Chin J Cancer Res 23(2): 112-117, 2011 www.springerlink.com 112
Immediate Versus Delayed Treatment with EGFR Tyrosine Kinase
Inhibitors after First-line Therapy in Advanced
Non-small-cell Lung Cancer
Zhi-jie Wang1,2, Tong-tong An1*, Tony Mok4, Lu Yang1, Hua Bai1,2, Jun Zhao1,2, Jian-chun Duan1,2
Mei-na Wu1,2, Yu-yan Wang1,2, Ping-ping Li1,3, Hong Sun3, Ping Yang5, Jie Wang1,2
1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), 2Department of Thoracic Medical Oncology,
3Department of Integrative Medicine, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, China;
4Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong; China; 5Department of Oncology, General Hospital of
Navy, Beijing, China
Chinese Anti-Cancer Association and Springer-Verlag Berlin Heidelberg 2011
Objective: To analyze the outcomes of patients who received TKI immediately after the first-line without
progression as maintenance treatment (immediate group) vs. those received delayed treatment upon disease
progression as second-line therapy (delayed group).
Methods: The study included 159 no-small-cell lung cancer (NSCLC) patients who received gefitinib or erlotinib
as maintenance treatment in the immediate group (85 patients) or as second-line therapy in the delayed group (74
patients). The primary end point was progression-free survival (PFS). EGFR mutation status was detected using
denaturing high-performance liquid chromatography (DHPLC).
Results: PFS was 17.3 and 16.4 months in the immediate and delayed groups, respectively (hazard ratio [HR],
0.99; 95% Confidence Interval [CI]: 0.69-1.42; P=0.947). In a subgroup analysis that included only patients with EGFR
mutation, however, PFS was significantly longer in the immediate group than in the delayed group (HR, 0.48; 95% CI:
0.27-0.85; P=0.012). In patients with wild type EGFR, the risk for disease progression was comparable between the
two groups (HR, 1.23; 95% CI: 0.61-2.51; P=0.564). No significant difference was demonstrated between the
immediate and delayed group in terms of the overall survival (OS) (26.1 months vs. 21.6 months, respectively;
HR=0.53; 95% CI: 0.27 to 1.06; P=0.072). There was also no difference in the incidence of adverse events between
the two groups.
Conclusions: EGFR TKI maintenance improves PFS in patients with EGFR mutation. Prospectively designed
clinical studies that compare TKI immediate vs. delayed treatment after first-line chemotherapy upon disease
progression are needed.
Key words: EGFR tyrosine kinase inhibitor; Maintenance therapy; Non-small-cell lung cancer
Non–small-cell lung cancer (NSCLC) is the leading
cause of cancer-related death worldwide. Most of
patients were in advanced stage when diagnosed. Four to
six cycles of platinum-based chemotherapy are
recommend as standard first-line therapy. For treatment
subsequent to disease control, the standard practice is to
initiate second-line therapy only upon disease
Received 2010-12-06; Accepted 2011-02-24
This work was supported by the grants from the China National Funds
for Distinguished Young Scientists (No. 81025012) and the Capital
Development Foundation (No. 30772472)
*Contributed equally to this study
progression, using either the same drugs as in the initial
treatment or other agents that are not cross-resistant with
the initial drugs.
Theoretically, maintenance therapy immediately after
achieving disease control has several advantages. First,
the early use of non-cross-resistant regimens may delay
the occurrence of eventual resistance. Second, the tumor
burden is low at the time of the treatment. A numbers of
randomized clinical trials
improvement in progression-free survival (PFS) or time to
progression (TTP) patients with advanced NSCLC
receiving immediate maintenance
However, prolonged overall survival (OS) was only
observed in two trials with pemetrexed (the JMEN study)
and erlotinib (the SATURN study). Further perplexing the
issue, only a small portion of patients in the placebo arms
received pemetrexed/erlotinib as post-study therapy in
www.springerlink.com Chin J Cancer Res 23(2): 112-117, 2011 113
the two trials.
