Journal of Cancer Therapy, 2012, 3, 467-476
http://dx.doi.org/10.4236/jct.2012.324060 Published Online September 2012 (http://www.SciRP.org/journal/jct)
467
Efficacy and Safety of Gefitinib or Platinum plus Taxane in
Egfr-Mutant Advanced Non-Small Cell Lung Cancers: A
Meta-Analysis of First-Line Randomized Controlled
Trials*
Adnan Aydiner
Istanbul University, Institute of Oncology, Istanbul, Turkey.
Received February 13th, 2012; revised March 7th, 2012; accepted March 26th, 2012
ABSTRACT
Purpose: The discovery of EGFR mutations renewed interest in lung cancer translational research since EGFR-depen-
dent pathway plays an important role in the development and progression of human epithelial cancers, including non-
small cell lung cancer (NSCLC). The present meta-analysis was performed to review the recent advances with the se-
lective oral EGFR-TK inhibitor gefitinib among EGFR mutation positive patients with NSCLC. Methods: Using the
keywords “gefitinib” and “lung cancer” MEDLINE was searched. The primary reports of interest were the randomized
controlled trials in NSCL published in peer-reviewed journals. Three recent studies concerning the effect of gefitinib in
NSCLC were identified to be relevant for the meta-analysis based on their similarity in terms of study design. PFS and
objective response rate (ORR) in gefitinib and platinum/taxane combination were compared by the Hazard ratio (HR) or
Odds Ratio (OR) of meta-analysis. Results: The HR (95% CI) of the meta-analysis of 0.41 (0.34 - 0.49) demonstrated
that in patients EFGR mutation positive patients, PFS was significantly longer among those who received gefitinib
compared to platin derivative/taxane combination. Furthermore, OR of the meta-analysis for ORR was 3.83 (2.72 -
5.40). While hematological toxicity was observed in the majority of the taxane/platinum group, major adverse events in
gefitinib patients were skin rashes/acnea, dry skin, elevated liver enzymes and diarrhea. Conclusion: This meta-analysis
strongly confirms the efficacy and better tolerability of gefitinib in EGFR positive NSCLC, and the importance of
EGFR mutation testing in order to plan first-line treatment in routine clinical practice in NSCLC.
Keywords: Gefitinib; EGFR Mutation; Lung Cancer; Meta-Analysis
1. Introduction
In recent years, various molecular targeted therapies have
been developed for the treatment of advanced NSCLC in
an attempt to improve prognosis. One such target has
been the EGFR, which is frequently expressed at high
levels in tumor tissue compared to the corresponding
healthy tissue [1]. Accordingly, in the last decade, two
small molecules, orally active, selective and reversible
EGFR-tyrosine kinase inhibitors (EGFR-TKIs) gefitinib
and erlotinib have been developed for the treatment of
NSCLC [2].
In fact, increased demand to identify sub-sets of
NSCLC patients to improve outcomes in this heteroge-
neous disease having a median survival barely exceeding
12 months [3], great efforts in clinical and laboratory re-
search in recent years led to a better knowledge of pre-
dictive factors of the efficacy of EGFR-TKIs [4].
Identification of somatic mutations in the tyrosine
kinase domain of the EGFR in patients with NSCLC by
three groups of investigators in 2004 [5-7] revealed al-
most ubiquitous presence of these mutations in patients
who had radiographic and clinical responses to gefitinib
[4-6].
Accordingly, subsequent population-based efforts to
sequence EGFR in NSCLC have consistently identified
EGFR mutations in an enriched cohort of women, non-
smokers, adenocarcinomas and East Asians including
small inframe deletions around the conserved LREA mo-
tif of exon 19 (residues 747 - 750), followed by a single
point mutation in exon 21-L858R as the most prevalent
EGFR mutations [4]. In particular, increasing evidence
has been accumulated, supporting a strong predictive role
of EGFR gene mutation in tumor cells. In parallel, EGFR
inhibition strategy, that was originally limited to patients
*Conflicts of interest: No conflicts of interest.

Efficacy and Safety of Gefitinib or Platinum plus Taxane in Egfr-Mutant Advanced Non-Small Cell
Lung Cancers: A Meta-Analysis of First-Line Randomized Controlled Trials
468
who had already failed previous standard treatment, has
been tested as first-line strategy [2].
