Erlotinib in Previously Treated Non–Small-Cell Lung Cancer

Lung cancer is the leading cause of
cancer  death  among  men  and  women  in
North America.
1
 In advanced non–small-cell
lung  cancer,  chemotherapy  offers  symptomatic  re-
lief and modest improvement in survival
2
; respons-
es are brief, with a median time to progression of
three  to  five
months.  Second-line  chemotherapy
with docetaxel can prolong survival after platinum-
based  therapy  for  non–small-cell  lung  cancer.
3,4
However,  there  is  at  present  no  defined  role  for
third-line
chemotherapy.  The  futility  of  offering
third-line chemotherapy was demonstrated by Mas-
sarelli et al.,
5
 who reported a response rate of only
2  percent  and  a  median  survival  of  four  months.
Sheph
erd et al.
6
 showed that among patients treat-
ed  with  docetaxel  after  the
failure  of  two
or  more
chemotherapy  regimens,  survival
was  identical  to
that among patients treated with supportive care.
The  epidermal  growth  factor  receptor  (EGFR)
family is part of a complex signal-transduction net-
work that is central to several critical cellular pro-
cesses.  Since  EGFR  is  often  found  in  non–small-
cell  lung  cancer  cells,
7,8
  it  has  been  the  focus  of
efforts
to develop new agents that target the EGFR
pathway. Erlotinib (Tarceva, OSI Pharmaceuticals)
and
gefitinib (Iressa, AstraZeneca) inhibit the ty-
rosine kinase activity of EGFR and have been stud-
ied
extensively.
9-12
 In randomized phase 2 trials of
gefitinib (Iressa Dose Evaluation in Advanced Lung
Cancer [IDEAL] 1 and 2),
10,11
 the tumors of 10 to
20 percent of patients who were previously treat-
ed with platinum-based regimens responded, and
in  a  phase  2  trial  of  erlotinib  among  previously
treated patie
nts with non–small-cell lung cancer in
which  10
percent  or  more  of  the  cells  expressed
EGFR, the response rate was 12.3 percent.
12
 These
promising rates are perhaps higher than those pos-
sible with other forms of chemotherapy,
3-6
 but it
is unknown whether treatment with an EGFR inhib-
itor
prolongs survival. For this reason, the National
Cancer  Institute  of  Canada  Clinical  Trials  Group
(NCIC CTG) conducted a trial (BR.21) to compare
erlotinib with placebo after the failure of standard
chemotherapy for non–small-cell lung cancer. The
inclusion of a control group receiving placebo was
considered ethical in view of the lack of benefit from
further chemotherapy after the failure of standard
treatment.
5,6
study design
This  international,  phase  3,  randomized,  double-
blind, placebo-controlled trial of erlotinib after the
failure  of  first-line  or  second-line  chemotherapy
for non–small-cell lung cancer was designed by the
NCIC CTG. Patients were randomly assigned in a
2:1 ratio to receive oral erlotinib at a dose of 150 mg
daily or placebo. Randomization was performed
centrally by Applied Logic Associates (Houston),
with  the  use  of  the  minimization  method.
13
  Pa-
tients  were  stratified  according  to  center,  Eastern
Cooperative  Oncology  Group  performance  status
(0  or  1  vs.  2  or  3,  with  higher  scores  indicating
greater impairment), best response to prior thera-
py (complete or partial response vs. stable disease
vs. progressive disease), number of prior regimens
received (one vs. two), and exposure to prior plati-
num therapy (yes vs. no).
The  primary  end  point  was  overall  survival.
Secondary  end  points  included  progression-free
survival, overall response rate (complete and par-
tial), duration of response, toxic effects, and qual-
ity of life. Responses were assessed with the use of
the Response Evaluation Criteria in Solid T
umors
(RECIST),
14
 and toxic effects were assessed accord-
ing to
the Common Toxicity Criteria of the
Nation-
al Cancer Institute (version 2.0). The European Or-
ganization  for  Research  and  Treatment  of  Cancer
(EORTC) quality-of-life questionnaire (QLQ-C30)
and  the  quality-of-life  questionnaire  for  patients
with lung cancer (QLQ-LC13) were used to evalu-
ate p
atients’ quality of life.
The protocol was approved by the ethics review
boards
at all participating institutions, and all pa-
tients provided written informed consent. Support
was provided by the NCIC and OSI Pharmaceuti-
cals.  Data
were  collected,  managed,  and  analyzed
by the
NCIC CTG, and the manuscript was written
by  membe
rs  of  the  NCIC  CTG.  OSI  Pharmaceuti-
cals  reviewed  the  final  manuscript  and  provided
comments on it. Confidentiality was maintained by
both the NCIC CTG and OSI Pharmaceuticals. The
study chair, Dr. Shepherd, and the physician coordi-
nator, Dr.
