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Kris MG, Natale RB, Herbst RS, et al. Efficacy of Gefitinib, an Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase, in Symptomatic Patients With Non–Small Cell Lung Cancer: A Randomized Trial. JAMA. 2003;290(16):2149–2158. doi:10.1001/jama.290.16.2149
Author Affiliations: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center and the Weill Medical College of Cornell University, New York, NY (Dr Kris); Cedars-Sinai Comprehensive Cancer Center, Los Angeles, Calif (Dr Natale); University of Texas M. D. Anderson Cancer Center, Houston (Dr Herbst); Massachusetts General Hospital Cancer Center, Boston (Dr Lynch); UCLA Medical Center, Los Angeles, Calif (Dr Prager); University of Pittsburgh Cancer Institute, Pittsburgh, Pa (Dr Belani); University of Wisconsin Hospital, Madison (Dr Schiller); University of Colorado Health Sciences Center, Denver (Dr Kelly); Hematology Oncology Consultants Inc, Columbus, Ohio (Dr Spiridonidis); Vanderbilt University, Nashville, Tenn (Dr Sandler); Loyola University Medical Center, Maywood, Ill (Dr Albain); Northwestern University, Evanston, Ill (Dr Cella); AstraZeneca Pharmaceuticals, Wilmington, Del (Drs Wolf, Averbuch, Ochs, and Kay).
Context More persons in the United States die from non–small cell lung
cancer (NSCLC) than from breast, colorectal, and prostate cancer combined.
In preclinical testing, oral gefitinib inhibited the growth of NSCLC tumors
that express the epidermal growth factor receptor (EGFR), a mediator of cell
signaling, and phase 1 trials have demonstrated that a fraction of patients
with NSCLC progressing after chemotherapy experience both a decrease in lung
cancer symptoms and radiographic tumor shrinkages with gefitinib.
Objective To assess differences in symptomatic and radiographic response among
patients with NSCLC receiving 250-mg and 500-mg daily doses of gefitinib.
Design, Setting, and Patients Double-blind, randomized phase 2 trial conducted from November 2000
to April 2001 in 30 US academic and community oncology centers. Patients (N
= 221) had either stage IIIB or IV NSCLC for which they had received at least
2 chemotherapy regimens.
Intervention Daily oral gefitinib, either 500 mg (administered as two 250-mg gefitinib
tablets) or 250 mg (administered as one 250-mg gefitinib tablet and 1 matching
Main Outcome Measures Improvement of NSCLC symptoms (2-point or greater increase in score
on the summed lung cancer subscale of the Functional Assessment of Cancer
Therapy-Lung [FACT-L] instrument) and tumor regression (>50% decrease in lesion
size on imaging studies).
Results Of 221 patients enrolled, 216 received gefitinib as randomized. Symptoms
of NSCLC improved in 43% (95% confidence interval [CI], 33%-53%) of patients
receiving 250 mg of gefitinib and in 35% (95% CI, 26%-45%) of patients receiving
500 mg. These benefits were observed within 3 weeks in 75% of patients. Partial
radiographic responses occurred in 12% (95% CI, 6%-20%) of individuals receiving
250 mg of gefitinib and in 9% (95% CI, 4%-16%) of those receiving 500 mg.
Symptoms improved in 96% of patients with partial radiographic responses.
The overall survival at 1 year was 25%. There were no significant differences
between the 250-mg and 500-mg doses in rates of symptom improvement (P = .26), radiographic tumor regression (P = .51), and projected 1-year survival (P =
.54). The 500-mg dose was associated more frequently with transient acne-like
rash (P = .04) and diarrhea (P = .006).
Conclusions Gefitinib, a well-tolerated oral EGFR-tyrosine kinase inhibitor, improved
disease-related symptoms and induced radiographic tumor regressions in patients
with NSCLC persisting after chemotherapy.