The epithelial growth factor receptor tyrosine kinase
inhibitors (EGFR-TKIs; e.g., gefitinib or erlotinib) have
been recommended as the first-line therapy for patients
with EGFR mutations. In comparison to classic cytotoxic
agents, EGFR-TKIs are highly selective and have much
more favorable toxicity profile, and hence could improve
quality of life (QoL). As a result, EGFR-TKIs represent an
attractive choice for maintenance therapy in patients with
In this retrospective study, we compared the efficacy
and safety of maintenance EGFR TKI maintenance
therapy, implemented immediately after achieving
disease control with first-line chemotherapy vs. delayed
treatment at the time of disease progression. Data analysis
was stratified based on EGFR mutation status.
MATERIAL AND METHODS
Patients and Treatment
Between November 2005 and November 2009, a total
of 568 consecutive patients with histologically or
cytologically confirmed advanced-stage NSCLC (stage
IIIB with pleural effusion or stage IV) were treated with
oral gefitinib or erlotinib at the Beijing Cancer Hospital or
General Hospital of Navy, Beijing, China. All patients
selected for the current study met the following criteria: 1.
Platinum-based chemotherapy was used as first line
therapy; 2. Patient must completed no less than 2 cycles
of first-line chemotherapy; 3. Patient must attain disease
control (DC) defined as complete response (CR), partial
response (PR) or stable disease (SD) according to RECIST
criteria. 4. EGFR TKI treatment started either within one
month after the first-line chemotherapy and without
evidence of disease progression (referred to as
“immediate group”), or upon confirmation of progressive
disease (PD) according to RECIST criteria (referred to as
All patients gave consents to the standard therapy
indicated for their illness. The retrospective review of the
clinical data was approved by the Institutional Review
Board of the Beijing Cancer Hospital.
Study Endpoints and Assessment
The primary endpoint of the study is PFS. The
secondary endpoints included objective response rate
(ORR), OS and adverse events. Baseline tumor
measurement (obtained with CT or MRI) was available for
all subjects. Treatment responses were assessed every two
cycles during the initial first-line chemotherapy and every
6-8 weeks during the period of EGFR TKI treatment using
the Response Evaluation Criteria In Solid Tumors
(RECIST). Imaging data were reviewed by an
independent radiologist. PFS was defined as the period
from the beginning of first-line chemotherapy to cessation
of gefitinib/erlotinib due to PD, or death from any cause.
OS was defined as the period from the beginning of
first-line chemotherapy until death from any cause. The
responses in the TKI treatment phase were evaluated
relative to the tumor status at the beginning of TKI use.
Adverse events were evaluated according to the Common
Terminology Criteria for Adverse Events (version 3.0).
Detection of EGFR Mutation
Specimen collection, DNA extraction and denaturing
high-performance liquid chromatography (DHPLC) were
performed as previously described. To confirm
mutations identified by DHPLC, the PCR products used
for DHPLC were sequenced bi-directionally using a Big
Dye Terminator Cycle
Biosystems, Foster City, CA). The reactions were carried
out in an automated DNA analyzer (ABI Prism 377;
The PFS and OS were estimated by the Kaplan-Meier
method and were analyzed by using the the log-rank test.
In addition, a Cox proportional hazards regression model
was used to caculate hazard ratios. The models included
effects for treatment groups. The 95%CI for median time
was caculated by using the method of Brookmeyer and
Crowley.Categorical valuables were compared using χ2
test. All statistical comparisons
statistically significant with a P value of less than 0.05
(two sided). A SPSS software for PC (version 13.0 for
windows; SPSS Inc., IL, USA) was used for all statistical
A total of 159 patients fulfilled the selection criteria:
85 in the immediate group and 74 in the delayed group. In
the immediate group, majority of patients (67/85, 79%)
were placed under EGFR-TKI treatment within 2 weeks
after the completion of first-line chemotherapy. More
patients were female in the immediate group (61.2%
versus 43.2% in the delayed group, P=0.024; Table 1).