Seymour, reviewed all the data and con-
firmed their co
mpleteness and accuracy.
l
methods
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n engl j med
353;2
www.nejm.org
july
14, 2005
erlotinib in previously treated non–small-cell lung cancer
125
eligibility criteria
Patients  18  years  of  age  or  older  with  an  Eastern
Cooperative Oncology Group (ECOG) performance
status between 0 and 3 were eligible in the presence
of documented pathological evidence of non–small-
cell lung cancer. The patients had to have received
one or two regimens of combination chemother-
apy and not be eligible for further chemotherapy.
Patients 70
years of age or older may have received
therapy with one or two single agents. Patients had
to have recovered from any toxic effects of therapy
and were randomly assigned to the study treatment
at  least  21  days  after  chemotherapy  (14  days  after
treatment with vinca alkaloids or gemcitabine) and
7 days after radiation. Adequate hematologic and
bioc
hemical values were required.
Patients with prior breast cancer, melanoma, or
hypernephroma were ineligible, as were those with
other  malignant  diseases  (except  basal-cell  skin
cancers) within the preceding five years. Other ex-
clusion
criteria were symptomatic
brain metasta-
ses, clinically significant cardiac
disease
within one
year, ventricular arrhythmias
requiring med
ication,
and clinically significant ophthalmologic or gastro-
intestinal
abnormalities.
study procedures
Within seven days before randomization, a history
and physical examination were obtained and hema-
tologic and biochemical testing, chest radiography,
and assessments of toxic effects and quality of life
were obtained. Computed tomographic scans of
the  chest  and  abdomen  were  obtained  within  28
days before randomization. For a patient to be eval-
uated for a response, at least one measurable lesion
was required, but measurable disease was not man-
datory  for  eligibility.  Only  patients  with  measur-
able disea
se were included in the analyses of com-
plete or partial response.
Administration  of  the  study  medication  was  to
start  within  two  days  after  randomization.  For
grade 2 diarrhea, loperamide was recommended
without  reduction  of  the  dose  of  erlotinib.  For
grade  3  diarrhea,  the  study  treatment  was  with-
held until the
diarrhea was grade 1 or less, and then
erlotinib at a dose of 100 mg daily was started. For
grade 1
or 2 rash, treatment modification was not
recommended.  For  grade  3  rash,  treatment  was
withheld, the rash was treated symptomatically, and
erlotinib  at  a  dose  of  100  mg  daily  was  restarted
when t
he rash was grade 1 or less.
History taking, physical examination, and he-
matologic and biochemical testing were performed
every four weeks, and radiologic investigations ev-
ery eight weeks. Patients’ quality of life was evaluat-
ed every four weeks in countries with validated ver-
sions of the questionnaires.
egfr expression
Separate written consent for optional tissue bank-
ing and correlative studies was obtained. EGFR ex-
pression was determined with the use of immuno-
histochemistry  in  a  central  laboratory  that  used
Dako
kits (DakoCytomation). Positivity was defined
as more than 10 percent of cells staining at any in-
tensity for EGFR.
statistical analysis
The trial was designed to detect, with 90 percent
power
and a two-sided type I error of 5 percent, a
33  percent  improvement  in  median  survival  from
four months as estimated in the placebo group. For
the  final  analysis,  582  deaths  were  required  and
were
projected to occur with a sample size of 700
patients enrolled over a period of 14 months with
6  months  of  follow-up.  The  required  number  of
deaths
had occurred by January 2004, and the data-
base was locked as of April 23, 2004. There was no
interim  analysis.  Tumor  responses  were  validated
centrally for the first 333 patients in the trial.
The stratified log-rank test, accounting for strat-
ification  factors
at  randomization  (except  center)
and EGFR protein expression (positive vs. negative
vs. unknown), was used to compare progression-
free
survival and overall survival between treatment
groups. Exploratory forward stepwise regression
analys
es  with  the  use  of  the  Cox  model  were  per-
formed to adjust for treatment effect and to iden-
tify prog
nostic factors for progression-free survival
and overall survival. Candidate covariates includ-
ed EGFR expression, stratification factors (except
center), sex, age (60 years or less vs. more than 60
years), race or ethnic group (Asian vs. others), prior
radiotherapy (yes vs. no), histologic subtype of can-
cer (adenocarcinoma vs. others), and smoking sta-
tus (smoker vs. nonsmoker vs. unknown). Race was
self-reported or
determined by study personnel and
was not based on country of domicile. Fisher’s exact
test was used to
compare response rates between
levels of potential p
redictors and rates of toxic ef-
fects  between  t
reatments.  Times  to  deterioration
(a 10-point increase from the baseline score) for
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