More persons in the United States die from non–small cell lung
cancer (NSCLC) than from breast, colorectal, and prostate cancer combined.1 Each year, more than 60 000 persons develop stages
IIIB and IV NSCLC; nearly all go on to die from metastatic spread. In addition,
most individuals experience symptoms caused directly by lung cancer. These
symptoms are often the first manifestations of the illness and increase in
frequency and severity as the disease progresses. Cough, shortness of breath,
weight loss, loss of appetite, and chest tightness impair the quality of lives
already cut short by NSCLC. For patients with advanced lung cancer, physical
well-being and changes in quality of life correlate with survival.2 Especially among patients with metastatic NSCLC, who
are rarely cured, lessening lung cancer symptoms without adding burdensome
adverse effects is an important goal of care. No anticancer therapy has been
proven to be beneficial to persons seeking additional care after receiving
2 or more chemotherapy regimens.
The epidermal growth factor receptor (EGFR) mediates cancer cell growth,
proliferation, invasion, and metastasis, and inhibits apoptosis.3 When
ligands bind to the receptor, the molecule is phosphorylated by constitutive
tyrosine kinases, causing activation of downstream pathways.4 Preclinically,
drugs targeting these tyrosine kinases block EGFR activation and the intracellular
events that follow.5 Compounds disrupting EGFR
tyrosine kinases inhibit the growth of human tumors that express EGFR and
cause overexpressing tumors to regress.5-7 These
same agents reduce levels of vascular endothelial growth factor and enhance
Many lines of evidence suggest that EGFR has relevance to patients with
NSCLC and thus may serve as a potential therapeutic target. Expression of
EGFR has been detected by immunohistochemistry testing in from 62%8-11 to
93% of resected primary tumors,12 and EGFR
mRNA has been found in 100%.11 The overexpression
of EGFR has been variably correlated with clinical outcomes.11,13-15
The oral drug gefitinib (ZD1839, Iressa, AstraZeneca Pharmaceuticals,
Wilmington, Del) blocks EGFR tyrosine kinases and prevents epidermal growth
factor–induced proliferation in cell culture. It inhibits growth and
causes regressions in human tumor xenografts with EGFR overexpression.5 When given to patients with cancer, gefitinib inhibits
EGFR activation in skin.16 Phase 1 trials identified
diarrhea as dose-limiting at daily oral gefitinib doses of 700 to 1000 mg.17-20 A
continuous gefitinib dosing schedule was developed because it was determined
to be the best schedule to counter the continuous oncogenic signaling through
this receptor, as seen in animal models5 and
presumed to occur in persons with cancer. An acne-like rash was also noted.
Unlike conventional chemotherapy, gefitinib did not cause myelosuppression,
neuropathy, or significant alopecia. In these same phase 1 studies, rapid
symptom improvement and radiographic regressions were documented in patients
with NSCLC who had previously received chemotherapy.21
In light of preclinical activity in EGFR-expressing tumors, evidence
of EGFR expression in NSCLC, and antitumor effects in patients with NSCLC
persisting after chemotherapy in the phase 1 trials, we initiated this phase
2 trial of gefitinib. We hypothesized that blocking EGFR tyrosine kinases
with gefitinib would lead both to symptomatic benefits and objective regressions
in patients with NSCLC. We further tested whether there were important differences
in outcomes or adverse effects comparing 250-mg and 500-mg doses of gefitinib
using a randomized, double-blind, phase 2 design.
From November 2000 to April 2001, 221 patients were enrolled at 30 sites
in the United States for the second Iressa Dose Evaluation in Advanced Lung
Cancer (IDEAL2) trial. Patients were included if they had pathological confirmation
of NSCLC; stage IIIB or IV disease extent22;
treatment with 2 or more regimens containing cisplatin or carboplatin and
docetaxel, given either concurrently or as separate regimens; disease progression
or unacceptable toxicity with the last chemotherapy regimen; symptomatic NSCLC
as determined by a score of 24 or lower out of 28 using the lung cancer subscale
of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality-of-life
instrument23,24; measurable or
evaluable indicator lesions25; World Health
Organization performance status of 0-2; and if they had provided written informed
consent. Patients were excluded if they had received chemotherapy or irradiation
within 14 days; unresolved toxicity greater than grade 2 from prior chemotherapy;
neutrophil count less than 1.5 ×109 cells/L, platelet count
less than 75 ×109 cells/L, bilirubin level more than 1.25
times the upper limit of normal, and alanine aminotransferase or aspartate
aminotransferase levels more than 2.5 times the upper limit of normal; and
creatinine clearance less than 30 mL/min (0.50 mL/s).