As reviewed recently [2], the background of gefitinib
treatment has been based on the ground of randomized
clinical trials (RCTs) conducted in unselected patients
with advanced NSCLC pretreated with chemotherapy as
second line treatment [8-14], as first-line treatment of
unselected patients in chemotherapy naïve patients [15-
19], small studies concerning gefitinib as first-line treat-
ment of patients selected for the presence of EGFR mu-
tation [20-24], or selected according to other clinical or
molecular putative predictive factors [25,26] followed by
randomized phase III trials [27-30] conducted in East
Asian countries comparing gefitinib vs. platinum-based
chemotherapy as first-line treatment in patients with ad-
vanced NSCLC (Table 1).
Besides gefitinib, two other anti-EGFR-TKI including
erlotinib [31] and afatinib [32,33] were reported to be
superior to chemotherapy in terms of PFS as first-line
treatment of patients with EGFR-mutation positive tu-
mors [2]. In a randomised trial (OPTIMAL, CTONG-
0802) conducted in China [31], non-small-cell lung can-
cer patients with a confirmed activating mutation of
EGFR (exon 19 deletion or exon 21 point mutation) re-
ceived either oral erlotinib or gemcitabine plus carbo-
platin in the first line setting. Median progression-free
survival was significantly longer in erlotinib-treated pa-
tients than in those on chemotherapy [hazard ratio (HR)
0.16 (0.10 - 0.26); p < 0.0001). In the interim analysis of
EURTAC trial in Asia, the first line erlotinib showed
significant benefit of PFS over standard chemotherapy in
EGFR-mutated cases [HR = 0.42 (0.27 - 0.64), p <
0.0001] [34]. No overall survival differences could be
detected in these trials. Since patients included in OP-
TIMAL-CTONG-0802 trial received either oral erlotinib
or gemcitabine plus carboplatin rather than platinum/
taxane combination in the first line setting, the present
meta-analysis included only gefitinib trials.
Providing a basis for the present meta-analysis, RCTs
comparing gefitinib versus standard first-line chemothe-
rapy of platinum/taxane combination for advanced NSC-
LC demonstrated a striking progression-free survival
(PFS) prolongation for patients receiving gefitinib, al-
though no difference in overall survival (OS) could be
detected, possibly related to the crossover design as re-
ported in a recent meta-analysis [27,29,30].
Table 1. A brief recent history of gefitinib trials in NSCLC.
Year Development
2003 FDA approval for gefitinib based on 2 phase II trials [8,41].
2003 IDEAL I and IDEAL II phase II studies had objective response rate of 12% - 18% and demonstrated favorable tolerability [8,9].
2004 Iressa NSCLC Trial Assessing Combination Treatment (INTACT) -1 and -2, failed to show a significant survival benefit with the
addition of gefitinib to chemotherapy (either cisplatin/gemcitabine or carboplatin/paclitaxel) [15,16].
2005 Gefitinib was approved in other countries. Phase III ISEL trial led to restriction of gefitinib use in USA that showed no statistical
significance in overall survival [10].
2006
A subgroup analysis of the ISEL study revealed a significant survival benefit in two patients who had never smoked or who were of
Asian ethnicity compared with those who received best supportive care. Biomarker analyses of samples from ISEL suggested that high
EGFR gene copy number was a predictor of clinical benefit from gefitinib [42].
2008 Iressa NSCLC Trial Evaluating Response and Survival versus Taxotere (INTEREST) trial demonstrated non-inferiority of gefitinib for
OS in pretreated patients but with a more favorable tolerability profile and significantly improved quality of life [14].
2008
Phase II study Iressa in NSCLC versus Vinorelbine Investigation in the Elderly (INVITE) comparing gefitinib with vinorelbine in
elderly chemonaive patients failed to demonstrate a statistically significant efficacy benefit for first-line gefitinib in these patient
settings [43].
2009 Iressa NSCLC Trial Evaluating Poor Performance Status Patients (INSTEP) comparing gefitinib with best supportive care in patients
with poor performance status failed to demonstrate a statistically significant efficacy benefit for first-line gefitinib [44].
Randomized Controlled Phase III Trials evaluating first-line gefitinib vs standard platinum-base chemotherapy
2009
Iressa Pan-Asia Study (IPASS) met its primary endpoint of demonstrating non-inferiority and, furthermore, demonstrated the
superiority of first-line gefitinib compared with standard carboplatin/paclitaxel in PFS (Overall HR = 0.74; 95% CI: 0.65 - 0.85;
p < 0.001; HR in EGFR mutation-positive patients = 0.48; 95% CI: 0.36 - 0.64 ) [27].
