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Impact of Specific Epidermal Growth Factor Receptor
(EGFR) Mutations and Clinical Characteristics on
Outcomes After Treatment With EGFR Tyrosine Kinase
Inhibitors Versus Chemotherapy in EGFR-Mutant Lung
Cancer: A Meta-Analysis
Chee Khoon Lee, Yi-Long Wu, Pei Ni Ding, Sarah J. Lord, Akira Inoue, Caicun Zhou, Tetsuya Mitsudomi,
Rafael Rosell, Nick Pavlakis, Matthew Links, Val Gebski, Richard J. Gralla, and James Chih-Hsin Yang
Listen to the podcast by Dr Oxnard at www.jco.org/podcasts
Chee Khoon Lee, Pei Ni Ding, Sarah J.
Lord, and Val Gebski, National Health and
Medical Research Council Clinical Trials
Centre, The University of Sydney; Chee
Khoon Lee and Matthew Links, Cancer
Care Centre, St George Hospital; Pei Ni
Ding, Liverpool Hospital; Sarah J. Lord,
School of Medicine, The University of
Notre Dame; Nick Pavlakis, Royal North
Shore Hospital, Sydney, Australia; Yi-Long
Wu, Guangdong Lung Cancer Institute,
Guangdong General Hospital and Guang-
dong Academy of Medical Sciences,
Guangdong; Caicun Zhou, Shanghai Pulmo-
nary Hospital, School of Medicine, Tongji
University, Shanghai, China; Akira Inoue,
Tohoku University Hospital, Sendai;
Tetsuya Mitsudomi, Kinki University School
of Medicine, Osaka-Sayama, Japan; Rafael
Rosell, Catalan Institute of Oncology,
Germans Trias i Pujol Health Sciences Insti-
tute and Hospital, Barcelona, Spain; Richard
J. Gralla, Albert Einstein College of Medi-
cine, Jacobi Medical Center, Bronx, NY;
James Chih-Hsin Yang, Graduate Institute
of Oncology, National Taiwan University,
and National Taiwan University Hospital,
Taipei, Taiwan.
Published online ahead of print at
www.jco.org on April 20, 2015.
Presented in part at the 15th World
Conference on Lung Cancer, Sydney,
Australia, October 27-30, 2013.
Authors’ disclosures of potential conflicts
of interest are found in the article online at
www.jco.org. Author contributions are
found at the end of this article.
Corresponding author: James Chih-Hsin
Yang, MD, PhD, Department of Oncol-
ogy, National Taiwan University Hospi-
tal, National Taiwan University College
of Medicine, Taipei 10051, Taiwan;
e-mail: chihyang@ntu.edu.tw.
© 2015 by American Society of Clinical
Oncology
0732-183X/15/3317w-1958w/$20.00
DOI: 10.1200/JCO.2014.58.1736
ABSTRACT
Purpose
We examined the impact of different epidermal growth factor receptor (EGFR) mutations and
clinical characteristics on progression-free survival (PFS) in patients with advanced EGFR-mutated
non–small-cell lung cancer treated with EGFR tyrosine kinase inhibitors (TKIs) as first-line therapy.
Patients and Methods
This meta-analysis included randomized trials comparing EGFR TKIs with chemotherapy. We
calculated hazard ratios (HRs) and 95% CIs for PFS for the trial population and prespecified
subgroups and calculated pooled estimates of treatment efficacy using the fixed-effects inverse-
variance-weighted method. All statistical tests were two sided.
Results
In seven eligible trials (1,649 patients), EGFR TKIs, compared with chemotherapy, significantly prolonged
PFS overall (HR, 0.37; 95% CI, 0.32 to 0.42) and in all subgroups. For tumors with exon 19 deletions, the
benefit was 50% greater (HR, 0.24; 95% CI, 0.20 to 0.29) than for tumors with exon 21 L858R substitution
(HR, 0.48; 95% CI, 0.39 to 0.58; P
interaction
⬍.001). Never-smokers had a 36% greater benefit (HR, 0.32;
95% CI, 0.27 to 0.37) than current or former smokers (HR, 0.50; 95% CI, 0.40 to 0.63; P
interaction
⬍.001).
Women had a 27% greater benefit (HR, 0.33; 95% CI, 0.28 to 0.38) than men (HR, 0.45; 95% CI, 0.36 to
0.55; treatment-sex interaction P⫽.02). Performance status, age, ethnicity, and tumor histology did not
significantly predict additional benefit from EGFR TKIs.
Conclusion
Although EGFR TKIs significantly prolonged PFS overall and in all subgroups, compared with
chemotherapy, greater benefits were observed in those with exon 19 deletions, never-smokers,
and women. These findings should enhance drug development and economic analyses, as well as
the design and interpretation of clinical trials.
J Clin Oncol 33:1958-1965. © 2015 by American Society of Clinical Oncology
INTRODUCTION
Advanced non–small-cell lung cancer (NSCLC)
with activating mutations in the epidermal
growth factor receptor (EGFR) gene is a distinct
subtype of disease that is characterized by a high
tumor response rate when treated with small-
molecule EGFR tyrosine kinase inhibitors (TKIs).
Randomized trials
1-8
and meta-analyses
9-11
have
consistently demonstrated longer progression-
free survival (PFS) with EGFR TKI therapy com-
pared with chemotherapy.
Deletions in exon 19 and substitution of leu-
cine for arginine (L858R) in exon 21 of the EGFR
gene (so-called common mutations) constitute ap-
proximately 90% of all EGFR mutations that are
detected in patients with advanced NSCLC who are
enrolled onto randomized trials.
1,2,6,7
Common and
uncommon mutation status is used as a stratifica-
tion factor in many EGFR TKI trials. Although the
two common mutations have been regarded as sim-
ilar in predicting the benefit of EGFR TKIs, sub-
group analyses of two studies
6,8
suggested that the
benefit of EGFR TKIs is greater in exon 19 deletion
JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT
VOLUME 33 䡠NUMBER 17 䡠JUNE 10 2015
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than in exon 21 L858R substitution tumors. However, these findings
have not been consistently observed in other trials.
2-5,7
In the landmark NCIC Clinical Trials Group study BR.21,
12
Asian origin, adenocarcinoma histology, never smoking, and erlotinib
were associated with improved overall survival (OS). Subsequent mo-
lecular analysis also showed that the benefit of erlotinib was strongly
associated with EGFR mutation in this trial, and EGFR mutations were
also more commonly detected in women, patients of Asian origin,
patients with adenocarcinoma, and never-smokers.