Patients were randomized to receive either two 250-mg tablets of gefitinib
(500-mg total dose) or one 250-mg gefitinib tablet and 1 matching placebo
tablet (250-mg total dose) daily. These dosages were chosen, based on phase
1 study results, to maximize the potential for therapeutic activity with an
ample safety margin. Responses had been observed at doses as low as 150 mg
in the phase 1 studies.21 Gefitinib and placebo
(both supplied by AstraZeneca Pharmaceuticals) were dispensed on day 1 of
each 28-day treatment cycle. One blinded dose reduction from 250 to 100 mg
or from 500 to 250 mg was permitted.
Symptom assessments were measured using the FACT-L instrument.23,26 This instrument was completed pretreatment
and then every 28 days. Weekly, patients recorded the presence and severity
of 7 symptoms using the lung cancer subscale: shortness of breath, weight
loss, clarity of thinking, cough, appetite, chest tightness, and difficulty
breathing. Severity was assessed using a 0-4 scale (0-1, most symptomatic;
2-3, less symptomatic; 4, asymptomatic); thus, on the 0 to 28 summed lung
cancer subscale score, a score of zero denotes the worst symptoms and 28,
none of the 7 symptoms. A 2-point change in the summed score has been proven
to correlate with both survival and performance status.23,24 Symptom
improvement required confirmation of the 2-point increase with no interim
worsening over the subsequent 4 weeks. Time to symptom improvement was measured
from randomization. The duration of improvement was measured from the first
visit at which a 2-point change in the summed lung cancer subscale score was
observed until the visit when worsening occurred. Patients were removed from
the study based on radiographic criteria or toxicity.
Partial radiographic responses required a greater than 50% decrease
in lesion size.25 Imaging studies were repeated
4 and 8 weeks after randomization, then every 8 weeks. As prespecified, the
investigators' assessment of response was used in the analysis. Eighty-eight
percent of participants had at least 1 bidimensionally measurable indicator
lesion. The National Cancer Institute Common Toxicity Criteria (NCI CTC version
2.0) were used to describe and quantitate adverse effects.
Tumor specimens for immunohistochemical analysis for EGFR were requested
from all patients. Of the 97 specimens received, 70 were suitable for analysis.
Results of these immunohistochemical tests were presented27 and
will be reported separately. Baseline characteristics of the 70 patients with
adequate samples were similar to the entire group enrolled.
Patients were stratified by World Health Organization performance status
(0-1 vs 2) and number of prior chemotherapy regimens (2 vs 3 vs 4 or more).
Coprimary end points were rates of symptom improvement and radiographic tumor
regression. We included all patients who received any gefitinib. Sample size
was chosen to independently evaluate each coprimary end point for each dose.
For both rates, 100 patients per group yielded a power of 0.90 for a 1-sided
.0125 significance-level test that the rate of symptom or radiographic improvement
is 5% or less when the true rate is 15%.28
Secondary end points included overall survival by dose, frequency, and
severity of adverse events, and overall quality of life using the FACT-L instrument.
Quality of life analyses have been presented29 and
will be reported separately. Kaplan-Meier plots were calculated by dose using
an unadjusted log-rank test. Analyses were planned to correlate the symptom
improvement and radiographic response rates with each other and with survival.
We used logistic regression and χ2 tests to explore the coprimary
outcomes in relation to disease and demographic factors. The data cutoff date
for this analysis was August 1, 2001. Radiographic responses were updated
to December 17, 2001, when the trial closed. Survival data were updated May
7, 2002. Statistical analyses were carried out using SAS version 8.1 (SAS
Institute Inc, Cary, NC) and StatXact version 4 (Cytel Software Corp, Cambridge,
Mass); P<.05 was used to determine statistical
From November 7, 2000, to April 6, 2001, 221 patients were enrolled
at 30 sites in the United States (listed at the end of this article). The
flow of patients through the trial is illustrated in Figure 1. Five individuals who never received gefitinib were excluded
after randomization. Baseline patient characteristics are summarized in Table 1. No significant differences were
observed between the treatment groups receiving 250 mg and 500 mg of gifitinib.