2010 In WJTOG3405 trial by West Japan Oncology Group, patients with EGFR mutations were included, and had longer PFS if they were
treated with gefitinib compared to cisplatin/docetaxel (HR = 0.49; 95% CI: 0.34 - 0.71; p < 0.002) [29].
2010 In the RCT by North-East Japan Study Group, in patients who were selected on the basis of EGFR mutations, gefitinibe improved PFS
with acceptable toxicity, as compared with carboplatin/paclitaxel (HR = 0.30; 95% CI: 0.22 - 0.41; p < 0.001) [30].

Efficacy and Safety of Gefitinib or Platinum plus Taxane in Egfr-Mutant Advanced Non-Small Cell
Lung Cancers: A Meta-Analysis of First-Line Randomized Controlled Trials
469
Since there is no debate on the clinical superiority of
gefitinib, a meta-analysis seems to be useful for consoli-
dation of the existing knowledge by increasing the statis-
tical power rather than resolving conflicting areas by
providing HR for PFS and OS that may help to draw the
attention of the physicians and the health authority to
consider EGFR mutation test and gefitinib use into rou-
tine practice of NSCLC. Therefore, the present meta-
analysis was focused on data from EGFR mutation-posi-
tive patients in 3 recent phase III RCTs with homogenous
design and same TKI in Asian population [27,29,30] that
consistently support the role of gefitinib treatment option
in advanced NSCLC compared to platinum/taxane com-
bination. Both the efficacy and safety of gefitinib or che-
motherapy in the first-line treatment of EGFR mutated
NSCLC were evaluated in this meta-analysis.
2. Materials and Methods
MEDLINE was searched using the keyword “gefitinib”
and “lung cancer”. Of more than 1900 published reports
retrieved, older studies and studies with diverse method-
ology were excluded while the primary reports of interest
were the RCTs in NSCLC published in peer-reviewed
journals since 2005 after which gefitinib use was intensi-
fied. Four recent studies concerning the effect of first-
line gefitinib vs standard chemotherapy in advanced
NSCLC were identified to be relevant for the meta-
analysis based on their similarity in terms of study design.
However, one of these studies was also excluded since
results have not been yet published in a peer-reviewed
journal yet, but only its abstract could be accessed [28].
Furthermore, the standard therapy arm (carboplatin/
gemcitabine) was different that the other 3 included RCT
(carboplatin/taxane) [27,29,30].
Additionally, since the primary endpoint of all three
selected trials was progression free survival while the
overall survival results were only reported in two of the
selected trials, present meta-analysis was based only on
PFS rather than OS. Accordingly, overall survival was
reported as 0.78 (95% CI 0.50 - 1.20) for OS in EGFR-
M(+) subgroup by Mok et al., 2009 [27] and not as HRs
but as survival time and 2 year survival rate of 30.5 vs
23.6 months; and 61.4% vs 46.7% for gefitinib and car-
boplatin-paclitaxel patients, respectively (p = 0.31) by
Maemondo et al. 2010 [30], while not reported by Mitsu-
domi et al., 2010 [29].
Characteristics of trial design and the main outcomes
are summarized in Table 2. The primary efficacy mea-
sure was PFS at all 3 studies included in the meta-analy-
sis. Pooled HR for PFS and Odds Ratio (OR) for object-
tive response rate (ORR) as efficacy endpoints are calcu-
lated; and adverse events are listed recorded at the RCTs
included at the meta-analysis. OS at two studies included
in the meta-analysis. Regarding toxicity data the toxicity
analysis was actually based on a data obtained for EGFR
mutated population in two trials [29,30] and in an unse-
lected population of patients including all but not only
EGFR-mutated patients in one trial [27].
Statistical Analysis
“Comprehensive Meta-Analysis version 2” software pro-
gram (USA) was used. For the effect estimates, HRs or
ORs with the 95% confidence intervals (CIs) obtained in
EGFR mutation-positive patients were used for the meta-
analysis.