Higher percentage of patients in the immediate group
received less than 4 cycles of first-line chemotherapy
(median: 3 cycles versus 5 cycles in the delayed group,
P<0.001) and. Otherwise, the two groups did not differ in
demographics and baseline characteristics. For both
groups, adencarcinoma was the most common type.
Tissue samples for EGFR mutation were available in 116
out of 159 patients (immediate group: 66; delayed group:
The main cause leading to discontinuation of the
first-line chemotherapy was adverse events. The most
common cause of death was disease progression
(156/159), followed by infection (2 cases) and acute
cardiac infarction (1 case). The median duration of the
follow-up was 20.3 months (range: 4.4-50.9 months).
The most common adverse events were rash and
diarrhea (mostly grade 1 or 2) that dissipated
spontaneously during the treatment (Table 2). Other
adverse events included anorexia, nausea/vomiting,
fatigue and elevated aminotransferase level, but were
Sequencing kit (Applied
Chin J Cancer Res 23(2): 112-117, 2011 www.springerlink.com 114
relatively uncommon. Five patients (5.9%) in the
immediate group and three (4.1%) in the delayed group
developed grade 3/4 toxicity, and either discontinued TKI
or reduced the dosage. No hematological toxicity or
adverse-event related death was recorded. One patient
Table 1. Baseline characteristics and demographic distribution in overall population
(1.2%) in the immediate group developed grade 3 hepatic
damage; gefitinib was adjusted to 250 mg every two days
until recovery. The toxicity profile did not differ between
the two EGFR TKIs.
WHO performance statusc
0 or 1
Disease stage at entry
JIIB with pleural effusion
First-line agents combined with
Cycle numbers of previous
2 or 3
4 to 6
EGFR mutation statuse
a: The statistic was analyzed by pearson Chi-square tests. b: Never smokers were defined as patients who had smoked <100 cigarettes in their
lifetime. c: The World Health Organization (WHO) performance status measures level of activity and is assessed on a scale of 0 to 4, with lower
numbers indicating a higher degree of activity. The time point assessing WHO performance status in our study was that at the beginning of
gefitinib or erlotinib. d: The subgroup of adenocarcinoma also included bronchoalveolar carcinoma. e: Sixty-six and 50 patients had records of
EGFR mutation status in immediate group and delayed group respectively.
Table 2. Adverse events in the EGFR-TKI phase
Immediate group (n=85)
All adverse events CTC grade 3 or 4b
a: Calculations were based on the total 159 patients. The Common Terminology Criteria (CTC) grade is defined on the basis of the national
Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. b: No death occurred due to TKI related adverse events. c: No
Hematologic toxicity was considered to be associated with TKI therapy.
Delayed group (n=74)
All adverse events CTC grade 3 or 4b
Efficacy Comparation between Immediate and Delayed
ORR did not differ between the immediate and
delayed groups (43.5% vs. 44.6%, P=0.893). Tumor
www.springerlink.com Chin J Cancer Res 23(2): 112-117, 2011 115
response rate was also similar between the two groups
regardless of mutation status (62.6% vs. 69.0%, P=0.578 for
patients with EGFR mutation; 11.5% vs. 9.5%, P=0.824 for
patients without mutation).
Disease progression (assessed up to November 1,
2009) did not differ between the two groups (63/85, 74.1%
in the immediate group vs. 57/74, 76.0% in the delayed
group; Figure 1A). The median PFS was 17.3 and 16.4
months in the immediate
respectively. The hazard ratio [HR] was 0.99 (95%
confidence interval: 0.69-1.42; P=0.947). In an effort to
reduce the influence of the unbalanced cycle number
during the first-line chemotherapy, we also calculated PFS
from the completion of first-line treatment to TKI
treatment failure. The results of such analysis also failed
and delayed groups,
to show any difference between the two groups (14.2 vs.
