VOLUME 26 䡠 NUMBER 14 䡠 MAY 10 2008

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

Lapatinib Versus Hormone Therapy in Patients With

From the Department of Medical
Oncology, Hôpital Saint André,
Bordeaux; Department of Medical
Oncology, Centre René Gauducheau, St
Herblain; Department of Medical Oncol-
ogy, Hôpital Pasteur, Colmar, France;
Department of Medical Oncology,
Christie Hospital, Manchester;
GlaxoSmithKline, Greenford; Depart-
ment of Medical Oncology, Guys and
St Thomas’s Hospitals; Department of
Medical Oncology, Royal Marsden
Hospital, London, United Kingdom;
Department of Medical Oncology,
Rigshospital, Copenhagen, Denmark;
Department of Medical Oncology, Tech-
nische Universität München, München,
Germany; Department of Medical
Oncology, Université Catholique de
Louvain, Brussels; and Department of
Medical Oncology, Universitair Zeiken-
huis Gasthuisberg, Leuven, Belgium.
Submitted September 18, 2007;
accepted January 25, 2008.
Both A.R. and R.H. contributed equally
to this work.
Presented at the 42nd Annual Meeting
of the American Society of Clinical
Oncology, June 2-6, 2006, Atlanta, GA.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Advanced Renal Cell Carcinoma: A Randomized Phase III
Clinical Trial
Alain Ravaud, Robert Hawkins, Jason P. Gardner, Hans von der Maase, Niko Zantl, Peter Harper,
Frédéric Rolland, Bruno Audhuy, Jean-Pascal Machiels, Frank Pétavy, Martin Gore, Patrick Schöffski, and
Iman El-Hariry
A B S T R A C T
Purpose
Lapatinib is an orally reversible inhibitor of epidermal growth factor receptor (EGFR)/human
epidermal growth factor receptor 2 (HER-2) tyrosine kinases with demonstrated activity in patients
with HER-2–positive breast cancer. In the current phase III open-label trial, lapatinib was compared
with hormone therapy (HT) in patients with advanced renal cell carcinoma (RCC) that express
EGFR and/or HER-2.
Patients and Methods
Patients with advanced RCC who had experienced disease progression through first-line cytokine
therapy—stratified by Karnofsky performance status and number of metastatic sites—were randomly
assigned to lapatinib 1,250 mg daily or HT. The primary end point was time to progression (TTP);
secondary end points included overall survival (OS), safety, and biomarker analyses.
Results
Four hundred sixteen patients were enrolled onto the study. Median TTP was 15.3 weeks for lapatinib
versus 15.4 weeks for HT (hazard ratio [HR] ⫽ 0.94; P ⫽ .60), and median OS was 46.9 weeks for
lapatinib versus 43.1 weeks for HT (HR ⫽ 0.88; P ⫽ .29). In a biomarker analysis of patients with
EGFR-overexpressed tumors (3⫹ by immunohistochemistry [IHC]; n ⫽ 241) median TTP was 15.1
weeks for lapatinib versus 10.9 weeks for HT (HR ⫽ 0.76; P ⫽ .06), and median OS was 46.0 weeks
for lapatinib versus 37.9 weeks for HT (HR ⫽ 0.69; P ⫽ .02). These results were confirmed by Cox
regression analysis. No unexpected toxicities were observed; the most commonly reported drug-
related adverse events (all grades) for lapatinib were rash (44%) and diarrhea (40%).
Conclusion
Lapatinib was well tolerated with equivalent overall efficacy to HT in advanced RCC patients who
had experienced disease progression while receiving cytokines, and the study supports that
lapatinib prolonged OS relative to HT in patients with 3⫹ EGFR status determined by IHC.
J Clin Oncol 26:2285-2291. © 2008 by American Society of Clinical Oncology