3. Results
Selected Trials
Three randomized phase III trials comparing gefitinib to
Table 2. Summary of RCTs included in this meta-analysis
Ref # Inclusion criteria Study arm
Number (%) of
patients with
EGFR-M
Number (%) of
never smokers
Number (%) of
patients with stage
IIIB/IV disease
Number (%) of
female patients
Gefitinib 132 (59.2) 124 (93.9) 132 (100.0) 108 (81.8)
27*
Age > 18 years
NSCLC (stage IIIb or IV)
Non-smoker/former light smoker
Chemotherapy -naive Carboplatin/Paclitaxel 129 (60.3) 122 (94.6) 129 (100.0) 103 (79.8)
Gefitinib 86 (100.0) 61 (70.9) 51 (59.3) 59 (68.6)
29
Age < 75
WHO PS 0 - 1
Activating EGFR-M (exon 19
deletion or L858R inexon 21) Cisplatin/Docetaxel 86 (100.0) 57 (66.3) 50 (58.1) 60 (69.8)
Gefitinib 114 (100.0) 75 (65.8) 103 (90.4) 72 (63.2)
30
Age < 75
ECOG PS 0 - 2
Sensitive EGFR-M (absence of
resistant EGFR
mutation T790 M
)
Carboplatin/Paclitaxel 114 (100.0) 66 (57.9) 105 (92.1) 73 (64.0)
ECOG PS: Eastern Cooperative Oncology Group Performance status; EGFR-M: Epithelium growth factor receptor mutation; NSCLC: Non-small cell lung
cancer; WHO: World Health Organisation; *Data for EGFR-M (+) patients are obtained from the Supplementary Appendix of the article that can be accesses
via www.nejm.org.

Efficacy and Safety of Gefitinib or Platinum plus Taxane in Egfr-Mutant Advanced Non-Small Cell
Lung Cancers: A Meta-Analysis of First-Line Randomized Controlled Trials
470
platinum-based chemotherapy in patients with advanced
NSCLC eligible for first-line treatment were included in
the present meta-analysis [27,29,30].
Being conducted in East Asian countries, patients as-
signed to the experimental arm received oral gefitinib at
the standard dose (250 mg daily) while the chemotherapy
arm received different platinum-based doublets including
carboplatin plus a taxane (paclitaxel in 2 trials [27,30],
docetaxel in 1 trial [29].
In relation to the previous evidence demonstrating
high frequency of EGFR mutations, and high activity of
gefitinib in NSCLC patients with these characteristics,
inclusion criteria of one of the three trials [27] was based
on a clinical selection according to clinical factors known
to be associated with higher prevalence of EGFR muta-
tion (adenocarcinoma, including bronchioloalveolar car-
cinoma, and either never smokers or former light-smok-
ers). Of 1217 patients included [27], 261 patients were
determined to be EGFR mutation positive. The remain-
ing two trials [29,30] were based on biomarker-driven se-
lection that only patients with EGFR mutation-positive
tumor were considered to be eligible. All patients (172
and 228 patients, respectively) included were EGFR mu-
tation-positive with respect to inclusion criteria. Accord-
ingly, after exclusion of patients without mutations, a
total of 661 patients with EGFR mutation from three tri-
als were included in the present meta-analysis (332 allo-
cated to gefitinib, and 329 to platinum/taxane arm).
Progression free survival: The HR (95% CI) of the
meta-analysis of 0.41 (0.34 - 0.49; p < 0.001) demon-
strated that in patients who were positive for the EFGR
gene mutation, PFS was significantly longer among those
who received gefitinib than among those who received
platinum derivative/taxane combination. In other words,
a 2.44 times longer PFS time was obtained with gefitinib
in these patients (Table 3 and Figure 1). Based on dis-
ease stage [27,29] and gender [29,30] related evaluation,
hazard ratios (HRs) of gefinib treatment was lower in
Table 3. Effect estimates obtained at the individual RCTs and the meta-analysis in EGFR mutation (+) patients.