14.3 months, log rank test P=0.857). In patients completing
only 4 cycles during first-line chemotherapy (immediate
group: 30, 35.3%, and delayed group: 30, 40.5%), disease
progression seemed to be lower in the immediate group
but a statistically the difference was not significant
(HR=0.67; 95% CI: 0.36-1.23; P=0.194; Figure 1C).
Similar to PFS, there was no significant difference in
terms of OS between the two groups either in the overall
analysis (26.1 months in the maintenance group vs. 21.6
months in the delayed group; HR=0.77; 95% CI: 0.51-1.16;
P=0.205; Figure 1B), or in the subgroup of patients
receiving only 4 cycles during first-line chemotherapy
(HR=0.52; 95% CI: 0.27-1.10; P=0.082; Figure 1D).
Figure 1. Kaplan-Meier curves for progression-free survival (PFS) and overall survival(OD). Kaplan-Meier curves for
progression-free survival are shown for the overall population (Panel A) and patients who received only 4 cycles of first-line
chemotherapy (Panel C), patients who were positive for the EGFR mutation (Panel E), and patients with EGFR mutation wide type
(Panel G). Kaplan-Meier curves for overall survivaol are shown for the overall population (Panel B) and patients who reeived ony 4
cycles of first-line chemotherapy (Panel D), patients who were positive for the EGFR utation (Panel F), and patients with EGFR
mutation wide type (Panel H). Hazard ratios were calculated with the use of a Cox proportional-hazards model, with sex smoking
history (never smoker or ever smoker), and histology (adeocarvinoma or non-adenocarcinoma) as covariates.
Chin J Cancer Res 23(2): 112-117, 2011 www.springerlink.com 116
The Influence of EGFR Mutation Status
Incidence of EGFR mutation (deletion in exon 19 and
missense mutation at exon 21) was balanced between the
two groups (40/66, 60.6% in the immediate group, and
29/50, 58.0% in the delayed group). For PFS, there was a
significant interaction between treatment and EGFR
mutation. PFS was significantly longer in patients with
EGFR mutation in the immediate group (HR=0.48; 95%
CI: 0.27-0.85; P=0.012; Figure 1E), and there was no
difference in terms of OS between the two groups with
Table 3. Clinical outcome by subgroups: EGFR mutation status, tumor histology, sex and smoking history
EGFR mutation (HR=0.53; 95% CI: 0.27 to 1.06; P=0.072;
Figure 1F). But in patients without EGFR mutation,
neither PFS (HR=1.23; 95% CI: 0.61-2.51; P=0.564; Figure
1G) nor OS (HR=1.19; 95% CI: 0.55-2.58; P=0.660; Figure
1H) differed between the immediate and delayed groups.
Stratification based upon other clinical characteristics,
including gender smoking history, and histology
(adenocarcinoma and non-adenocarcinoma), did not affect
the results (Table 3).
Subgroup Progression-free survival (months)a
Immediate Delayed PFS for P
Median Median HR(95%CI)b P
Overall survival (months)a
Immediate Delayed OS for P
Median Median HR(95%CI)b P
EGFR mutation positivec
EGFR mutation negative
a: The statistical analysis was based upon the entire sample of 159 subjects; b: Hazard ratio was calculated against the delayed group using a Cox
proportional-hazards model, with sex, smoking history, and histology as covariantes; c: EGFR mutation included exon 19 deletion and exon 21 L858R
only; d: Also included bronchoalveolar carcinoma; e: <100 cigarettes in lifetime.