13,14
Among pa-
tients with EGFR mutations, the influence of these clinical character-
istics on the additional benefit of EGFR TKIs is unknown.
Individual randomized trials have not been designed nor ad-
equately powered to demonstrate a treatment difference between
subgroups of patients with these common mutations and other
clinicopathologic characteristics. Identifying such factors may be
important for future clinical trial design and development of newer
generations of EGFR TKIs. To address these questions, this study
was designed with the primary objective of testing the hypothesis
that the relative effect on PFS of first-line therapy with EGFR TKIs
versus chemotherapy is affected by mutation type. Secondary ob-
jectives were to test for interactions between clinical characteristics
(age, sex, ethnicity, smoking status, performance status, tumor
histology) that might be associated with EGFR TKI benefit in a
population with EGFR mutations.
Ideally, a meta-analysis of randomized trials with OS as the pri-
mary end point will address these questions. However, in all of these
trials, the effect of EGFR TKIs on OS has been diminished for two
reasons: first, nearly all of the patients who were randomly assigned to
chemotherapy crossed over to receive EGFR TKIs after disease pro-
gression, and second, EGFR TKIs are commercially available outside
of clinical trial settings. Furthermore, unlike with EGFR TKIs, the
benefit of chemotherapy diminished in second-line as compared with
first-line settings. For these reasons, we performed this meta-analysis
of PFS outcome using randomized trial data from patients undergoing
first-line treatment with first-and second-generation EGFR TKIs.
PATIENTS AND METHODS
Study Eligibility and Identification
Eligible studies were identified from our previous broad systematic re-
view that assessed the effectiveness of EGFR TKIs by EGFR mutation status.
9
The included studies were randomized trials that compared EGFR TKIs
against platinum-based combination chemotherapy in adult patients with
good performance status who did not receive any systemic therapy for their
histologically or cytologically confirmed, newly diagnosed advanced NSCLC
with sensitizing EGFR mutations. In brief, we updated our bibliographic
search of MEDLINE, EMBASE, CANCERLIT, and the Cochrane Central
Register of Controlled Trials (CENTRAL) databases for articles published in
English between January 1, 2004, and February 28, 2014, using the following
search terms: lung neoplasms, non–small-cell lung cancer, gefitinib, erlotinib,
afatinib, EGFR, meta-analysis, systematic review, randomized, and clinical
trials. To identify unpublished studies, we also searched abstracts from confer-
ence proceedings of the American Society of Clinical Oncology, the European
Society for Medical Oncology, and the World Lung Cancer Conference. Indi-
vidual study sponsors and study investigators were contacted for conference
presentation slides whenever slides were unavailable.
Data Extraction
For each included trial, we extracted the trial name, year of publication or
conference presentation, clinicopathologic characteristics, type of chemother-
apy, and type of EGFR TKIs. We also retrieved treatment estimates for these
subgroups: age (⬍65 vⱖ65 years), sex (female vmale), ethnicity (Asian v
non-Asian), smoking status (never-smoker vcurrent or former smoker),
Eastern Cooperative Oncology Group (ECOG) performance status (0 and
1v2), tumor histology (adenocarcinoma vother), and EGFR mutation
(exon 19 deletion vexon 21 L858R substitution) subtype. Data were
extracted independently by two authors (P.N.D. and C.K.L.), and discrep-
ancies were resolved by consensus that included a third author (S.J.L.).
Risk of bias for PFS analysis in each trial was assessed by examining the
methods used in random assignment, allocation concealment, outcome
assessments, handling of patient attrition, use of intention-to-treat analy-
sis, and handling of missing data for subgroup analyses.
Statistical Analyses
We extracted the hazard ratios (HRs) and 95% CIs for the overall cohort
and subgroups. Data from independent assessment of PFS were used in pref-
erence to investigator assessment whenever both types of review were avail-
able. We used the fixed-effects inverse-variance-weighted method to pool the
results from the studies and to estimate the size of the treatment benefit. Tests
for interaction were used to assess differences in treatment effect across sub-
groups as defined by their baseline clinicopathologic characteristics.
Subgroups with statistically significant heterogeneity in treatment effect
were examined further using individual patient data from four trials: NEJ002
(North East Japan 002),
2,15
OPTIMAL,
4
EURTAC (European Tarceva Versus
Chemotherapy),
5
and WJTOG (West Japan Thoracic Oncology Group) trial
3405.
3,16
We re-estimated the HRs and 95% CIs in multivariable analyses for
the treatment effect for each of these subgroups after adjusting for the other
baseline characteristics. We repeated the tests for interaction on the basis of the
adjusted HRs to assess differences in treatment effect.
Comparisons between EGFR mutations with exon 19 deletions versus
exon 21 L858R substitution, with respect to baseline characteristics, involved
data from the four trials.
2-5,15,16
The Kaplan-Meier approach was used to
examine the difference in PFS between exon 19 deletion and exon 21 L858R
substitution in patients who were randomly assigned to the chemotherapy and
EGFR TKIs arms separately, and univariable Cox regressions were used to
estimate the HRs and 95% CIs.
We performed three sensitivity analyses in which, first, studies were
excluded if they reported highly significant subgroup differences in the treat-
ment effect, given that such studies might skew the results if there was selective
reporting of chance positive findings; second, the analysis was limited to
first-generation EGFR TKIs (gefitinib and erlotinib) because we recognized
that there might be differences in efficacy between first- and second-
generation EGFR TKIs (afatinib); and third, studies were excluded if the
median PFS of the chemotherapy arm differed substantially from that of other
included trials because we recognized that there might be differences in efficacy
between the different types of platinum combination chemotherapies.
Publication bias was evaluated using the approach of Gleser and Olkin,
17
with an examination of a funnel plot of the effect size for each subgroup of the
trial against the reciprocal of its SE.
We used the
2
Cochran Q test to detect any heterogeneity across the
different studies and between subgroups. The nominal level of significance was
set at 5%. All 95% CIs were two sided.
RESULTS
We identified seven eligible studies
2-8,15,18
for inclusion in this meta-
analysis (Fig 1). Trial data were obtained from published manuscripts
and conference abstracts for three trials.