With their last chemotherapy regimen before starting gefitinib, 170 patients
(79%) had disease progression and 38 (18%) had intolerable toxicity, mainly
peripheral neuropathy. Overall, 58% of patients had received 3 or more prior
chemotherapy regimens. Table 2 shows
the severity of 7 lung cancer symptoms at baseline. Pulmonary symptoms were
most common. The median number of days receiving gefitinib was 56 and 53 for
the groups receiving 250 mg and 500 mg, respectively. The median number of
days in the study was 56 for both groups. Patients completed 84% of lung cancer
subscale assessments while in the study.
Table 3 lists outcome measures.
The symptom improvement rate was 43% (95% confidence interval [CI], 33%-53%)
for patients who received 250 mg of gefitinib and 35% (95% CI, 26%-45%) for
those who received 500 mg (P = .26). Fifty-five percent
of symptom improvements in patients receiving 250 mg and 58% of symptom improvements
in patients receiving 500 mg were apparent after 1 week of treatment. For
those patients with symptom improvement, the median durations of benefit were
not reached (range, 1+ to 7+ months for patients receiving 250 mg and 1+ to
8+ months for those receiving 500 mg). For all participants, the best median
symptom score improved by 25%, from a baseline of 16 (out of 28) to 22 after
treatment with gefitinib (P<.001). For all but
1 study week, the mean change in the summed lung cancer subscale score for
all patients was 2 or more, the predefined level for significant symptom improvement
(Figure 2). The greatest mean improvement
in summed lung cancer subscale scores (4.8) occurred in the patients with
partial radiographic responses. Mean changes were 2.6 for individuals with
stable disease and 1.0 for those with progression. The change in mean summed
lung cancer subscale scores for patients with disease progression did not
improve by the prespecified 2-point cutoff defining improvement.
The response rate (all partial) was 12% (95% CI, 6%-20%) for the group
receiving 250 mg of gefitinib and 9% (95% CI, 4%-16%) for the group receiving
500 mg (P = .51). The P value
for the test that the true rate is greater than 5% was .005 for the group
receiving 250 mg and .06 for the group receiving 500 mg. The median duration
of radiographic response was 7 (range, 3 to 9+) months for patients receiving
250 mg and 6 (range, 3 to 8+) months for patients receiving 500 mg. Symptoms
improved in 96% of patients with partial responses, 73% of those with no partial
response but no progression (stable disease), and 17% of those with disease
progression (P<.001). Rates of symptom improvement
were improved comparing the patients with partial response and those with
stable disease (P = .02). Figure 3 displays correlations between symptom improvement and radiographic
Symptom improvement and radiographic responses were observed in all
patient subgroups. Symptom improvement was more common with adenocarcinoma
than with other histologic types (43% vs 30%, P =
.06). Response rates were 13% for adenocarcinoma vs 4% for other types (P = .046). The incidence of adenocarcinoma was 79% in women
and 58% in men. A multivariable comparison (which included sex, histologic
subtype, performance status, age, number of prior regimens, and months from
initial diagnosis) demonstrated only female sex to be predictive of response
both for symptom improvement (50% vs 31% for women vs men, respectively; P = .006) and radiographic regression (19% vs 3%, P = .001). Eighteen of 22 partial responses (82%) occurred
Partial response rates did not differ significantly whether patients
had received 2 (8%), 3 (10%), or 4 or more (15%) prior chemotherapy regimens
(P = .38), and rates of symptom improvement were
similar based on the number of prior regimens (P =
.38). Radiographic response rates did not differ among patients with performance
status of 0, 1, or 2 (12%, 9%, and 14%, respectively; P = .53). Rates of symptom improvement also were unaffected by performance
status (P = .53).
The projected median survival was 7 months for patients receiving 250
mg of gefitinib and 6 months for those receiving 500 mg (P = .40). The estimated 1-year survival was 27% for patients receiving
250 mg and 24% for those receiving 500 mg (P = .54). Figure 4 displays the overall survival by
dose. Using a landmark analysis to examine the survival of only patients who
lived at least 2 months (the time needed to assess radiographic response),
median survival differences were observed among partial responders (13 months),
patients with no partial response but no progression (ie, stable disease)
(9 months), and those with progression (5 months) (P<.001).