Corresponding author: Alain Ravaud,

MD, PhD, Department of Medical
Oncology, Hôpital Saint André, CHU
Bordeaux, 1 rue Jean Burguet, 33075
Bordeaux cedex, France; e-mail:
alain.ravaud@chu-bordeaux.fr.
© 2008 by American Society of Clinical
Oncology
0732-183X/08/2614-2285/$20.00
DOI: 10.1200/JCO.2007.14.5029
INTRODUCTION
The incidence of renal cell carcinoma (RCC) is in-
creasing in Europe and the United States.1 Meta-
static RCC is insensitive to chemotherapy and shows
low rates of response to immunotherapy.2 However,
antiangiogenic-targeted therapies such as sunitinib
and sorafenib have emerged as important new stan-
dard treatments in first-line treatment or after fail-
ure of immunotherapy.3,4
Epidermal growth factor receptor (EGFR) and
its ligands, EGF and transforming growth factor ␣
(TGF-␣), are overexpressed in RCC.5,6 Both ligands
stimulate the proliferation of human RCC cell lines,
while inhibitors of EGFR inhibit proliferation and
tumor growth in vitro and in vivo.5,6 In addition,
EGFR signaling is involved in the tumorigenesis as-
sociated with mutations of the von Hippel-Lindau
(VHL) tumor suppressor gene, which are found in
the majority of cases of clear cell RCC.7,8 The role of
the related receptor, human epidermal growth fac-
tor receptor 2 (HER-2, or ErbB2), in RCC pathogen-
esis is less clear; however, co-overexpression of
EGFR and HER-2 is associated with metastatic dis-
ease.9 Lapatinib (Tykerb/Tyverb; GlaxoSmithKline,
Research Triangle Park, NC) is a dual inhibitor of the
intracellular tyrosine kinase domains of EGFR and
HER-2, and has recently demonstrated efficacy in a
randomized phase III study in combination with
chemotherapy in HER-2– overexpressing breast