6-8
Updated individual patient
data from the NEJ002
2,15
and OPTIMAL
4
trials were used for sub-
group results. Individual patient data with longer follow-up than
previously published for EURTAC
5
and WJTOG 3405
3,16
trials were
used. Data that were based on independent reviews for PFS were used
Impact of EGFR Mutations and Clinical Characteristics in NSCLC
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for two studies.
6,7
Hoffmann-La Roche provided unpublished sub-
group data for the ENSURE trial that was based on investigator assess-
ment only.
8
All included trials were open label. Risk of bias was
assessed as unclear in one unpublished trial,
8
and low for all other
studies, although one trial
4
did not include independent review of
disease progression.
A total of 1,649 patients participated in these trials. All trials
except NEJ002,
2
LUX-Lung 3,
6
and LUX-Lung 6
7
recruited only pa-
tients with the two common EGFR mutations, exon 19 deletions and
exon 21 L858R substitution. Other clinicopathologic characteristics of
patients are summarized in Table 1.
Benefit of EGFR TKIs for PFS
Of the 1,649 patients, 950 (58%) had been randomly assigned to
EGFR TKIs, and 699 (42%) patients had been randomly assigned to
chemotherapy. Treatment with EGFR TKIs compared with chemo-
therapy was statistically significantly associated with a 63% reduction
in the risk of disease progression or death (HR, 0.37; 95% CI, 0.32 to
0.42; P⬍.001).
Subgroup Analyses
Of the 1,558 patients with common mutations, 872 (56%) pa-
tients had exon 19 deletions and 686 (44%) had exon 21 L858R
Studies identified from updated
database searches from 2012 through
Feb. 28, 2014, and conference proceedings
(n = 827)
Records after duplicates removed
(n = 817)
Title and abstracts screened for eligibility
Studies identified from previous meta-analyses
(n = 23)
Studies included in quantitative synthesis
(meta-analysis)
(n = 7)
Articles assessed for eligibility (n = 15)
)41 = n( txet lluF
Conference presentation (n = 1)
)8 = n( dedulcxe selcitrA
Insufficient data for this meta-analysis
as no subgroup analysis for different
exon mutations/clinical factors
)208 = n( dedulcxe selcitrA
Ineligible study designs/secondary publications (n = 648)
)04 = n( puorg noitalupop gnorW
Wrong intervention/comparator arm (n = 86)
Inappropriate outcome measure (n = 17)
EGFR TKI as subsequent/maintenance treatment (n = 11)
Fig 1. Flow diagram showing inclusion
and exclusion of studies. EGFR, epidermal
growth factor receptor; TKI, tyrosine ki-
nase inhibitor.
Table 1. Characteristics of Patients in Constituent Trials
Study Name, Year
Treatment
Comparison
Median
PFS
(months)
No. of
Patients
Exon 19
Deletion (%)
Exon 21
L858R
Substitution
(%)
Age ⬍65
Years
(%)
ECOG PS 0
and 1 (%)
Asian
(%)
Women
(%)
Never-Smoker
(%)
Adenocarcinoma
(%)
NEJ002, 2010,
2013
2,15ⴱ
Gefitinib vCP 10.8 v5.4 224† 51 43 49 99 100 63 62 93
WJTOG 3405,
2010, 2012
3,16
Gefitinib vCisD 9.6 v6.5 172 51 49 53 100 100 69 69 97
OPTIMAL, 2011,
2012
4,18
Erlotinib vCG 13.1 v4.6 154 53 47 75 94 100 59 71 87
EURTAC, 2012
5
Erlotinib v
platinum-G or
platinum-D
9.7 v5.2 173 66 34 49 86 0 73 69 92
LUX-Lung 3, 2013
6ⴱ
Afatinib vCisPem 11.1 v6.9 345 49 40 61 100 72 65 68 100
LUX-Lung 6, 2014
7ⴱ
Afatinib vCisG 11.0 v5.6 364 51 38 76 100 100 65 77 100
ENSURE, 2014
8
‡ Erlotinib vCisG 11.0 v5.5 217 54 45 79 94 100 61 71 94
Abbreviations: CG, carboplatin-gemcitabine; CisD, cisplatin-docetaxel; CisG, cisplatin-gemcitabine; CisPem, cisplatin-pemetrexed; CP, carboplatin-paclitaxel; ECOG,
Eastern Cooperative Oncology Group; EURTAC, European Tarceva Versus Chemotherapy; NEJ002, North East Japan 002; PFS, progression-free survival; PS,
performance status; WJTOG, West Japan Thoracic Oncology Group.
ⴱ
Includes patients with uncommon mutations of the EGFR gene.
†NEJ002 recruited a total of 228 patients; PFS outcome was only reported for 224 patients.
‡Reported in abstract only.
Lee et al
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substitution. In the subgroup with exon 19 deletions, the pooled HR
for PFS was 0.24 (95% CI, 0.20 to 0.29; P⬍.001). In the exon 21 L858R
substitution subgroup, the pooled HR for PFS was 0.48 (95% CI, 0.39
to 0.58; P⬍.001). Compared with chemotherapy, treatment with
EGFR TKIs demonstrated 50% greater benefit in exon 19 deletions
than in exon 21 L858R substitution (interaction P⬍.001; Fig 2).
Of the 1,649 patients, most were never-smokers (n ⫽1,155;
70%) and 494 (30%) were current or former smokers. Among the
never-smokers, the pooled HR for PFS was 0.32 (95% CI, 0.27 to 0.37;
P⬍.001). Among the current or former smokers, the pooled HR for
PFS was 0.50 (95% CI, 0.40 to 0.63; P⬍.001). Compared with
chemotherapy, treatment with EGFR TKIs demonstrated a 36%
greater benefit in never-smokers than current or former smokers
(interaction P⫽.002; Fig 2).
Most patients (n ⫽1,073; 65%) were women; 576 (35%) were
men. Among the women, the pooled HR for PFS was 0.33 (95% CI,
0.28 to 0.38; P⬍.001). Among the men, the pooled HR for PFS was
0.45 (95% CI, 0.36 to 0.55; P⬍.001). Compared with chemotherapy,
EGFR TKI treatment demonstrated a 27% greater benefit in women
than men (interaction P⫽.02; Fig 2).