Also using the landmark method, patients with symptom improvement had a median
survival of 13 months vs 5 months for those without symptom benefit (P<.001).
Table 4 presents deaths,
discontinuations, withdrawals, and gefitinib-related diarrhea and skin toxicities.
Skin toxicity, described variably as rash, acne, dry skin, or pruritus, was
observed in 62% of patients receiving 250 mg of gefitinib vs 75% of those
receiving 500 mg (P = .04). The rash appeared on
the face, neck, and trunk, and commonly faded or improved despite continuing
therapy. It occurred during the first treatment cycle in 82% of patients.
Although all 22 patients with partial responses had some skin toxicity, 65%
of those who did not have a partial response also experienced this adverse
effect. Skin toxicity was documented in 86% (72/84) of patients with symptom
improvement and in 58% (76/132) of those whose symptoms did not improve (observed
difference, 28%; 95% CI, 17%-39%).
Diarrhea was noted in 57% of patients receiving 250 mg of gefitinib
and in 75% of those receiving 500 mg (P = .006).
No routine prophylactic antidiarrheal medication was given. Only 1 patient
receiving 250 mg had diarrhea greater than grade 2 (up to 6 daily bowel movements)
compared with 6 patients in the group receiving 500 mg. Two individuals receiving
500 mg withdrew because of diarrhea. In 76% of patients, diarrhea was observed
during the first treatment cycle. Symptoms were generally controllable with
loperamide taken after each bowel movement. Approximately one third took an
antidiarrheal medication. Diarrhea was documented in 82% (69/84) of patients
with symptom improvement and in 56% (74/132) whose symptoms did not improve
(observed difference, 26%; 95% CI, 14%-38%).
Nineteen percent of patients reported grade 1 or 2 eye toxicities such
as redness or itchiness. All were self-limited and in no case led to study
withdrawal. Treatment-related vomiting or nausea (grade 1 or 2 only) was observed
in 15% and 10% of patients, respectively. There were no cases of investigator-identified
interstitial lung disease following gefitinib administration (observed rate,
0%; 95% CI, 0%-1.7%). Pulmonary events (collected as pneumonia, aspiration
pneumonia, lung disorder, respiratory distress syndrome) were noted in 13
patients (6 of grade 3 or 4) receiving 250 mg of gefitinib and in 14 patients
(8 of grade 3 or 4) receiving 500 mg. None of the pulmonary events were considered
drug-related by the investigators. One patient had grade 3 thrombocytopenia
and 3 had reversible grade 3 elevations of alananine aminotransferase and
aspartate aminotransferase levels that were deemed drug-related. No grade
3 or 4 neutropenia, anemia, or neuropathy occurred.
Only 1 possible treatment-related death was recorded. This patient experienced
cavitation of his primary tumor, developed massive hemoptysis, and died on
day 11. Only 1 patient receiving 250 mg of gefitinib and 5 patients receiving
500 mg experienced a drug-related adverse event leading to study withdrawal.
Dose reductions for toxicity occurred in 1 patient receiving 250 mg and 10
receiving 500 mg. Grade 3 or 4 drug-related adverse events were observed in
7 patients receiving 250 mg and 20 patients receiving 500 mg. Thirty-day all-cause
mortality was 3.8% for patients receiving 250 mg and 8.8% for those receiving
500 mg. Sixty-day all-cause mortality was 8.8% for patients receiving 250
mg and 18% for those receiving 500 mg.