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 Ravaud et al
cancer patients.10 Lapatinib is a particularly attractive agent to study in
advanced RCC.
Therefore, we conducted a prospective, open-label, randomized
phase III trial of lapatinib in patients with advanced RCC that ex-
pressed EGFR or HER-2, and had experienced disease progression
while receiving first-line cytokine therapy. At the time this trial was
designed, there were limited treatment options for RCC patients who
had experienced disease progression while receiving cytokine therapy.
Hormone therapy (HT) was selected for the control arm in the trial
because it is well tolerated and was used as a standard comparison
treatment in a seminal randomized trial.11
PATIENTS AND METHODS
Patients
Eligible patients had histologically or cytologically confirmed, locally
advanced or metastatic RCC of any histologic subtype that was not amenable
to curative surgery or radiotherapy. Other inclusion criteria included disease
progression after or intolerance to first-line cytokine-based therapy; expres-
sion of EGFR and/or HER-2 in tumor tissue with immunohistochemistry
(IHC) 1⫹, 2⫹, or 3⫹; measurable disease according to the Response Evalua-
tion Criteria in Solid Tumors; cardiac ejection fraction within institutional
normal limits as measured by multigated acquisition scan or echocardiogra-
phy; age ⱖ 18 years; Karnofsky performance status (KPS) ⱖ 70%; and life
expectancy ⱖ 12 weeks. Prior systemic neoadjuvant or adjuvant therapy was
allowed. Patients had to have adequate hematologic, renal, and hepatic func-
tion, defined as granulocyte count ⱖ 1,500/␮L; platelet count ⱖ75,000/␮L;
hemoglobin ⱖ 9 g/dL; serum creatinine ⱕ 180 ␮mol/L and estimated creati-
nine clearance ⱖ 30 mL/min; total bilirubin less than 1.5⫻ the upper limit of
normal (ULN); ALT less than 3⫻ ULN unless due to disease, in which case up
to 5⫻ ULN was allowed. Exclusion criteria included prior or concurrent
treatment with an EGFR or HER-2 inhibitor; concurrent systemic corticoste-
roid therapy; recently completed or concurrent treatment with another inves-
tigational therapy; active CNS metastases; malabsorption syndrome or other
GI disease or resection that could affect absorption; and severe cardiovascular
disease or cardiac disease requiring a device. The study was approved by the
institutional review board or independent ethics committee at each clinical
site. All patients gave written informed consent before participating in the trial.
Study Design
Patients were randomly assigned to receive lapatinib 1,250 mg daily or
HT. Randomization was done centrally via an interactive voice response sys-
tem, and stratified according to KPS (70% to 80%, or 90% to 100%) and the
number of metastatic sites (ⱕ two or ⬎ two).
Lapatinib was administered the same time each day immediately after the
morning meal; HT was also administered daily, and consisted of megestrol
acetate or tamoxifen selected and provided by the investigator. All patients
were treated until disease progression or withdrawal from the study, and were
evaluated for toxicity every 4 weeks. Those patients who had derived clinical
benefit as determined by the investigator were allowed to continue receiving
treatment even after evidence of radiologic disease progression.
The study was designed in 2001, initially as a phase II randomized trial
using objective response rate as the primary end point. In 2002, emerging
evidence demonstrated that time to disease progression was a more suitable
end point for targeted therapies than response rate, and the design was modi-
fied to incorporate time to progression (TTP) as a new primary end point.12,13
A total of 110 patients were recruited after completing the phase II part of the
study. The study accrual was stopped for 3 months in the interim until the
protocol was amended and local ethics committee approvals were obtained.
The study was also expanded to a phase III design based on results from a
preplanned interim analysis of safety data alone. Throughout the amendment,
the investigators and the sponsor were blinded to the results.
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The primary end point was TTP, defined as the interval between date of
randomization and the earliest date of radiologically confirmed progression by
independent review or death due to RCC, in the intent-to-treat population.
Secondary end points included tumor response rate; time to response; clinical
benefit; overall survival (OS); and correlative analysis of tumor biomarkers,
including analysis of TTP and OS, depending on level of expression of EGFR
and/or HER-2.
Further determination of efficacy was based on objective measurements
of disease using Response Evaluation Criteria in Solid Tumors.14 Disease
assessment was done at baseline, then every 8 weeks after initiating treatment.
Patients experiencing a partial response (PR) or complete response had to have
a confirmatory assessment at least 4 weeks later. Disease assessments were
continued until progressive disease was documented, even if treatment was
discontinued. All scans were reviewed by a blinded, independent radiologic
review board (Synarc, San Francisco, CA).
Safety was assessed by analyzing the physical examination findings,
CBCs, coagulation parameters, clinical chemistry, urinalysis, and KPS (as-
sessed every 4 weeks); 12-lead ECG, conducted at baseline and follow-up;
multigated acquisition scan or echocardiography (conducted every 8 weeks);
and adverse events. All randomly assigned patients who received at least one
dose of the study drug were included in the safety population. Adverse events
were rated by the investigators using the National Cancer Institute Common
Toxicity Criteria v2.0.15
IHC for EGFR (PharmDx; Dako, Glostrup, Denmark) and HER-2 (Her-
cepTest, Dako) expression was performed centrally in a blinded, independent
manner by Quest Diagnostics (Madison, NJ) using fresh or paraffin-
embedded biopsy tissue taken from primary and/or metastatic tumor sites
before the patient was enrolled onto the study. Moderate to strong complete
membrane staining in more than 10% of the tumor cells was classified as 3⫹
strongly positive.
Statistical Analysis
It was determined that a total of 257 TTP events would be required to
detect a 50% increase in the median TTP (from 4 to 6 months) between groups
using a log-rank test at the two-sided 5% significance level with 90% power. To
allow for losses to follow-up of up to 10% of patients, it was determined that
400 patients would need to be enrolled. Interim analyses for safety and futility
were dictated by the protocol after 100 and an additional 100 patients (total of
200 patients) were enrolled and observed for at least 16 weeks. An independent
data-monitoring committee evaluated the interim data to provide an opportunity
to terminate the study if concerns about safety arose or if there was adequate
evidence to reject the alternative hypothesis that lapatinib improves TTP by 50%
compared with hormonal treatment in favor of the null hypothesis.
TTP was summarized using inverse cumulative incidence curves, from
which median TTP was calculated. Treatment arms were compared using the
stratified log-rank test, and an estimate of the hazard ratio (HR) and corre-
sponding 95% CI were calculated. Tumor response rates and clinical benefit
(overall response rate [complete response ⫹ PR] ⫹ stable disease at 6 months)
rates in each group were compared using stratified Fisher’s exact tests, with
95% CI calculated for differences in rates between groups.
A Cox regression analysis for OS was performed on the following sub-
groups: treatment with lapatinib versus HT and EGFR (0, 1⫹, or 2⫹ v 3⫹).
The regression model was adjusted for KPS and number of metastatic sites. A
risk factor analysis was also conducted according to key categoric variables
relevant in this patient population: KPS (⬍ 80% or ⱖ 80%), hemoglobin (less
than normal or more than normal), corrected serum calcium (ⱕ 10 or ⬎ 10
mg/dL) to define risk groups.16
RESULTS
Patients
Between December 2002 and February 2005, a total of 416 pa-
tients from 116 centers in 11 countries were randomly assigned to
receive lapatinib (n ⫽ 209) or HT (n ⫽ 207). Figure 1 shows the
patients’ progression through the trial, and Table 1 lists the baseline
JOURNAL OF CLINICAL ONCOLOGY
 Phase III Trial of Lapatinib Versus HT in RCC