In multivariable analysis using data from the four trials,
2-5,15,16
the pooled HRs for PFS were 0.26 and 0.44, adjusted for smoking
status and sex, for exon 19 deletions and exon 21 L858R substitution
subgroups, respectively (interaction P⫽.004). There was negligible
difference in the result between unadjusted and adjusted HRs (exon 19
deletions: unadjusted pooled HR, 0.26; exon 21 L858R substitution:
unadjusted pooled HR, 0.45; interaction P⫽.004). Table 2 compares
the unadjusted and adjusted HRs of treatment effect to assess any
potential inter-related impact of type of EGFR mutation, sex, and
smoking on benefit with EGFR TKIs.
The improvement in PFS with EGFR TKI treatment compared
with chemotherapy did not differ by ethnicity (interaction P⫽.37),
age (interaction P⫽.27), tumor histologic subtype (interaction P⫽
.59), or performance status (interaction P⫽.85; Fig 3).
Favors
EGFR TKI
Favors
chemotherapy
1010.01 0.1
Favors
EGFR TKI
Favors
chemotherapy
1010.01 0.1
IC %59 RH IC %59 RH lairT
noitutitsbus R858L 12 noxE snoiteled 91 noxE
19.0 ot 23.0 45.0 33.0 ot 21.0 02.0 ERUSNE
79.0 ot 92.0
35.0 34.0 ot 71.0 72.0 CATRUE
61.1 ot 64.0 37.0 44.0 ot 81.0 82.0 3 gnuL-XUL
45.0 ot 91.0 23.0 23.
0 ot 31.0 02.0 6 gnuL-XUL
45.0 ot 02.0 33.0 83.0 ot 51.0 42.0 200JEN
84.0 ot 41.0 62.0 42.0 ot 70.0
31.0 LAMITPO
70.1 ot 44.0 96.0 66.0 ot 62.0 24.0 5043 GOTJW
85.0 ot 93.0 84.0 92.0 ot 02.0 42.0 ll
A
rekoms remrof ro tnerruC rekoms-reveN
67.0 ot 71.0 63.0 45.0 ot 02.0 33.0 ERUSNE
)remrof( 45.1 ot 22
.0 95.0 93.0 ot 51.0 42.0 CATRUE
)tnerruc( 68.1 ot 22.0 46.0
)remrof( 33.1 ot 91.0 05.0 76.0 ot 33.0 74.0 3 gnuL-XUL
)tnerruc( 99.1 ot 45.0 40.1
)remrof( 92.2 ot 70.0 93.0 53.0 ot 61.0 42.0 6 gnuL
-XUL
)tnerruc( 89.0 ot 22.0 64.0
47.0 ot 82.0 64.0 14.0 ot 81.0 72.0 200 JEN
94.0 ot 90.0 12.0 42
.0 ot 80.0 41.0 LAMITPO
99.0 ot 13.0 65.0 77.0 ot 53.0 25.0 5043 GOTJW
36.0 ot 04.0 05.0 73.0 ot 72
.0 23.0 llA
elaM elameF
16.0 ot 02.0 53.0 84.0 ot 02.0 13.0 ERUSNE
48.0 ot 91.0 04.0 84.0 ot 91.0 03.0 CATRUE
10.1 ot 73.0 16.0 77.0 ot 83.0 45.0 3 gnuL-XUL
36.0 ot 12.0 63.0 53.0 ot 61.0 42.0 6 gnuL-XUL
77.0
ot 03.0 84.0 83.0 ot 71.0 52.0 200JEN
94.0 ot 41.0 62.0 42.0 ot 70.0 31.0 LAMITPO
62.1 ot 04.0 17.0
17.0 ot 33.0 84.0 5043 GOTJW
55.0 ot 63.0 54.0 83.0 ot 82.0 33.0 llA
Fig 2. Forest plot of the effect of treatment on progression-free survival in subgroups of patients according to mutations of the epidermal growth factor receptor (EGFR) gene,
smoking status, and sex. Hazard ratios (HRs) for each trial are represented by the squares, and the horizontal line crossing the square represents the 95% CI. The diamonds represent
the estimated overall effect based on the meta-analysis fixed effect. All statistical tests were two sided. EURTAC, European Tarceva Versus Chemotherapy; NEJ002, North East Japan
002; TKI, tyrosine kinase inhibitor; WJTOG, West Japan Thoracic Oncology Group.
Impact of EGFR Mutations and Clinical Characteristics in NSCLC
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Benefit of EGFR TKIs for OS
At the point of data cutoff for this analysis, several trials had
reported preliminary OS data and had patients still in active follow-up.
The data for OS remained immature for many of these studies. The OS
data for the ENSURE trial was unavailable.
8
With the available prelim-
inary OS data from the remaining six trials, treatment with EGFR TKIs
compared with chemotherapy was not statistically significantly asso-
ciated with reduction in the risk of death (HR, 1.01; 95% CI, 0.86 to
1.19; P⫽.88).
Association Between Mutations and Baseline
Clinical Characteristics
In four trials,
2-5,15,16
there were no significant correlations be-
tween EGFR mutation type and age, performance status, sex, histol-
ogy, or smoking status (Table 3).
Prognostic Outcomes for Patients With
Common Mutations
Of the 348 patients in the four trials
2-5,15,16
who were randomly
assigned to chemotherapy, those with exon 21 L858R substitution
(n ⫽158) had a median PFS of 6.1 months, which was statistically
significantly longer than those with exon 19 deletions (n ⫽190), who
had a median PFS of 5.1 months (HR, 0.70; 95% CI, 0.56 to 0.89; P⫽
.003). In comparison, of the 362 patients who were randomly assigned
to EGFR TKIs in these trials, patients with exon 21 L858R substitution
(n ⫽154) had a median PFS of 10.0 months, which was statistically
significantly shorter than that of patients with exon 19 deletions (n ⫽
208), who had a median PFS of 11.8 months (HR, 1.39; 95% CI, 1.10
to 1.76; P⫽.006).
Publication Bias
A funnel plot of the effect size for each subgroup category of the
trial against the precision showed no asymmetry (not shown). A
formal test
17
for potential publication bias yielded no potential un-
published studies.
Sensitivity Analyses
Two trials
6,8
individually demonstrated greater PFS benefit for
EGFR TKIs versus chemotherapy in tumors with exon 19 deletions
compared with those with exon 21 L858R substitution; therefore, we
excluded these studies and observed consistent results (HR, 0.24 v
0.42; interaction P⬍.001; Appendix Fig A1, online only).