EGFR TKIs (e.g., gefitinib and erlotinib) are the currently
second-line therapy for advanced NSCLC[15,16,17]. An
increasing number of randomized clinical trials suggested
that maintenance therapy with TKIs immediately after
first-line therapy in NSCLC patients achieving disease
control is a promising strategy[8,18]. The results from the
current study suggested immediate TKI maintenance is
potentially superior to delayed therapy in NSCLC patients
with EGFR mutation.
Both PFS and OS were prolonged by immediate TKI
maintenance and delayed TKI treatment. Although the
differences between the two groups were not statistically
significant, there was a trend towards longer PFS and OS in
the immediate group. Female NSCLC patients seem to have
better prognosis than males[19,20]. The gender composition
was significantly different between the two groups in our
study. However, a stratified analysis failed to show a
significant difference in either PFS or OS between the two
groups. Responses to chemotherapy typically occur within
the first two to four cycles. Therefore, only subjects who
completed no less than 2 cycles of the first-line chemotherapy
were included in our study. Despite of such effort, patients in
the immediate group received less cycles of initial
chemotherapy than the delayed group. In order to minimize
the potential influence of such a bias, we took two measures.
First, we defined the survival time from the end of initial
treatment to disease progression so that the starting point
was identical in the two groups. We also conducted a
separate analysis for patients who received only four cycles
of first-line chemotherapy. Such an analysis failed to reach
statistical significance, but suggested a trend towards
decreased risk of progression/death in the immediate group
compared with delayed group.
EGFR mutation is a powerful predictor for treatment
response to EGFR-TKIs[22-27]. In the BR.21 study, patients
harboring EGFR mutation had a 23% reduction in risk of
death with erlotinib versus placebo (HR, 0.77). In SATURN
study, patients with EGFR mutation who received
immediate erlotinib maintenance versus placebo as
maintenance had a remarkable reduction of progression risk
www.springerlink.com Chin J Cancer Res 23(2): 112-117, 2011 117 Download full-text
(91%, HR, 0.09), suggesting that the patients with EGFR
mutation could benefit from immediate TKI treatment. Our
study showed that patients with EGFR mutation could
benefit from immediate TKI maintenance treatment. A
possible explanation underlying this phenomenon is the
smaller tumor burden in patients who receive two treatment
regimens without significant delay vs. those who received
two regimens with a substantial interval.
In summary, immediate maintenance treatment with
EGFR-TKIs after achieving disease control improves PFS
(and potentially OS as well) in patients with EGFR mutation.
This finding encourages prospectively designed clinical
studies that compare immediate TKI maintenance with
We thank Dr. Ning Wang, for conducting imaging evaluation and Yan
Zhang for contribution in statistical analysis. We also thank Dr. Liang Li from
Peking University Third Hospital for the support in the study.
Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J
Clin 2007; 57: 43-66.
Mok TS, Ramalingam SS. Maintenance therapy in non-small-cell lung
cancer: a new treatment paradigm. Cancer 2009; 115: 5143-54.
Goldie JH, Coldman AJ. A mathematic model for relating the drug
sensitivity of tumors to their spontaneous mutation rate. Cancer Treat
Rep. 1979; 63: 1727-33.
Brodowicz T, Krzakowski M, Zwitter M, et al. Cisplatin and
gemcitabine first-line chemotherapy followed by maintenance
gemcitabine or best supportive care in advanced non-small cell lung
cancer: a phase III trial. Lung Cancer 2006; 52: 155-63.
Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate
compared with delayed docetaxel after front-line therapy with
gemcitabine plus carboplatin in advanced non–small-cell lung cancer.
J Clin Oncol 2009; 27: 591-8.
Ciuleanu T, Brodowicz T, Zielinski C,et al. Maintenance pemetrexed
plus best supportive care versus placebo plus best supportive care for
non-small-cell lung cancer: a randomised, double-blind, phase 3 study.
Lancet 2009, 374:1432-40.