416 Randomized

209 allocated to lapatinib 207 allocated to HT

205 received allocated intervention 199 received allocated intervention

4 did not receive allocated 8 did not receive allocated
intervention intervention
(1 died, 1 progressed, 1 withdrew (1 progressed, 2 withdrew
consent, 1 unspecified) consent, 1 protocol violation,
4 unspecified)

Fig 1. Trial profile. HT, hormone therapy;

ITT, intent to treat.

2 Lost to follow-up 3 Lost to follow-up

186 Discontinued intervention 187 Discontinued intervention

146 progressive disease 160 progressive disease
20 adverse event, 11 adverse events
8 died 7 died
5 withdrew consent 4 withdrew consent
1 protocol violation 1 protocol violation
6 not specified 3 not specified

209 included in efficacy analysis (ITT) 207 included in efficacy analysis (ITT)

205 included in safety analysis 199 included in safety analysis

characteristics of the enrolled patients. The two treatment arms were
well balanced for all baseline factors, including EGFR expression levels
and the relevant prognostic risk factors in this patient population.16
The majority of patients had clear cell histology (87%) and high (IHC
3⫹) tumor expression of EGFR (58%).
Efficacy
The planned analysis of efficacy end points, including EGFR
expression, was performed when 257 progression events by indepen-
dent assessment were achieved in September 2005, and the results are
presented here. For time-to-event end points, the last date of known
contact was used for those patients that had not reached the event at
the time of analysis, and such patients were considered as censored in
the analysis.
Median TTP, the primary end point, was similar between treat-
ment arms in the intent-to-treat analysis (Fig 2A). The median TTP
was 15.3 weeks in the lapatinib arm versus 15.4 weeks in the HT arm
(HR, 0.94; P ⫽ .595; 95% CI, 0.75 to 1.18). Median OS (Fig 2B), was
46.9 weeks in the lapatinib arm and 43.1 weeks in the HT arm (HR,
0.88; P ⫽ .290; 95% CI, 0.69 to 1.12).
Tumor response rate (PR only) was 1.4% and 0.5% in the lapa-
tinib and HT groups, respectively. Approximately one third of pa-
tients in each arm experienced stable disease at 2 months as the best
response to treatment (66 [32%] in the lapatinib arm, and 65 [31%] in
the HT arm). Rates of clinical benefit (PR or stable disease ⱖ 6
months) were similar between arms: 8.1% with lapatinib and 9.7%
with HT.
Exploratory analyses of TTP and OS were conducted based on
EGFR tumor expression levels as part of the secondary biomarker end
point. Significant differences were not observed between groups for
TTP or OS for patients with EGFR 0, 1⫹, or 2⫹ staining intensity (Figs
2C and 2D). In the group of patients with EGFR 3⫹ tumors, median
TTP was prolonged over 4 weeks in the lapatinib arm (HR, 0.76; 95%
CI, 0.6 to 1.0; P ⫽ .06) from 10.9 to 15.1 weeks, and median OS was
significantly increased by more than 8 weeks (HR, 0.69; 95% CI, 0.5 to
1.0; P ⫽ .019) from 37.9 to 46.0 weeks (Figs 2E and 2F). These results
were confirmed by multivariate Cox regression modeling, which
demonstrated no treatment difference in the patients with low expres-
sion of EGFR (HR, 1.18; 95% CI, 0.80 to 1.73; P ⫽ .40), and a
significant effect on OS between the two treatment groups for patients
with EGFR 3⫹ expression (HR, 0.66; 95% CI, 0.48 to 0.91; P ⫽ .012).
After progression, approximately half of the patients in each arm
(92 receiving lapatinib and 105 receiving HT) received subsequent
therapy. Those patients who had derived clinical benefit continued to
receive treatment as determined by the investigator after disease pro-
gression. These included 49 patients in the lapatinib arm (average
duration 25 days), and 45 patients in the HT arm (average duration 28
days). Other therapies included antiangiogenesis agents, and were
evenly distributed between the arms (13 after lapatinib v 15 after HT).