Restricting our analyses to trials of first-generation reversible
EGFR TKIs, erlotinib
4,5,8,18
and gefitinib
2,3,15,16
(Appendix Fig A2,
online only), we also found consistent results: greater benefit with
EGFR TKIs for exon 19 deletions (interaction P⬍.001), never-
smokers (interaction P⫽.03), and women (interaction P⫽.03).
Two trials
3,6
individually demonstrated median PFS greater
than 6 months in the chemotherapy arm. Given that this was a
longer PFS than reported in other studies (Table 1), we excluded
these two studies and observed consistent results: greater benefit
for EGFR TKIs for exon 19 deletions (interaction P⬍.001),
never-smokers (interaction P⫽.003), and women (interaction
P⫽.01; Appendix Fig A3, online only).
DISCUSSION
Treatment with EGFR TKIs compared with chemotherapy is associ-
ated with a 63% overall reduction in the risk of disease progression or
death. Furthermore, the relative effect of EGFR TKIs compared with
chemotherapy on PFS is 50% greater for patients with exon 19 dele-
tions than for those with exon 21 L858R substitution. Other crucial
findings include a 36% greater PFS benefit for never-smokers than
Table 2. Unadjusted and Adjusted Treatment Effect of EGFR TKIs Versus
Chemotherapy in Four Clinical Trials
Subgroup
Unadjusted
Analysis Adjusted Analysis
HR 95% CI HR 95% CI
Exon 19 deletions
EURTAC 0.27 0.17 to 0.43 0.25
ⴱ
0.15 to 0.41
NEJ002 0.24 0.15 to 0.38 0.24
ⴱ
0.15 to 0.38
OPTIMAL 0.13 0.07 to 0.25 0.12
ⴱ
0.06 to 0.22
WJTOG 3405 0.42 0.26 to 0.68 0.46
ⴱ
0.28 to 0.76
Pooled result 0.26 0.20 to 0.34 0.26 0.20 to 0.33
Exon 21 L858R
substitution
EURTAC 0.53 0.29 to 0.97 0.51
ⴱ
0.28 to 0.94
NEJ002 0.33 0.20 to 0.54 0.33
ⴱ
0.20 to 0.55
OPTIMAL 0.26 0.14 to 0.49 0.23
ⴱ
0.12 to 0.45
WJTOG 3405 0.69 0.44 to 1.07 0.69
ⴱ
0.44 to 1.08
Pooled result 0.45 0.34 to 0.58 0.44 0.34 to 0.58
Treatment-EGFR mutation
interaction P⫽.004 P⫽.004
Never-smoker
EURTAC 0.24 0.15 to 0.39 0.23† 0.14 to 0.38
NEJ002 0.27 0.18 to 0.41 0.24† 0.16 to 0.37
OPTIMAL 0.14 0.08 to 0.25 0.14† 0.08 to 0.25
WJTOG 3405 0.52 0.35 to 0.77 0.52† 0.34 to 0.79
Pooled result 0.29 0.24 to 0.37 0.28 0.22 to 0.35
Current or former smoker
EURTAC (former) 0.59 0.22 to 1.54 0.67† 0.25 to 1.78
EURTAC (current) 0.64 0.22 to 1.86 0.56† 0.19 to 1.71
NEJ002 0.46 0.28 to 0.74 0.45† 0.28 to 0.73
OPTIMAL 0.21 0.09 to 0.49 0.20† 0.08 to 0.47
WJTOG 3405 0.56 0.31 to 0.99 0.57† 0.32 to 1.02
Pooled result 0.46 0.34 to 0.62 0.46† 0.34 to 0.62
Treatment-smoking
interaction P⫽.02 P⫽.01
Women
EURTAC 0.30 0.19 to 0.48 0.29‡ 0.18 to 0.47
NEJ002 0.25 0.17 to 0.38 0.21‡ 0.14 to 0.33
OPTIMAL 0.13 0.07 to 0.24 0.13‡ 0.07 to 0.24
WJTOG 3405 0.48 0.33 to 0.71 0.50‡ 0.33 to 0.76
Pooled result 0.30 0.24 to 0.38 0.28 0.22 to 0.36
Men
EURTAC 0.40 0.19 to 0.84 0.37‡ 0.17 to 0.81
NEJ002 0.48 0.30 to 0.77 0.45‡ 0.28 to 0.74
OPTIMAL 0.26 0.14 to 0.50 0.23‡ 0.12 to 0.45
WJTOG 3405 0.71 0.40 to 1.26 0.69‡ 0.39 to 1.22
Pooled result 0.46 0.34 to 0.61 0.43 0.32 to 0.58
Treatment-sex interaction P⫽.02 P⫽.03
Abbreviations: EGFR, epidermal growth factor receptor; EURTAC, European
Tarceva Versus Chemotherapy; HR, hazard ratio; NEJ002, North East Japan
002; TKI, tyrosine kinase inhibitor; WJTOG, West Japan Thoracic Oncology
Group.
ⴱ
HR (EGFR TKI vchemotherapy) adjusted for smoking status and sex.
†HR (EGFR TKI vchemotherapy) adjusted for sex and type of EGFR mutation.
‡HR (EGFR TKI vchemotherapy) adjusted for smoking status and type of
EGFR mutation.
Lee et al
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current or former smokers and a 27% greater PFS benefit for women
than men with EGFR TKIs compared with chemotherapy.
Consistent with previous studies, patients with exon 19 deletions
have a longer OS than those with exon 21 L858R substitution after
gefitinib or erlotinib therapy.
19,20
In contrast, in patients who are not
treated with EGFR TKIs, exon 21 L858R substitution, rather than exon
19 deletions, has been associated with longer OS.
14
Using data from
four trials,
2-5,15,16
we found that patients randomly assigned to che-
motherapy who had exon 21 L858R substitution had statistically sig-
nificantly longer PFS than those with exon 19 deletions (median PFS,
6.1 v5.1 months; P⫽.003). This indicates that patients who harbor
exon 19 deletions and are not treated with EGFR TKIs have a poorer
prognosis than those with exon 21 L858R substitution. Treatment
with EGFR TKIs improves the prognosis more in those with exon 19
deletions than in those with exon 21 L858R substitution (median PFS,
11.8 v10.0 months; P⫽.006).
