study (50.6%) was comparable to that seen in
both the cediranib and bevacizumab arms in HORIZON III (46.3%
and 47.3%, respectively),
10
and to that in the bevacizumab armof the
phase III NO16966 trial [A Study of Bevacizumab Plus FOLFOX4/
Table 3. Most Commonly Reported Adverse Events and Grade
3 Adverse Events
Adverse Event by MedDRA
Term
Cediranib
(20 mg)
(n 500)
Placebo
(n 358)
No. % No. %
Any grade
Diarrhea 355 71.0 172 48.0
Nausea 257 51.4 169 47.2
Vomiting 233 46.6 131 36.6
Hypertension 230 46.0 43 12.0
Decreased appetite 229 45.8 126 35.2
Fatigue 203 40.6 104 29.1
Thrombocytopenia 146 29.2 88 24.6
Neutropenia 144 28.8 77 21.5
Peripheral sensory neuropathy 142 28.4 89 24.9
Abdominal pain 137 27.4 79 22.1
Hand-foot syndrome 123 24.6 57 15.9
Stomatitis 119 23.8 49 13.7
Paresthesia 97 19.4 86 24.0
Constipation 87 17.4 79 22.1
Grade 3
Diarrhea 106 21.2 29 8.1
Neutropenia 79 15.8 38 10.6
Thrombocytopenia 63 12.6 25 7.0
Hypertension 55 11.0 7 2.0
Fatigue 38 7.6 11 3.1
Vomiting 34 6.8 18 5.0
Hypokalemia 27 5.4 10 2.8
Peripheral sensory neuropathy 24 4.8 11 3.1
Decreased appetite 23 4.6 5 1.4
Hand-foot syndrome 21 4.2 4 1.1
Dehydration 20 4.0 6 1.7
NOTE. For any adverse event, 20% incidence in either arm; for grade 3
adverse events, 4% incidence in either arm.
Abbreviation: MedDRA, Medical Dictionary for Regulatory Activities.
CAPOXas a First-Line Therapy in Patients With Metastatic Colorec-
tal Cancer] (47%).
5
The rate of liver resection was assessed to determine whether
cediranib treatment conferred any improvement over placebo in re-
ducing liver metastases to a size suitable for resection, which is associ-
ated with improved long-term survival.
22
In this study, the resection
rate was foundtobe comparable betweenthe twotreatment arms (see
Results inthe Appendix, online only); however, because the study was
not designed specically to assess resection rates, the rate was low in
both arms.
Compared with the placebo arm, chemotherapy dose-intensity
was reduced by approximately 10% in the cediranib arm, fewer pa-
tients were treatedtoprogressionwithchemotherapy, andfewer com-
plete chemotherapy cycles were administered, despite a longer PFS.
Differences in chemotherapy dosing between the arms were observed
within 3 months and were more marked by 6 months; this 6-month
treatment period was affected least by disease progression and there-
fore most accurately reects the differences intolerability betweenthe
arms. Before the protocol amendment mandating treatment to pro-
gression, a large proportion of patients discontinued FU after 6
months. Following the amendment, higher treatment-to-progression
rates were observed. Treatment-to-progression rates were generally
higher for patients receiving oral capecitabine comparedwithintrave-
nous FU. Overall, these ndings suggest that treatment withcediranib
led to patients receiving less chemotherapy compared with those re-
ceiving placebo. There was a higher incidence of grade 3 AEs, SAEs,
and AEs requiring a pause or discontinuation of randomly assigned
therapy in the cediranib arm; the additive toxicity of both cediranib
and chemotherapy in the combination arm is likely to have contrib-
uted to the observed reduction in chemotherapy dose-intensity, with
more patients treated with cediranib discontinuing chemotherapy
because of AEs. This may have affectedthe clinical outcomes observed
in the two treatment arms.
The overall AE prole of cediranib was consistent with previous
studies and was generally similar across the different chemotherapy
regimens used. Diarrhea was the most common AE and had the
greatest impact on cediranib dosing. Grade 3 diarrhea, hyperten-
sion, neutropenia, and thrombocytopenia were all experienced by
5%more of the patients inthe cediranib armthaninthe placebo arm.
An exploratory analysis was performed to assess whether there
was a relationship between the early onset of hypertension in patients
and efcacy. Development of hypertension was found to be weakly
prognostic of increased PFS and OS but was not predictive of a differ-
ential outcome with cediranib treatment. These results are supportive
of ndings from a phase II trial of cediranib in patients with non
small-cell lung cancer; however, the prognostic effect was weaker in
this trial.
23
In conclusion, a statistically signicant prolongation in PFS was
observed in patients with mCRC who were treated with cediranib 20
mg in addition to FOLFOX/CAPOX, conrming the biologic activity
of this tyrosine kinase inhibitor. However, the study did not meet its
other coprimary end point of improving OS; therefore, cediranib in
combination with an oxaliplatin-based regimen cannot be recom-
mended as a treatment for patients with mCRC.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) and/or an authors immediate family member(s) indicated a
nancial 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 conict of interest policy,
please refer to the Author Disclosure Declaration and the Disclosures of
Potential Conicts of Interest section in Information for Contributors.
Employment or Leadership Position: Laura Pike, AstraZeneca (C);
Anitra Fielding, AstraZeneca (C); Jane D. Robertson, AstraZeneca (C)
Consultant or Advisory Role: Paulo M. Hoff, AstraZeneca (C); Andreas
Hochhaus, Novartis (C), Pzer (C), Ariad Pharmaceuticals (C); Jin Li,
Eli Lilly (C), sano-aventis (C); Krassimir D. Koynov, sano-aventis (C),
GlaxoSmithKline (C), Pzer (C), AstraZeneca (C), Roche (C), Merck
Serono (C), Eli Lilly (C) Stock Ownership: Laura Pike, AstraZeneca;
Anitra Fielding, AstraZeneca; Jane D. Robertson, AstraZeneca
Honoraria: Jin Li, Roche, Pzer; Krassimir D. Koynov, sano-aventis,
GlaxoSmithKline, Pzer, AstraZeneca, Roche, Merck Serono, Eli Lilly,
Amgen, Actavis; Mark P. Saunders, AstraZeneca Research Funding:
Paulo M. Hoff, AstraZeneca; Andreas Hochhaus, AstraZeneca, Novartis,
Pzer, Ariad Pharmaceuticals, Merck Sharp & Dohme; Niall C. Tebbutt,
AstraZeneca; Jin Li, Merck Expert Testimony: None Other
Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Paulo M. Hoff, Jane D. Robertson
Provision of study materials or patients: Jin Li, Galina Kurteva, Brigitte
van Eyll, Mark P. Saunders
Collection and assembly of data: Andreas Hochhaus, Bernhard C.
Pestalozzi, Niall C. Tebbutt, Jin Li, Krassimir D. Koynov, Galina Kurteva,
Tamas Pinter, Ying Cheng, Brigitte van Eyll, Anitra Fielding, Jane D.
Robertson, Mark P. Saunders
Data analysis and interpretation: Andreas Hochhaus, Bernhard C.
Pestalozzi, Niall C. Tebbutt, Tae Won Kim, Laura Pike, Anitra Fielding,
Jane D. Robertson
Manuscript writing: All authors
Final approval of manuscript: All authors
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Cediranib Plus FOLFOX/CAPOXVersus Placebo Plus

FOLFOX/CAPOXin Patients With Previously Untreated

Because patients who were randomly assigned to the cediranib 30 mg arm

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