This trial demonstrated that oral gefitinib given once daily caused
rapid symptom improvement and tumor regressions in patients with NSCLC. Until
now, only chemotherapy, surgery, and radiotherapy have demonstrated the ability
to cause lung tumors to regress. Once these modalities have been exhausted,
only supportive care measures remain. Gefitinib, which was designed to achieve
its anticancer effects through a different mechanism, can help fill this therapeutic
There is no comparable prospective series treating a cohort of symptomatic
patients who had received both cisplatin or carboplatin and docetaxel. In
a retrospective review of 43 individuals treated with various chemotherapies,
the response rate for a third regimen was 2%.30 One
study randomized individuals who had received 1 or more chemotherapy regimen(s)
to either docetaxel or supportive care alone. The response rate with docetaxel
was 6%. Those who did not receive chemotherapy had a median survival of 5
months.31 In another "second-line" trial conducted
in the United States, radiographic tumor regressions were induced in 7% of
patients receiving docetaxel vs in 1% of those receiving vinorelbine or ifosfamide.32 The 10% response rate with gefitinib, achieved without
myelosuppression or neurotoxicity, and with virtually no hair loss, is provocative
in comparison. The results of this trial are consistent with the gefitinib
phase 1 experience in patients with NSCLC.21 The
recent international phase 2 trial (IDEAL1) also compared 250-mg and 500-mg
gefitinib doses, but in patients pretreated with 1 or 2 prior chemotherapy
regimens who were not required to have symptoms at trial entry. For the 250-mg
dose, they reported an 18% radiographic response rate.33 Similar
efficacy has been observed with the EGFR tyrosine kinase inhibitor erlotinib
(OSI-774, Tarceva, OSI Pharmaceuticals, Melville, NY).34 In
our study, approximately 15% of patients with the "best response" of progression
had some symptomatic improvement by study criteria. This likely reflects either
a placebo effect or the resolution of adverse effects of the prior chemotherapy
Adverse effects of gefitinib were generally mild, manageable, noncumulative,
and reversible with the cessation of the drug and sometimes even with continued
use. Among individuals receiving 250 mg, some degree of skin toxicity occurred
in 62% and of diarrhea in 57%. For the 250-mg dose, toxicity caused just 1
patient to stop taking gefitinib and 1 to reduce the dosage. Interstitial
lung disease has been associated with use of gefitinib in Japan and reported
to occur in 1% to 2% of patients.35 This is
a recognized but uncommon adverse effect of cytotoxic drugs36 and
also has been described following treatment with the tyrosine kinase inhibitor
imatinib (STI571, Gleevec, Novartis Pharmaceuticals, Basel, Switzerland).37 With no case of interstitial lung disease reported
in this trial, the 95% confidence limit for the true incidence of this complication
after gefitinib administration ranges from 0% to 1.7%, lower than that observed
with many chemotherapeutic agents.36
There were no significant differences in the incidence of symptomatic
or radiographic improvement between the 250-mg and 500-mg doses of gefitinib.
The incidence and severity of both rash and diarrhea, however, were higher
among patients receiving 500 mg. Consistent with the proposed mechanism of
action of gefitinib, once plasma levels adequate to block tyrosine kinases
such as EGFR have been achieved, additional dose escalations are unlikely
to improve response and will increase toxicity. That is likely what we observed
in this study. We recommend the 250-mg dose. The IDEAL1 trial reached the
Can the amount of EGFR protein in tumors predict response to gefitinib?
The answer appears to be no. In a combined analysis of tumor EGFR expression
levels determined by immunohistochemistry in 157 analyzable specimens submitted
from patients enrolled in the IDEAL1 trial and in this study, there were no
consistent associations between levels of EGFR expression and radiographic
or symptomatic improvements.27 In clinical
trials of the EGFR inhibitors cetuximab and erlotinib, response also did not
correlate with the degree of EGFR expression measured by immunohistochemistry.34,38
Of all clinical characteristics, only female sex and adenocarcinoma
histological type showed a correlation with response, both in our study and
in the international study.33 Patients in Japan
also had higher rates of radiographic response than those enrolled from other
countries.33 Investigators from Memorial Sloan-Kettering
Cancer Center also have reported that in a multivariable analysis of 140 patients
that included 6 people treated as part if this trial, individuals who have
never smoked cigarettes and those with any bronchioloalveolar histologic features
in their tumor specimens are more likely to respond to gefitinib.39 Although female sex has been associated with longer
survival in patients with advanced NSCLC, it has not been found to be a predictor
of radiographic response with chemotherapy.40 It
is likely that the consistently higher sensitivity to gefitinib in women,
Japanese patients, persons with adenocarcinoma histological type (especially
bronchioloalveolar), and those who have never smoked cigarettes has a biological
basis. Understanding these observations may help reveal the mechanisms that
underlie response to gefitinib. At this time, we do not recommend using any
pretreatment characteristics to routinely select patients to receive gefitinib.