Objective Response Rate
Ref # % OR (95% CI) OR of the meta-analysis (95% CI)
27 71.2 vs 47.3, p < 0.001 2.75 (1.65 - 4.60), p < 0.001
29 62.1 vs 32.2, p < 0.001 3.45 (1.61 - 7.38), p < 0.001
30 73.7 vs 30.7, p < 0.001 6.22 (3.55 - 11.35), p < 0.001
3.83 (2.72 - 5.40) p < 0.001
Progression Free Survival
Ref # Months HR (95% CI) HR of the meta-analysis (95% CI)
All EGFR mutation (+) patients 27 9.6 vs. 6.3; p < 0.001 0.48 (0.36 - 0.64)
All EGFR mutation (+) patients 29 9.2 vs 6.3; p < 0.001 0.49 (0.34 - 0.71)
All EGFR mutation (+) patients 30 10.8 vs 5.4; p < 0.001 0.30 (0.22- 0.41)
0.41 (0.34 - 0.49), p < 0.001
Patients with Stage IIIB/IV disease 27 9.6 vs. 6.3; p < 0.001 0.48 (0.36 - 0.64)
Patients with Stage IIIB/IV disease 29 - 0.33(0.20 - 0.54)
Patients with Stage IIIB/IV disease - -
0.44 (0.34 - 0.56), p < 0.001
Females 27 - -
Females 29 - 0.42 (0.27 - 0.65)
Females 30 6.5 vs 6.0; P = 0.01 0.68 (0.5 - 0.92)
0.59 (0.46 - 0.75), p < 0.001
Figure 1. Forest plot using boxes to represent the effect size and relative weights of gefitinib against platinum/taxane doublet.

Efficacy and Safety of Gefitinib or Platinum plus Taxane in Egfr-Mutant Advanced Non-Small Cell
Lung Cancers: A Meta-Analysis of First-Line Randomized Controlled Trials
471
patients with Stage III/IV patients (HR = 0.44 (0.34; 0.56;
p < 0.001) and in females (HR = 0.59 (0.46; 0.75; p <
0.001) (Table 3). Nonetheless, no gender comparison
was reported in the trial by Mok et al. 2009 [27] include-
ing patients in stage IIIb/IV, while no disease stage
comparison was evident in the trial by Maemondo et al.,
2010 [30] which stated that women had significantly
longer PFS than men (median 6.5 vs 6.0 months) whereas
HRs for PFS for gefitinib vs chemotherapy in males was
not provided. HR for PFS in early stage (post-op) group
was 0.57 (95% CI 0.31 - 1.05), in stage IIIb/IV group
was 0.33 (95% CI 0.20 - 0.54) in the trial by Mitsudomi
et al., 2010 [29] which stated HR for PFS in males to be
0.67 (95% CI 0.34 - 1.33) and in females to be 0.42 (95%
CI 0.27 - 0.65).
Objective Response Rate: The OR (95% CI) for the
ORR of the meta-analysis of 3.83 (2.72 - 5.40; p < 0.001)
in patients who were positive for the EFGR gene muta-
tion (Table 3).
Safety: The safety results of the individual RCTs
showed that hematological toxicity, fatigue, nausea and
alopecia were the most frequent adverse events in the
taxane/platinum group, while major adverse events in
gefitinib patients were skin rashes/acnea, dry skin, ele-
vated liver enzymes and diarrhea (Tables 4 and 5).
4. Discussion
The present meta-analysis provides the magnitude of
benefit obtained with the EGFR-TKI gefitinib when used
as front-line treatment in advanced, EGFR-M+, NSCLC
patients. The HR obtained with this meta-analysis more
strongly supports the efficacy of gefitinib, and stresses on
the importance of EGFR mutation test and gefitinib use
in routine practice of NSCLC safely.
Report of EGFR mutations in exons 19 or 21 amongst
patients responding to gefitinib, as compared to no muta-
tion found in non-responders [5-7,35] triggered studies
Table 4. Adverse events observed at the individual randomized controlled trials included in this meta-analysis.