Favors
EGFR TKI
Favors
chemotherapy
1010.01 0.1
Favors
EGFR TKI
Favors
chemotherapy
1010.01 0.1
IC %59 RH IC %59 RH lairT
naisA-noN naisA
ENSURE 0.34 0.22 to 0.52
94.0 ot 32.0 43.0 CATRUE
91.1 ot 93.0 86.0 67.0 ot 83.0 45.0 3 gnuL-XUL
LUX-Lung 6 0.28 0.20 to 0.39
NEJ002 0.32 0.24 to 0.44
OPTIMAL 0.16 0.10 to 0.26
WJTOG 3405 0.54 0.39 to 0.74
85.0 ot
13.0 24.0 24.0 ot 13.0 63.0 llA
egA sraey 56 < egA ≥ 65 years
89.0 ot 41.0 73.0 25.0 ot 12.0 33.0 ERUSNE
94.0 ot 61.0 82.0 76.0 ot 42.0 04.0
CATRUE
40.1 ot 93.0 46.0 77.0 ot 63.0 35.0 3 gnuL-XUL
83.0 ot 70.0 61.0 34.0 ot 12.0 03.0 6 gnuL-X
UL
25.0 ot 22.0 33.0 14.0 ot 51.0 52.0 200JEN
24.0 ot 70.0 71.0 23.0 ot 11.0 91.0 LAMITPO
90.1 ot
24.0 76.0 16.0 ot 52.0 93.0 5043 GOTJW
05.0 ot 23.0 04.0 04.0 ot 92.0 43.0 llA
epyt cigolotsih rehtO amonicraconedA
56.1 ot 50.0 92.0 35.0 ot 32.0 53.0 ERUSNE
48.1 ot 01.0 34.0 94
.0 ot 22.0 33.0 CATRUE
LUX-Lung 3 0.58 0.43 to 0.78
LUX-Lung 6 0.28 0.20 to 0.39
89.1 ot 50.0 23.0 54.0 ot 42.0 33.0 200JEN
77.0 ot 60.0 22.0 72.1 ot 11.0
71.0 LAMITPO
WJTOG 3405 0.51 0.37 to 0.71
36.0 ot 41.0 03.0 24.0 ot 23.0 73.0 llA
2 sutats ecnamrofrep GOCE 1–0 sutats ecnamrofrep GOCE
26.1 ot 80.0 63.0 74.0 ot 22.0 23.0 ERUSNE
51.
1 ot 51.0 93.0 35.0 ot 31.0 72.0 )0 SP( CATRUE
EURTAC (PS 1) 0.37 0.22 to 0.61
LUX-Lung 3 (PS 0) 0.50 0.31 to 0.81
LUX-Lung 3 (PS 1) 0.63 0.43 to 0.92
LUX-Lung 6 (PS 0) 0.22 0.12 to 0.41
LUX-Lung 6 (PS 1) 0.29 0.20 to 0.43
NEJ002 0.33 0.24 to 0.44
91.1 ot 40.0 12.0 62.0 ot 01.0 61.0 LAMITPO
WJTOG 3405 0.54 0.39 to 0.74
47.0
ot 51.0 43.0 14.0 ot 23.0 63.0 llA
Fig 3. Forest plot of the effect of treatment on progression-free survival in subgroups of patients according to ethnicity, age, tumor histologic subtype, and performance status (PS).
Hazard ratios (HRs) for each trial are represented by the squares, and the horizontal line crossing the square represents the 95% CI. The diamonds represent the estimated overall
effect based on the meta-analysis fixed effect. All statistical tests were two sided. ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; EURTAC,
European Tarceva Versus Chemotherapy; NEJ002, North East Japan 002; TKI, tyrosine kinase inhibitor; WJTOG, West Japan Thoracic Oncology Group.
Impact of EGFR Mutations and Clinical Characteristics in NSCLC
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The associations between different EGFR mutations and baseline
clinicopathologic characteristics remain unclear. Several studies re-
port that exon 21 L858R substitution is more frequently associated
with female sex, never smoking, and having adenocarcinoma.
21-23
Use
of the largest pooled individual patient data set of common mutations
(n ⫽714) from four trials
2-5,15,16
failed to detect any association
between the type of mutation and smoking status (P⫽.81), histology
(P⫽.11), or sex (P⫽.81).
Our finding that smoking status modifies EGFR TKI benefit is also
supported by existing studies. Smoking was found to be independently
associated with poorer tumor response with gefitinib.
24
Smoking was
also associated with significantly less drug exposure after ingestion of
erlotinib.
25
A phase I study
26
of smokers reported a maximum toler-
ated erlotinib dose of 300 mg, which was much higher than the dose of
150 mg per day used in randomized trials.
4,5,8
Whether this metabolic
difference is the true reason for the PFS difference or whether other
factors are involved has yet to be determined, and further research
is warranted.
Another interesting finding was that women had a 27% greater
PFS benefit with EGFR TKIs than men. The benefit of EGFR TKIs in
women has been previously attributed to the higher rate of EGFR
mutations in women.
14
In this meta-analysis involving only trials
conducted in populations with EGFR activating mutations, a differ-
ence in PFS benefit on the basis of sex was still detected. As a majority
of the nonsmokers were also women in these trials, it is possible that
smoking is confounding the interaction between sex and EGFR TKI
efficacy. However, multivariable analysis performed using individual
patient data from four trials
2-5,15,16
suggests that the predictive effect of
sex is largely independent of smoking status and EGFR mutation type
(Table 2). We acknowledge that there may be a difference between
current and former smokers, but our analysis does not discriminate
between these two cohorts of patients.
This meta-analysis has several strengths. We performed a com-
prehensive review, used the most up-to-date published data, and
contacted individual investigators or trial sponsors to obtain relevant
unpublished data. Another strength is that individual patient data
from four trials
2-5,15,16
were available to investigate the relationships
between different EGFR mutations and baseline clinical characteris-
tics, for multivariable adjustment, and for prognostic analyses.
There are also limitations of this study. We have not reported the
treatment effects within subgroups for OS because many of the trials
have yet to report mature OS data. In a recently presented pooled
analysis of two randomized trials, OS was longer with afatinib than
chemotherapy, and a statistically significant prolongation of OS was
reported in tumors with exon 19 deletions but not exon 21 L858R
substitution.
27
It remains unknown whether there would be a similar
finding in first-generation EGFR TKI trials. We restricted our study to
common EGFR mutations, and the predictive value of uncommon
mutations remains unknown. We are currently planning an individ-
ual patient data meta-analysis using all randomized trials with mature
OS data to address the limitations of our current work.