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 Ravaud et al

[n ⫽ 15] and 2.0% with HT [n ⫽ 3]). No grade 4 events were reported

Table 1. Baseline Patient Characteristics of the 416 Patients
Included in the Analysis
in the lapatinib arm. Adverse events led to treatment discontinuation
in 13% (n ⫽ 26) and 9% (n ⫽ 18) of patients in the lapatinib and HT
Lapatinib HT
(n ⫽ 209) (n ⫽ 207) arms, respectively. Two patients in the lapatinib group died as a result
No. of No. of
of a serious, drug-related adverse event. One of these patients devel-
Characteristic Patients % Patients % oped a fatal cerebral hemorrhage 265 days after starting lapatinib. The
Age, years other patient developed interstitial pulmonary fibrosis after complet-
Median 61 62 ing lapatinib treatment 201 days earlier, and this event was categorized
Range 31-83 19-81 by the investigator as drug related.
Sex
Male 149 71 156 75
Female 60 29 51 25 DISCUSSION
KPS
90%-100% 117 56 128 62
70%-80% 92 44 79 38 This large, phase III trial of lapatinib versus HT did not meet the
Stage primary end point in the overall population of advanced RCC patients
III 7 3 4 2 whose disease had previously progressed after cytokine-based therapy.
IV 201 96 202 98 However, based on an exploratory analysis of EGFR level expression in
Histology
tumors, treatment with lapatinib seemed to prolong survival relative
Clear cell 175 84 187 90
Papillary 16 8 8 4
to HT in patients with high levels of tumor EGFR.
Chromophobe 6 3 3 1 EGFR is a well-described potential therapeutic target in RCC.
Collecting duct 0 1 ⬍1 Both EGFR and its ligand TGF-␣ are overexpressed in RCC, and
Unclassified 12 6 8 4 TGF-␣ is a critical mitogen for the autonomous growth of VHL-
Prior nephrectomy 196 94 194 94 inactivated (VHL⫺/⫺) RCC cells.8 Indeed, the TGF-␣/EGFR path-
No. of metastatic sites way seems to be an important pathway for carcinogenesis in VHL⫺/⫺
ⱕ2 106 51 105 51
RCC. When EGFR is inhibited, the autonomous growth of VHL⫺/⫺
⬎2 103 49 102 49
Common sites of metastasis
RCC cells is abolished in vitro.8 As such, several EGFR inhibitors have
Lung 167 43 169 46 been evaluated in phase II trials in RCC. The anti-EGFR monoclonal
Bone 70 18 58 16 antibody (mAb), cetuximab, produced no responses among 55 pa-
Liver 44 11 52 14 tients with metastatic RCC treated in a single-arm phase II trial,17
Lymph node 109 28 90 24 whereas a similar anti-EGFR mAb, panitumumab, produced three
Risk factor levelⴱ major responses, two minor responses, and disease stabilization in 44
Favorable 86 41 77 37
patients with metastatic RCC treated in a dose-ranging trial (N ⫽
Intermediate 65 31 76 37
Poor 58 28 54 26
88).18 The small-molecule tyrosine kinase inhibitors, gefitinib and
EGFR expression IHC scoring erlotinib, have not demonstrated significant activity with respect to
0 3 1 1 ⬍1 response rates in phase II trials, although disease stabilization was
1⫹ 25 12 21 10 reported in approximately 25% to 50% of patients.19-22 Dual targeted
2⫹ 65 31 60 29 therapy with a combination of erlotinib and bevacizumab, a mAb
3⫹ 116 56 125 60
directed against vascular endothelial growth factor, seemed to have
HER-2 expression IHC scoring
0 196 94 193 93
promising activity in metastatic RCC in a single-arm, open-label tri-
1⫹ 10 5 8 4 al.23 However, the combination was not found to be superior to
2⫹ 2 ⬍1 1 ⬍1 bevacizumab alone in this setting.24 None of these studies with EGFR
3⫹ 0 0 inhibitors selected patients for target expression or analyzed the results
Abbreviations: HT, hormone therapy; KPS, Karnofsky performance status; based on EGFR levels.
HER-2, human epidermal growth factor receptor 2; EGFR, epidermal growth To our knowledge, this was the first randomized phase III trial of
factor receptor; IHC, immunohistochemistry.
ⴱ
The variables considered in the risk factor assessment included hemoglobin
an EGFR/HER-2 inhibitor in RCC patients who were selected for
(⬍ normal or ⬎ normal), corrected serum calcium (ⱕ 10 or ⬎ 10 mg/dL), and expression of either target receptor. EGFR was overexpressed (IHC
KPS (⬍ 80% or ⱖ 80%) The favorable category was defined by the presence 3⫹) by the majority (58%) of patients; conversely, HER-2 was de-
of 0 factors, intermediate by one factor and poor by two or three factors.16
Forty-one patients had missing values for one factor, and five patients had tected in only 5% of patients. The exploratory subset analysis in the
missing values for two factors. EGFR-overexpressing patients (n ⫽ 241) was conducted as part of the
biomarker secondary end point of this study to generate hypotheses
and showed that OS was more prolonged in the lapatinib arm than in
the HT arm (HR ⫽ 0.69). Two nonexclusive hypotheses could explain
Safety the results observed in the current study. First, EGFR is a poor prog-
Table 2 summarizes the most commonly reported drug-related nostic factor in several malignancies, and is associated with reduction
adverse events in the safety population. In the lapatinib arm, these in survival. Previous smaller studies in RCC have suggested that the
events were rash (44%), diarrhea (40%), and nausea (18%). The presence and/or expression level of EGFR could have a deleterious
majority of drug-related adverse events were grade 1 and 2, and the impact on survival.5,25 Therefore, patients in the control arm with high
overall incidence of grade 3 and 4 events was low (7.3% with lapatinib EGFR-expressing tumors may have significantly worse prognosis than