Gefitinib (n (%)) Platinum/Taxane (n (%))
Ref [27] (n = 607)Ref [29] (n = 87) Ref [30] (n = 114)Ref [27] (n=589) Ref [29] (n = 88) Ref [30] (n = 113)
Adverse event All CTC
grade ≥ 3 All CTC grade ≥ 3All CTC grade ≥ 3All CTC grade ≥ 3All CTC grade ≥ 3 All CTC grade ≥ 3
Non-hematological toxicity
Rash or acne 402 (66.2) 19 (3.1) 74 (85.1)* 2 (2.3)81 (71.1)6 (5.3)132 (22.4)5 (0.8) 7 (79.5) 0 (0.0) 25 (22.1)3 (2.7)
AST NA NA 61 (70.1)* 14 (16.1)63 (55.3)30 (26.3)NA NA 17 (19.3) 1 (1.1) 37 (32.7)1 (0.9)
ALT NA NA 61 (70.1)* 24 (27.6)NA NA NA NA 35 (39.8) 2 (2.3) NA NA
Dry skin 145 (23.9) 0 (0.0)47 (54.0)* 0 (0.0)NA NA 17 (2.9)0 (0.0) 3 (34.1) 0 (0.0) NA NA
Diarrhea 283 (46.6) 23 (3.8) 47 (54.0) 1 (1.1)39 (34.2)1 (0.9)128 (21.7)8 (1.4) 35 (39.8) 0 (0.0) 7 (6.2)0 (0.0)
Fatigue NA NA 34 (39.1)* 2 (2.3)12 (10.5)3 (2.6)NA NA 73 (83.0) 2 (2.3) 31 (27.4)1 (0.9)
Paronychia 82813.5) 2 (0.3)28 (32.2)* 1 (1.1)NA NA 0 (0.0) 0 (0.0) 1 (1.1) 0 (0.0) NA NA
Stomatitis 103 (17.0) 1 (0.2)19 (21.8) 0 (0.0)NA NA 51 (8.7)1 (0.2) 13 (14.8) 0 (0.0) NA NA
Nausea 101 (16.6) 2 (0.3)15 (17.2)* 1 (1.1)NA NA 261 (44.3)9 (1.5) 83 (94.3) 3 (3.4) NA NA
Vomiting 78 (12.9) 1 (0.2)NA NA NA NA 196 (33.3)16 (2.7)NA NA NA NA
Constipation 73 (12.0) 0 (0.0)14 (16.1)* 0 (0.0)NA NA 173 (29.4)1 (0.2) 39 (44.3) 0 (0.0) NA NA
Anorexia 133 (21.9) 9 (1.5)NA NA 17 (14.9)6 (5.3)251 (41.6)16 (2.7)NA NA 64 (56.6)7 (6.2)
Pruritus 118 (19.4) 4 (0.7)NA NA NA NA 74 (12.6)1 (0.2) NA NA NA NA
Alopecia 67 (11.0) 0 (0.0)8 (9.2)* 0 (0.0)NA NA 344 (58.4)0 (0.0) 67 (76.1) 0 (0.0) NA NA
Arthralgia 39 (6.4) 1 (0.2)NA NA 3 (26.3)1 (0.9)113 (19.2)6 (1.0) NA NA 54 (47.8)8 (7.1)
Neuropathy 66 (10.9) 2 (0.3)7 (8.0)* 1 (1.1)1 (0.8)0 (0.0)NA NA 23 (26.1) 0 (0.0) 63 (55.8)7 (6.2)
Hematological toxicity
Leucopenia NA 9(1.5)13(14.9)* 0(0.0)NA NA NA 202(35.0)82(93.2) 43(48.9) NA NA
Thrombocytopenia NA NA 12(13.8)* 0(0.0)8(7.0)0(0.0)NA NA 29(33.0) 0(0.0) 32(28.3)4(3.5)
Neutropenia NA 22(3.7)7(8.0)* 0(0.0)7(6.1)1(0.9)NA 387(67.1)81(92.0) 74(84.1) 87(77.0)74(65.5)
Anemia NA 13(2.2)33(37.9)* 0(0.0)21(18.4)0(0.0)NA 61(10.6)79(89.8) 15(17.0) 73(64.6)6(5.3)
ALT: alanine aminotransferase; AST: aspartate aminotransferase; CTC: National Cancer Institute Common Tehcnology Criteria, *p < 0.001 compared to plati-
num/taxane group; NA: not available. Events are included if they occurred in at least 10% of patients in each treatment group.

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Table 5. Odds ratios of the meta-analysis for all grades of adverse events in gefitinib vs platinum/taxane treated patients.
Odds ratio %95 Confidence interval p
Non-hematological toxicity
Rash or acne 7.98 6.35 - 10.04 <0.001
AST 4.19 2.74 - 6.43 <0.001
Dry skin 12.56 7.80 - 20.23 <0.001
Diarrhea 3.09 2.47 - 3.87 <0.001
Fatigue 0.20 0.12 - 0.33 <0.001
Paronychia 30.52 5.86 - 158.92 <0.001
Stomatitis 2.05 1.48 - 2.84 <0.001
Nausea 0.21 0.16 - 0.27 <0.001
Constipation 0.31 0.24 - 0.41 <0.001
Anorexia 0.33 0.26 - 0.42 <0.001
Alopecia 0.08 0.06 - 0.11 <0.001
Arthralgia 0.28 0.20 - 0.40 <0.001
Neuropathy 0.47 0.35 - 0.64 <0.001
Hematological toxicity
Thrombocytopenia 0.26 0.15 - 0.45 <0.001
Neutropenia 0.01 0.01 - 0.03 <0.001
Anemia 0.10 0.06 - 0.16 <0.001
ALT: alanine aminotransferase; AST: aspartate aminotransferase; CTC: National Cancer Institute Common Tehcnology Criteria *p < 0.001 compared to plati-
num/taxane group.