Our results have several important clinical and research implica-
tions. Our findings will be useful for counseling patients. Our meta-
analysis demonstrates that exon 19 deletion and exon 21 L858R
substitution mutations have different prognostic and predictive roles
and are hence important as a stratification factor in future clinical
trials. Further drug development of EGFR TKIs to enhance antitumor
activity, particularly for tumors with exon 21 L858R substitution,
remains important.
Another potential use of these findings is in economic analyses.
With differences in PFS benefits for various subgroups, there will be
differences in the costs required to achieve these benefits. In addition,
economic factors related to patient screening may also identify greater
cost-benefit for different identifiable subgroups.
In conclusion, EGFR TKIs significantly prolong PFS in all patients
with advanced NSCLC with EGFR mutations compared with chemother-
apy. The relative benefits of EGFR TKIs compared with chemotherapy
were greatest in patients with exon 19 deletions. Greater PFS benefit with
EGFR TKIs compared with chemotherapy was also seen in never-
smokers and women. These findings have important implications for
clinical trial design and interpretation, economic analyses, and future drug
development for EGFR-mutated, advanced NSCLC.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Disclosures provided by the authors are available with this article at
www.jco.org.
AUTHOR CONTRIBUTIONS
Conception and design: Chee Khoon Lee, Yi-Long Wu, Pei Ni Ding,
Sarah J. Lord, Akira Inoue, Tetsuya Mitsudomi, Nick Pavlakis, Matthew
Links, Val Gebski, Richard J. Gralla, James Chih-Hsin Yang
Collection and assembly of data: Chee Khoon Lee, Yi-Long Wu, Pei Ni
Ding, Sarah J. Lord, Akira Inoue, Caicun Zhou, Tetsuya Mitsudomi,
Rafael Rosell, James Chih-Hsin Yang
Data analysis and interpretation: Chee Khoon Lee, Yi-Long Wu, Pei Ni
Ding, Sarah J. Lord, Akira Inoue, Tetsuya Mitsudomi, Rafael Rosell, Nick
Table 3. Association Between Baseline Characteristics and Exon 19 Deletion or
Exon 21 L858R Substitution: Pooled Data From Four Clinical Trials
Characteristic
Exon 19
Deletion
(n ⫽401)
Exon 21
L858R
Substitution
(n ⫽313)
PNo. % No. %
Age, years .20
⬍65 233 58 166 53
ⱖ65 168 42 147 47
ECOG PS .32
0 186 46 136 44
1 191 48 164 52
2 24 6 13 4
Sex .81
Female 268 67 206 66
Male 133 33 107 34
Smoking .81
Never 268 67 212 68
Ever 133 33 101 32
Histologic subtype .11
Adenocarcinoma 377 94 284 91
Other 24 6 29 9
Abbreviations: EGOG, Eastern Cooperative Oncology Group; PS, perfor-
mance status.
Lee et al
1964 © 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
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Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
Pavlakis, Matthew Links, Val Gebski, Richard J. Gralla, James Chih-Hsin
Yang
Manuscript writing: All authors
Final approval of manuscript: All authors
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■■■
Impact of EGFR Mutations and Clinical Characteristics in NSCLC
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Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Impact of Specific Epidermal Growth Factor Receptor (EGFR) Mutations and Clinical Characteristics on Outcomes After Treatment With EGFR
Tyrosine Kinase Inhibitors Versus Chemotherapy in EGFR-Mutant Lung Cancer: A Meta-Analysis
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I ⫽Immediate Family Member, Inst ⫽My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Chee Khoon Lee
Research Funding: GlaxoSmithKline (Inst)
Travel, Accommodations, Expenses: Boehringer Ingelheim
Yi-Long Wu
Honoraria: AstraZeneca, Roche, Eli Lilly
Pei Ni Ding
No relationship to disclose
Sarah J. Lord
No relationship to disclose
Akira Inoue
Honoraria: AstraZeneca, Chugai Pharma, Boehringer Ingelheim
Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim
Research Funding: AstraZeneca, Chugai Pharma, Boehringer Ingelheim
Caicun Zhou
No relationship to disclose
Tetsuya Mitsudomi
Honoraria: AstraZeneca, Chugai, Boehringer Ingelheim, Pfizer, Taiho,
Eli Lilly, Daiichi Sankyo
Consulting or Advisory Role: AstraZeneca, Norvatis, Chugai,
Boehringer Ingelheim, Pfizer, Roche, Synta, Clovis, Merck Sharpe &
Dohme
Research Funding: AstraZeneca (Inst), Chugai (Inst), Boehringer
Ingelheim (Inst), Pfizer (Inst), Taiho (Inst), Ono (Inst), Daiichi Sankyo
(Inst), Eli Lilly (Inst)
Rafael Rosell
No relationship to disclose
Nick Pavlakis
Honoraria: AstraZeneca, Roche, Boehringer Ingelheim
Consulting or Advisory Role: AstraZeneca, Roche, Boehringer
Ingelheim, Bristol-Myers Squibb, Pfizer
Matthew Links
Travel, Accommodations, Expenses: GlaxoSmithKline
Val Gebski
No relationship to disclose
Richard J. Gralla
Consulting or Advisory Role: Eli Lilly, Merck, Pierre Fabre
James Chih-Hsin Yang
Honoraria: Boehringer Ingelheim, Pfizer, Roche/Genentech,
AstraZeneca
Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim (Inst),
Roche/Genentech, Merck Serono, Novartis, Bayer, Takeda (Inst), Clovis
Oncology
Research Funding: Boehringer Ingelheim (Inst)
Lee et al
© 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
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Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
Acknowledgment
We thank Hoffmann-La Roche for providing us with unpublished data for this meta-analysis. We acknowledge the editorial support provided
by Rhana Pike (National Health and Medical Research Council Clinical Trials Centre).
Appendix
Favors
EGFR TKI
Favors
chemotherapy
1010.01 0.1
Favors
EGFR TKI
Favors
chemotherapy
1010.01 0.1
IC %59 RH IC %59 RH lairT
noitutitsbus R858L 12 noxE snoiteled 91 noxE
79.0 ot 92.0 35.0 34.0 ot 71.0 72.0 CATRUE
45.0 ot 91.0 23.0 13.0 ot 31.0 02.0 6 gnuL-XUL
45.0 ot 02.0 33.0 83.0 ot 51.0 42.0 200JEN
84.0 ot 41.0 62.0 42.0 ot 70.0 31.0 LAMITPO
70.1 ot 44.0 96.0 86.0 ot 62.0 24.0 5043 GOTJW
35.0 ot 33.0 24.0 03.0 ot 02.