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 Phase III Trial of Lapatinib Versus HT in RCC

A B
100 100
No Disease Progression

Cumulative Survival (%)

90 90
P = 0.595 P = 0.29
80 HR = 0.94 80 HR = 0.88
70 70
60 60 Lapatinib 1250 mg (N = 209; median OS, 46.9 wks)
50 50
40 40
Lapatinib 1250 mg (N = 209; median TTP, 15.3 wks)
30 30
20 20 Hormonal Therapy
Hormonal Therapy
10 (N = 207; median TTP, 15.4 wks) 10 (N = 207; median OS, 43.1 wks)

0 6 16 24 32 40 48 56 64 72 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144

No. at risk Time (weeks) No. at risk Time (weeks)

Lapatinib 209 141 79 46 29 17 10 3 1 1 Lapatinib 209 192 168 140 113 89 75 50 34 24 16 12 9 7 5 3 1 1
HT 207 137 71 40 22 12 6 3 2 1 HT 207 186 163 136 100 71 52 36 26 23 14 6 3 3 2 1

C D
100 100
No Disease Progression

Cumulative Survival (%)

90 90
P = 0.182 P = 0.56
80 HR = 1.25 80 HR = 1.11
70 70
60 60 Hormonal Therapy (N =82; median OS, 54.1 wks )
Hormonal Therapy (N = 82; median TTP, 19 wks)
50 50
40 40
Lapatinib 1250 mg
30 30 (N = 93; median OS, 46.9 wks)
20 Lapatinib 1250 mg 20
10 (N = 93; median TTP, 25.7 wks) 10

0 6 16 24 32 40 48 56 64 72 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144

No. at risk Time (weeks) No. at risk Time (weeks)

Lapatinib 93 64 36 18 10 7 4 2 1 1 Lapatinib 93 85 74 62 52 42 32 25 17 14 9 7 4 3 2 2 1 1
HT 82 60 37 26 16 8 5 3 2 1 HT 82 74 66 58 46 35 28 23 22 19 13 5 2 2 1 1

E F
100 100
No Disease Progression

Cumulative Survival (%)

90 90
P = 0.063 P = 0.019
80 HR = 0.76 80 HR = 0.69
70 70
60 60 Lapatinib 1250 mg (N = 116; median OS, 46.0 wks)
50 50
40 Lapatinib 1250 mg (N = 116; median TTP, 15.1 wks) 40
30 30
20 20
Hormonal Therapy Hormonal Therapy
10 (N = 125; median TTP, 10.9 wks)
10 (N =125; median OS, 37.9 wks)