that provided preliminary evidence about predictive fac-
tors of gefitinib efficacy. Accordingly the frequency of
somatic mutations within the tyrosine kinase domain of
the EGFR gene was shown to be low in unselected
Western patients with advanced NSCLC, but, interest-
ingly, these mutations appeared to be much more fre-
quent in Japanese and East Asian population [2]. Fur-
thermore, it was rapidly evident that some clinical or
pathological characteristics are associated with higher
prevalence of mutation: in detail, EGFR mutation is more
frequent in never smokers, in women, and in patients
with adenocarcinoma [2]. Based on this evidence, several
small trials were conducted testing gefitinib as first-line
treatment of patients selected for the presence of EGFR
mutation [20-24], or selected according to other clinical
or molecular putative predictive factors [25,26] followed
by randomized phase III trials [27-30] conducted in East
Asian countries comparing gefitinib vs. platinum-based
chemotherapy as first-line treatment in patients with ad-
vanced NSCLC.
Accordingly, indicating a high-level evidence, coming
from four prospective, randomized phase III trials [27-
30], two of which were conducted specifically in patients
with tumor harbouring EGFR mutation [29,30], in pa-
tients with advanced NSCLC selected for the presence of
EGFR mutation, the administration of first-line gefitinib,
compared to standard platinum-based chemotherapy
seems to be associated with longer PFS, higher ORR, a
more favorable toxicity profile and better quality of life.
Likewise, an estimate of the magnitude of benefit was
reported with EGFR-TKI (gefitinib and erlotinib) in a
recent meta-analysis, when used as front-line treatment
in advanced, EGFR-M+, NSCLC patients. In this setting,
EGFR-TKI has been considered to provide an unusually
large PFS benefit when compared with cytotoxic che-
motherapy, with an absolute reduction in the risk of pro-
gression of 22% - 30% as well as an advantage achieved
in terms of ORR [36].
As a matter of fact, the results of the recent meta-
analysis [36] indicated the significant role of attrition in
the observed magnitude of benefit of a “targeted” treat-
ment strategy that as the rate of patients analyzed or
positive for sensitizing EGFR mutation increases (and
thus the attrition rate decreases), the HR in favor of the
EGFR-TKI decreases. When the attrition is relatively low
(e.g. the Asian “clinically enriched” population of the two
retrospective front-line trials [27,28], a non-molecular
selection strategy may still be able to detect some de-
gree of benefit for EGFR-TKI in the target population.
Conversely, when the attrition bias is high (e.g. in mostly
Caucasian patient populations where the rate of EGFR
mutations is expected to be <10%), not only may a po-

Efficacy and Safety of Gefitinib or Platinum plus Taxane in Egfr-Mutant Advanced Non-Small Cell
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tential benefit for EGFR-M+ patients be easily missed
using a non selection strategy but we can also incur in the
risk of exposing patients to a significantly detrimental
effect, as observed in the Tarceva OR CHemotherapy
trial [37], comparing erlotinib with standard chemothe-
rapy as front-line treatment of unselected, advanced
NSCLC patients [36].
Concerning toxicity, gefitinib appears to be well toler-
ated when administered as first-line treatment of patients
with advanced NSCLC. Notably, in the IPASS trial [27],
gefitinib was associated with a lower rate of severe ad-
verse events (defined as grade 3 or 4 according to the
Common Terminology Criteria for Adverse Events,
28.7% vs 61.0% for gefitinib and chemotherapy, respec-
tively).