Although we observed higher rates of response in women, radiographic regressions
were nonetheless documented in men and symptoms were improved in 31%. For
now, the only way to predict which patients will benefit from gefitinib is
to administer the drug and observe its effects, which are quickly apparent.
In this trial, symptom improvement was documented in 75% of responding patients
within 3 weeks and in 85% by 4 weeks.
Why do these results not appear as striking as those from other "targeted"
approaches? The pathobiology of growth-factor signaling in lung cancer may
be fundamentally different from that in other tumors, in which blockade of
growth-factor receptors has proved to be of benefit. In breast cancer, persons
who respond to trastuzumab (Herceptin, Genentech Inc, San Francisco, Calif)
uniformly have high expression of HER2 protein caused by HER2 gene amplification. In lung cancer, even high-level EGFR protein
expression is not commonly linked to gene amplification.10 Growth-factor–mediated
proliferation in NSCLC also is different from that observed in gastrointestinal
stromal tumors, in which specific mutations of either the c-KIT or PDGFRA genes cause ligand-independent
activation of receptor proteins that drive tumor growth.41-44 No
similar controlling mutations of EGFR have been reported in NSCLC. The targeted
therapy imatinib inhibits several tyrosine kinases, including those expressed
by c-KIT and PDGFRA.45 Imatinib causes dramatic
regressions in gastrointestinal stromal tumors regardless of whether the controlling
mutations are in the PDGFRA or c-KIT genes, because it effectively blocks both tyrosine kinases and
the resulting oncogenic signals emanating from either receptor. Similarly,
gefitinib may inhibit other tyrosine kinases in addition to EGFR. If this
occurred in patients with lung cancer, oncogenic signaling in tumors in the
fraction of patients who derive substantial benefit from gefitinib could be
driven at least in part by activation of other tyrosine kinases in addition
to or instead of EGFR.
Preclinical studies have demonstrated the uncoupling of the effects
of EGFR tyrosine kinase inhibition and tumor growth.46,47 This
observation may be relevant in NSCLC. Since multiple genetic lesions are necessary
to initiate lung cancers, many cell-signaling pathways may be aberrant and
provide multiple mechanisms to maintain tumors and permit "signaling redundancy."
For example, Kristen-ras mutations,4PTEN promoter hypermethylation,48PI3-Ká amplification,49 and p53 mutations50 are all
downstream of EGFR and occur in lung tumors. Any or all of these aberrations
may be present in patients whose tumors fail to respond to gefitinib. We may
be able to help individuals with gefitinib-resistant tumors by determining
which downstream factor works in concert with EGFR and then designing a combination
therapy inhibiting both EGFR and the downstream aberration as well. Characterization
of the presence or absence of these additional lesions in a given patient's
tumor also could lead to more discriminate use of gefitinib.
The strength of downstream oncogenic signaling can be determined by
which member of the HER family dimerizes with EGFR.4 Identifying
the presence of other HER family members in tumors and their degree of dimerization
with EGFR may help identify persons with lung cancer more likely to be sensitive
to gefitinib. Investigations also have revealed that amino acid substitutions
in the ATP binding pocket in regions sequentially distant but conformally
important to the imatinib binding site have been identified in both clinically
and laboratory induced mutations of the Abelson tyrosine kinase in chronic
myelogenous leukemia.51 These substitutions
confer resistance to imatinib. This mechanism may have relevance to understanding
gefitinib resistance and provides yet another direction for research.
The results of this trial proved our study hypothesis. Blocking EGFR
tyrosine kinase with gefitinib leads to symptom improvement and radiographic
regressions in patients with NSCLC. These findings support the use of gefitinib
for the treatment of patients with NSCLC who have received cisplatin or carboplatin
and docetaxel, and other agents. The magnitude and duration of benefits, coupled
with the safety of gefitinib, justifies its use in patients previously treated
with chemotherapy. These results further demonstrate that a therapy that disrupts
biological pathways specific for cancer cells can improve the outcome of patients
with advanced NSCLC.