0 42.0 llA
Fig A1. Forest plot of effect of treatment on progression-free survival in subgroups of patients according to different mutations of the epidermal growth factor
receptor (EGFR), with exclusion of the LUX-Lung 3 and ENSURE trials. Hazard ratios (HRs) for each trial are represented by the squares, and the horizontal line crossing
the square represents the 95% CI. The diamonds represent the estimated overall effect based on the meta-analysis fixed effect (all P⬍.001). All statistical tests
were two sided. EURTAC, European Tarceva Versus Chemotherapy; NEJ002, North East Japan 002; TKI, tyrosine kinase inhibitor; WJTOG, West Japan Thoracic
Oncology Group.
Favors
EGFR TKI
Favors
chemotherapy
1010.01 0.1
Favors
EGFR TKI
Favors
chemotherapy
1010.01 0.1
IC %59 RH IC %59 RH lairT
noitutitsbus R858L 12 noxE snoiteled 91 noxE
19.0 ot 23.0 45.0 33.0 ot 21.0 02.0 ERUSNE
79.0 ot 92.0 35.0 34.0 ot 71.0 72.0 CATRUE
45.0 ot 02.0 33.0 83.0 ot 51.0 42.0 200JEN
84.0 ot 41.0 62.0 42.0 ot
70.0 31.0 LAMITPO
70.1 ot 44.0 96.0 86.0 ot 62.0 24.0 5043 GOTJW
95.0 ot 73.0 64.0 13.0 ot 02.0 52
.0 llA
rekoms remrof ro tnerruC rekoms-reveN
67.0 ot 71.0 63.0 45.0 ot 02.0 33.0 ERUSNE
)remrof( 45.1 ot 22
.0 95.0 93.0 ot 51.0 42.0 CATRUE
)tnerruc( 68.1 ot 22.0 46.0
47.0 ot 82.0 64.0 14.0 ot 81.0 72.0 2
00JEN
94.0 ot 90.0 12.0 42.0 ot 80.0 41.0 LAMITPO
99.0 ot 13.0 65.0 77.0 ot 53.0 25.0 5043 GOTJW
9
5.0 ot 33.0 44.0 73.0 ot 42.0 03.0 llA
elaM elameF
16.0 ot 02.0 53.0 84.0 ot 02.0 13.0 ERUSNE
48.0 ot 91.0 04.0 84.0 ot 91.0 03.0 CATRUE
77.0 ot 03.0 84.0 83.0 ot 71.0 52.0 200JEN
94.0 ot 41.0 62.0 42.0 ot 70.0 31.0 LAMITPO
62.1 ot 04.0
17.0 17.0 ot 33.0 84.0 5043 GOTJW
65.0 ot 33.0 34.0 73.0 ot 52.0 03.0 llA
Fig A2. Forest plot of effect of treatment on progression-free survival in subgroups of patients according to mutations of the epidermal growth factor receptor (EGFR)
gene, smoking status, and sex in gefitinib and erlotinib trials only. Hazard ratios (HRs) for each trial are represented by the squares, and the horizontal line crossing the
square represents the 95% CI. The diamonds represent the estimated overall effect based on the meta-analysis of fixed effect (all P⬍.001). All statistical tests were
two sided. EURTAC, European Tarceva Versus Chemotherapy; NEJ002, North East Japan 002; TKI, tyrosine kinase inhibitor; WJTOG, West Japan Thoracic
Oncology Group.
Impact of EGFR Mutations and Clinical Characteristics in NSCLC
www.jco.org © 2015 by American Society of Clinical Oncology
Downloaded from ascopubs.org by 38.145.79.153 on May 15, 2018 from 038.145.079.153
Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
Favors
EGFR TKI
Favors
chemotherapy
1010.01 0.1
Favors
EGFR TKI
Favors
chemotherapy
1010.01 0.1
IC %59 RH IC %59 RH lairT
noitutitsbus R858L 12 noxE snoiteled 91 noxE
19.0 ot 23.0 45.0 33.0 ot 21.0 02.0 ERUSNE
79.0 ot 92.0 35.0 34.0 ot 71.0 72.0 CATRUE
45.0 ot 91.0 23.0 23.0 ot 31.0 02.0 6 gnuL-XUL
45.0 ot 02.0 33.0 83.
0 ot 51.0 42.0 200JEN
84.0 ot 41.0 62.0 42.0 ot 70.0 31.0 LAMITPO
94.0 ot 03.0 83.0 62.0 ot 71.0 12
.0 llA
rekoms remrof ro tnerruC rekoms-reveN
67.0 ot 71.0 63.0 45.0 ot 02.0 33.0 ERUSNE
)remrof( 45.1 ot 22
.0 95.0 93.0 ot 51.0 42.0 CATRUE
)tnerruc( 68.1 ot 22.0 46.0
)remrof( 92.2 ot 70.0 93.0 53.0 ot 61
.0 42.0 6 gnuL-XUL
)tnerruc( 89.0 ot 22.0 64.0
47.0 ot 82.0 64.0 14.0 ot 81.0 72.0 200JEN
94.0 ot
90.0 12.0 42.0 ot 80.0 41.0 LAMITPO
65.0 ot 13.0 24.0 03.0 ot 02.0 42.0 llA
elaM elameF
16.0 ot 02.0 53.0 84.0 ot 02.0 13.0 ERUSNE
48.0 ot 91.0 04.0 84.0 ot 91.0 03.0 CATRUE
36.0 ot 12.0 63.0 53.0 ot 61.0 42.0 6 gnuL-XUL
77.0 ot 03.0 84.0 83.0 ot 71.0 52.0 200JEN
94.0 ot 4
1.0 62.0 42.0 ot 70.0 31.0 LAMITPO
94.0 ot 92.0 83.0 13.0 ot 12.0 52.0 llA
Fig A3. Forest plot of effect of treatment on progression-free survival in subgroups of patients according to different mutations of the epidermal growth factor
receptor (EGFR), with exclusion of the LUX-Lung 3 and WJTOG 3405 (West Japan Thoracic Oncology Group 3405) trials. HR, hazard ratio; NEJ002, North East Japan
002; TKI, tyrosine kinase inhibitor.
Lee et al
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