0 6 16 24 32 40 48 56 64 72 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144

No. at risk Time (weeks) No. at risk Time (weeks)

Lapatinib 116 77 43 28 19 10 6 1 Lapatinib 116 107 94 78 61 47 43 25 17 10 7 5 5 4 3 1
HT 125 77 34 14 6 4 1 HT 125 112 97 78 54 36 24 13 4 4 1 1 1 1 1

Fig. 2. Kaplan-Meier estimates of cumulative incidence of time to progression (TTP) according to the assessment of the independent review committee (A, C, E) and
overall survival (OS; B, D, F). (A) TTP in the intent-to-treat (ITT) population for lapatinib versus hormone therapy (HT). (B) OS in the ITT population for lapatinib versus
HT. (C) TTP for lapatinib versus HT in patients with tumor epidermal growth factor receptor (EGFR) 0, 1, 2⫹ intensity staining. (D) OS for lapatinib versus HT in patients
with tumor EGFR 0, 1, 2⫹ intensity staining. (E) TTP for lapatinib versus HT in patients with tumor EGFR 3⫹ intensity staining. (F) OS for lapatinib versus HT in patients
with tumor EGFR 3⫹ intensity staining. HR, hazard ratio.

patients with tumors expressing reduced EGFR. These observations levels of tumor EGFR expression (37.9 v 54.1 weeks; P ⬍ .01). Second,
were confirmed in the current study, where patients overexpressing lapatinib is an active inhibitor of tumor EGFR in vivo and is most
EGFR in the control arm had a poorer outcome than those with low efficacious in patients who express higher levels of EGFR (IHC 3⫹)

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 Ravaud et al

Table 2. Drug-Related Adverse Events in the Patients Included in the Safety Population
Lapatinib (n ⫽ 205) HT (n ⫽ 199)

Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4

No. of No. of No. of No. of No. of No. of

Adverse Event Patients % Patients % Patients % Patients % Patients % Patients %
Any drug-related event 161 79 58 29
Rash 90 44 4 2 0 6 3 0 0
Diarrhea 83 40 3 1 0 5 3 0 0
Nausea 36 18 2 ⬍1 0 7 4 0 0
Vomiting 15 7 2 ⬍1 0 4 2 0 0
Fatigue 13 6 1 ⬍1 0 1 ⬍1 0 0
Asthenia 9 4 1 ⬍1 0 1 ⬍1 0 0
LVEF decline 10 5 1 ⬍1 0 0 0 0
Vascular disorders 4 2 0 0 11 6 2 1 1 ⬍1
Stomatitis 4 2 1 ⬍1 0 0 0 0
Hand-foot skin reaction 1 ⬍1 0 0 0 0 0
Hands and feet skin erythrosis 1 ⬍1 0 0 0 0 0

Abbreviations: HT, hormone therapy; LVEF, left ventricular ejection fraction.