Cappuzzo F, Ciuleanu T, Stelmakh l, et al. Erlotinib as maintenance
treatment in advanced non-small-cell lung cancer: a multicentre,
randomised, placebo-controlled phase 3 study. Lancet Oncol 2010, 11:
Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with
bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006; 355:
10. Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus
gemcitabine with either placebo or bevacizumab as first-line therapy
for nonsquamous non-small-cell lung cancer: AVAil[J]. J Clin Oncol.
2009; 27: 1227-34.
11. Reck M, von Pawel J, Zatloukal P, et al. Overall survival with
cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy
for nonsquamous non-small-cell lung cancer: results from a
randomised phase III trial (AVAiL). Ann Oncol. 2010 21: 1804-9.
12. Pirker R, Pereira JR, Szczesna A,et al. Cetuximab plus chemotherapy in
patients with advanced non-small-cell lung cancer (FLEX): an
open-label randomised phase III trial. Lancet. 2009; 373: 1525-31.
13. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to
evaluate the response to treatment in solid tumors. J Natl Cancer Inst
2000; 92: 205-16.
14. Bai H, Mao L, Wang SH, et al. Epidermal growth factor receptor
mutations in plasma DNA samples predict tumor response in Chinese
patients with stages IIIB to IV non-small cell lung cancer. J Clin Oncol
2009; 27: 2653-9.
15. National Comprehensive Cancer Network: Clinical Practice Guidelines
in Oncology: Non-small cell lung cancer. http://www.nccn.org/
16. Kim ES, Hirsh V, Mok TS, et al. Gefitinib versus docetaxel in previously
treated non-small-cell lung cancer (INTEREST): a randomised phase III
trial. Lancet 2008; 372: 1809-18.
17. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in
previously treated non–small-cell lung cancer. N Engl J Med 2005;
18. Hida T, Okamoto I, Kashii T, et al. Randomized phase III study of
platinum-doublet chemotherapy followed by gefitinib versus
continued platinum-doublet chemotherapy in patients with advanced
non-small cell lung cancer: Results of West Japan Thoracic Oncology
Arm trial (WJTOG 0203). J Clin Oncol 2008; 26: (suppl; Abstr LBA8012).
19. Patel JD. Lung cancer in women. J Clin Oncol 2005; 23: 3212-8.
20. Båtevik R, Grong K, Segadal L, et al. The female gender has a positive
effect on survival independent of background life expectancy
following surgical resection of primary non-small cell lung cancer: a
study of absolute and relative survival over 15 years. Lung cancer
2005; 47: 173-81.
21. Socinski MA, Morris DE, Masters GA, et al. Chemotherapeutic
management of stage Ⅳ non-small cell lung cancer. Chest 2003; 123:
22. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the
epidermal growth factor receptor underlying responsiveness of
non–small-cell lung cancer to gefitinib. N Engl J Med 2004; 350:
23. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer:
correlation with clinical response to gefitinib therapy. Science 2004;
24. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are
common in lung cancers from “never smokers” and are associated
with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci
2004; 101: 13306-11.
25. Rosell R, Moran T, Queralt C, et al. Screening for Epidermal Growth
Factor Receptor Mutations in Lung Cancer. N Engl J Med 2009; 361:
26. Rosell R, Viterib S, Molina MA, et al. Epidermal growth factor receptor
tyrosine kinase inhibitors as first-line treatment in advanced
nonsmall-cell lung cancer[J]. Curr Opin Oncol 2010; 22: 112-20.
27. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or Carboplatin-
Paclitaxel in Pulmonary Adenocarcinoma. N Engl J Med 2009; 361:
28. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in Lung Cancer-Molecular
and Clinical Predictors of Outcome. N Engl J Med 2005; 353: 133-44.
29. Brugger W, Kim JH, Hansen O, et al. Molecular markers and clinical
outcome with erlotinib: results from the phase III placebo-controlled
SATURN study of maintenance therapy for advanced NSCLC. 2009
13th World Conference on Lung Cancer, Abstract, B9.1.