Differing substantially from toxicity reported, gefitinib
was associated with better tolerance in all randomized
trials comparing first-line gefitinib to platinum-based
chemotherapy [27-30]. Although the most common ad-
verse events in patients receiving gefitinib were cutane-
ous toxicity (skin rash, dry skin), diarrhea and liver dys-
function usually consisting in asymptomatic hypertrans-
aminasemia, patients assigned to gefitinib arm suffered
significantly less hematological toxicity, emesis, fatigue,
neurotoxicity, constipation and hair loss, compared to
patients treated with platinum-based chemotherapy. In
particular, as reviewed recently [2], lower rate of severe
adverse events (defined as grade 3 or 4 according to the
Common Terminology Criteria for Adverse Events,
28.7% vs 61.0% for gefitinib and chemotherapy, respec-
tively, a lower rate of adverse events leading to discon-
tinuation of the drug (6.9% vs 13.6%) and a lower rate of
dose modification due to toxic effects (16.1% for ge-
fitinib vs 35.2% for carboplatin and 37.5% for paclitaxel)
were reported in IPASS trial [27]. Likewise, in the
NEJ002 trial [32], gefitinib confirmed a significantly
lower incidence of severe toxic effects compared to car-
boplatin plus paclitaxel (41.2% vs 71.7%, p < 0.001).
Among potentially life-threatening events described
with the use of gefitinib, interstitial lung disease (ILD)
was relatively uncommon. As described recently [2], it
was identified in 16 patients (2.6%) in the IPASS trial
[27], 2 patients (2.3%) in the WJTOG3405 trial [29], 6
patients (5.3%) in the NEJ002 trial [30]. Five of these 24
cases were lethal, and further 2 lethal cases of ILD were
described in the 159 patients treated with gefitinib in the
First-SIGNAL trial [28], leading to a total of 7 lethal ILD
toxicities in the 967 patients overall evaluated in the 4
trials (0.7%).
In this regard, identification of sensitizing EGFR mu-
tations as the preferential molecular target of EGFR-TKI
was reported to be crucial to get impressive benefit
achieved with EGFR-TKI over classical cytotoxic che-
motherapy if compared with the benefit of chemotherapy
versus best supportive care in the same setting [38,39].
Importantly, this benefit was not gained at the expense of
an increased toxicity rate; hematological toxic effects
were significantly decreased in patients receiving gefit-
inib, thus further increasing the therapeutic index of such
a targeted approach. When a composite measurement of
both efficacy and toxicity is used, an EGFR M+ patient
was reported to be at least 67 times more likely to derive
clinical benefit than to be harmed by upfront treatment
with an EGFR-TKI rather than chemotherapy [36].
Whilst representing the strongest endpoint for clinical
research in oncology, none of these randomized trials
demonstrated a statistically significant improvement with
gefitinib in terms of OS. Indeed, differences in OS were
reported to be potentially conditioned by cross-over, and
a relevant number of patients assigned to chemotherapy
arm received an EGFR tyrosine kinase inhibitor (gefit-
inib or erlotinib) as second or third-line treatment after
disease progression [2]. As the number of trials is small
(n = 3), the limitations of the trials with respect to patient
populations (all patients are from Asia) are important.
How this may or may not impact generalization to West-
ern countries is not clear. Moreover, in a series of West-
ern patients with EGFR mutation positive NSCLC,
treated with erlotinib, similar OS was reported for pa-
tients receiving the EGFR tyrosine kinase inhibitor as
first-line or as second-line (median OS was 28.0 months
and 27.0 months, respectively) [40].
5. Conclusion
In patients with advanced NSCLC selected for the pre-
sence of EGFR mutation, the administration of first-line
gefitinib, compared to standard platinum-based chemo-
therapy, is associated with longer PFS, higher ORR. The
current meta-analysis does not provide any data on better
tolerability of gefitinib compared to chemotherapy be-
cause of different toxicity observed between two treat-
ment modalities. Since no data on EGFR M-negative
patients has been included in the meta-analysis the con-
clusion on the importance of EGFR mutation testing in
order to plan first-line therapy cannot be drawn from the
presented work, even though it is correct. Accordingly,
the HR and also OR for the ORR obtained within this
meta-analysis supports the efficacy of gefitinib strongly,
and as a superior medical evidence that may help to draw
the attention of the physicians and the health authority,
stresses on the importance of the identification of EGFR
mutation test as well as gefitinib use in routine practice
of NSCLC which is characterized by significant hetero-
geneity, premonitory for the likelihood of deriving sub-
stantial therapeutic benefit.

Efficacy and Safety of Gefitinib or Platinum plus Taxane in Egfr-Mutant Advanced Non-Small Cell
Lung Cancers: A Meta-Analysis of First-Line Randomized Controlled Trials
474
6. Acknowledgements
I would like to thank to Sule Oktay, MD, PhD and Cagla
Isman, MD for editorial support and Onder Ergonul, MD
for consultancy in statistical analysis.
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