than lower levels (IHC 0, 1⫹, or 2⫹) when compared with the control
arm. This rationale is consistent with previous studies of targeted
agents, including lapatinib, which have demonstrated efficacy in pa-
tients who overexpressed HER-2.10
Lapatinib is a dual-targeted inhibitor of EGFR and HER-2, and
potently blocks the intense signaling via the EGFR/HER-2 het-
erodimer pathway that has been shown to induce tumor cell prolifer-
ation. Therefore, a complementary hypothesis is that more complete
inhibition that translates to clinical benefit may be possible in RCC
when EGFR expression is upregulated, even though HER-2 expres-
sion is low. Additional biomarker studies are underway to investigate
these hypotheses and other potential pathways.
HT offers only symptomatic benefit to RCC patients with a
well-tolerated safety profile, and is widely administered to patients
who have experienced disease progression while receiving standard
first-line therapy.11 Furthermore, expression of hormone receptors
was detected in only 1% of RCC patients26; therefore, the use of HT in
the current trial would not be expected to influence the efficacy results
in the EGFR subpopulations.
Although patients were not stratified for the established risk
factors in the second-line RCC setting,16 a retrospective analysis dem-
onstrated that the distributions of KPS, corrected serum calcium, and
hemoglobin were well balanced between the two treatment arms and
in each of the EGFR subgroups. Moreover, the use of subsequent
therapies after progression, including antiangiogenesis agents and the
continuation of lapatinib or HT, was also equivalent and would not be
expected to bias the results.
Taken together, these results are consistent enough to hypothe-
size that an overall survival benefit could be obtained by targeting
EGFR/HER-2 inhibition in RCC. However, the significant difference
in the EGFR-overexpressing population was not observed with a sim-
ilar magnitude using the TTP end point. This may be due to the rapid
progression of approximately 50% of patients at the first disease as-
sessment (8 weeks), which could have contributed to an underpow-
ered primary end point despite the divergence of the Kaplan and Meier
curves at this time point. This may have masked the longer-term effect
of lapatinib on the EGFR pathway observed in the survival end point.
In conclusion, although this large randomized trial was negative
for the primary end point in the overall patient population, explor-
atory biomarker analysis has shown that second-line treatment with
lapatinib seems to prolong overall survival relative to HT in patients
with advanced RCC whose tumors overexpress EGFR.
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
ASCO’s 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: Jason P. Gardner,
GlaxoSmithKline (C); Frank Pétavy, GlaxoSmithKline (C); Iman
El-Hariry, GlaxoSmithKline (C) Consultant or Advisory Role: Alain
Ravaud, GlaxoSmithKline, Pfizer Inc, Bayer, Novartis, Wyeth (C);
Robert Hawkins, GlaxoSmithKline (C); Peter Harper, GlaxoSmithKline
(C); Martin Gore, GlaxoSmithKline (C) Stock Ownership: Jason P.
Gardner, GlaxoSmithKline; Frank Pétavy, GlaxoSmithKline; Iman
El-Hariry, GlaxoSmithKline Honoraria: Alain Ravaud, Pfizer Inc, Bayer;
Hans von der Maase, Novo Nordisk, Pierre Fabre, Eli Lilly & Co, Roche,
Bayer, Pfizer Inc; Peter Harper, GlaxoSmithKline; Bruno Audhuy,
GlaxoSmithKline Research Funding: Alain Ravaud, GlaxoSmithKline,
Roche; Martin Gore, GlaxoSmithKline Expert Testimony: None Other
Remuneration: Alain Ravaud, Pfizer Inc, Bayer, Roche, Novartis; Hans
von der Maase, Novo Nordisk, Pierre Fabre, Eli Lilly & Co, Roche, Bayer,
Pfizer Inc
AUTHOR CONTRIBUTIONS
Conception and design: Alain Ravaud, Robert Hawkins, Jason P.
Gardner, Niko Zantl, Peter Harper, Frank Pétavy, Martin Gore, Patrick
Schöffski, Iman El-Hariry

2290 © 2008 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

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 Phase III Trial of Lapatinib Versus HT in RCC

Administrative support: Jason P. Gardner, Iman El-Hariry
Provision of study materials or patients: Alain Ravaud, Robert
Hawkins, Jason P. Gardner, Hans von der Maase, Niko Zantl, Peter
Harper, Frédéric Rolland, Bruno Audhuy, Jean-Pascal Machiels, Frank
Pétavy, Martin Gore, Patrick Schöffski
Collection and assembly of data: Jason P. Gardner, Hans von der Maase,
Frank Pétavy, Iman El-Hariry
Data analysis and interpretation: Alain Ravaud, Robert Hawkins, Jason
P. Gardner, Hans von der Maase, Niko Zantl, Peter Harper, Frédéric
Rolland, Bruno Audhuy, Jean-Pascal Machiels, Frank Pétavy, Martin
Gore, Patrick Schöffski, Iman El-Hariry
Manuscript writing: Alain Ravaud, Robert Hawkins, Jason P. Gardner,
Iman El-Hariry
Final approval of manuscript: Alain Ravaud, Robert Hawkins,
Jason P. Gardner, Hans von der Maase, Niko Zantl, Peter
Harper, Frédéric Rolland, Bruno Audhuy, Jean-Pascal
Machiels, Frank Pétavy, Martin Gore, Patrick Schöffski,
Iman El-Hariry

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■ ■ ■

Acknowledgment
We thank the patients who participated in this study and their families; the medical, nursing, and research staff; the independent monitoring
committee; the monitors, staff, data managers, and statisticians (N. Compton, H. Hassani) at GlaxoSmithKline; and the editorial assistance of
L. Pender from The Phillips Group Oncology Communications.

Appendix
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