Erlotinib as a salvage treatment for patients with advanced non-small cell lung cancer after failure of gefitinib treatment.
ABSTRACT Several clinical trials showed that erlotinib was effective after the failure of gefitinib in advanced non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the feasibility of erlotinib treatment after the failure of gefitinib based on the data from our hospital.
The clinical data of 20 patients with advanced NSCLC who were admitted to Shanghai Chest Hospital from August 2007 to December 2008 were retrospectively analyzed. All of the patients were given erlotinib treatment after the failure of gefitinib. Survival analysis was made by Kaplan-Meier method. The Cox regression model was performed to analyze the relationship between the influential factors and the erlotinib progression-free survival (PFS).
Five patients had a partial response (PR), nine patients had stable disease (SD) and six patients had progressive disease (PD) with gefitinib treatment. The median PFS was 277 days (95% CI 0- 566). No patient had a PR, seven had SD and fourteen PD with the erlotinib therapy. The median PFS was 31 days (95% CI 9.1- 52.9). The response rate (RR) was 0, and the disease control rate (DCR) was 35% (7/20). Cox regression analysis demonstrated that sex (P = 0.96), age (P = 0.89), smoking history (P = 0.78), performance status (PS) (P = 0.98), gefitinib efficacy (P = 0.90) and whether chemotherapy was applied between using the two drugs (P = 0.45) had no significant correlation with erlotinib PFS. Fifteen patients had epidermal growth factor receptor (EGFR) mutation status determined. There were five cases got SD with the erlotinib treatment in ten mutation negative (wild-type) patients. No SD was recorded in the five mutation positive patients.
The efficacy of erlotinib treatment after gefitinib failure was limited. However, the patients who are EGFR mutation negative can probably benefit from erlotinib treatment after gefitinib failure.
- [show abstract] [hide abstract]
ABSTRACT: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are gaining an increasing role in the management of advanced non-small cell lung cancer (NSCLC). There is mounting interest in the benefit of administering a second TKI after failure of the first TKI, especially in Asian patients, in whom they are expected to be more efficacious. We did a retrospective analysis of patients receiving both gefitinib and erlotinib in our institution during a 2-year period. Patients were to have received the second TKI after progressive disease on the first TKI. EGFR gene mutation analysis was done on patient tumor samples. Fourteen patients were included in the analysis, all of whom received erlotinib after progression on gefitinib. Chinese race, females, never-smokers, and adenocarcinoma subtype were predominant in their respective categories. Disease control rate was 64.3% (9 of 14) for gefitinib. Disease control rate for erlotinib administered after progression on gefitinib was 35.7% (5 of 14). All patients who achieved disease control with erlotinib after progression on gefitinib were never-smokers with adenocarcinoma subtype, who had prior disease control on gefitinib. Presence of EGFR mutations predicted for disease control with gefitinib, and for disease control with erlotinib after gefitinib failure. A significant proportion of typical gefitinib-sensitive Asian NSCLC patients can have disease control with erlotinib after gefitinib failure. The role of subsequent administration of a second EGFR TKI after failure of the first TKI in advanced NSCLC should be further pursued.Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 05/2008; 3(4):400-4. · 4.55 Impact Factor
- The Oncologist 09/2005; 10(7):467-70. · 4.10 Impact Factor
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ABSTRACT: Epidermal growth factor receptor (EGFR) kinase inhibitors induce dramatic clinical responses in a subset of non-small cell lung cancer (NSCLC) patients with advanced disease, and such responses are correlated with the presence of somatic activating mutations within the EGFR kinase domain. Consequently, one of these inhibitors, erlotinib, has been Food and Drug Administration-approved as a second- or third-line treatment for chemotherapy-refractory advanced NSCLC. However, responses are typically relatively short-lived due to acquired drug resistance, prompting studies to determine whether first-line treatment with EGFR inhibitors could provide greater clinical benefit. NSCLC-derived cell lines have provided a powerful system for modeling EGFR mutation-correlated sensitivity to EGFR inhibitors and for modeling mechanisms of acquired drug resistance that are observed clinically. In a cell culture model of an erlotinib-sensitive EGFR-mutant NSCLC cell line, we tested the hypothesis that prior exposure to platinum agents, a standard component of NSCLC chemotherapy treatment, affects the subsequent response to erlotinib. Indeed, NSCLC cells initially selected for growth in cisplatin exhibit 5-fold reduced sensitivity to erlotinib, even after propagating the cisplatin-treated cells in the absence of cisplatin for several months. This lingering effect of cisplatin exposure appears to reflect changes in PTEN tumor suppressor activity and persistent EGFR-independent signaling through the phosphatidylinositol 3-kinase/AKT survival pathway. These preclinical findings suggest that first-line chemotherapy treatment of EGFR-mutant NSCLCs may reduce the benefit of subsequent treatment with EGFR kinase inhibitors and should prompt further clinical investigation of these inhibitors as a first-line therapy in NSCLC.Clinical Cancer Research 12/2008; 14(21):6867-76. · 7.84 Impact Factor
Chinese Medical Journal 2011;124(15):2279-2283
Erlotinib as a salvage treatment for patients with advanced
non-small cell lung cancer after failure of gefitinib treatment
SONG Zheng-bo, YU Yong-feng, CHEN Zhi-wei and LU Shun
Keywords: non-small cell lung cancer; erlotinib; gefitinib; efficacy; epidermal growth factor receptor mutation
Background Several clinical trials showed that erlotinib was effective after the failure of gefitinib in advanced non-small
cell lung cancer (NSCLC). The aim of this study was to evaluate the feasibility of erlotinib treatment after the failure of
gefitinib based on the data from our hospital.
Methods The clinical data of 20 patients with advanced NSCLC who were admitted to Shanghai Chest Hospital from
August 2007 to December 2008 were retrospectively analyzed. All of the patients were given erlotinib treatment after the
failure of gefitinib. Survival analysis was made by Kaplan-Meier method. The Cox regression model was performed to
analyze the relationship between the influential factors and the erlotinib progression-free survival (PFS).
Results Five patients had a partial response (PR), nine patients had stable disease (SD) and six patients had
progressive disease (PD) with gefitinib treatment. The median PFS was 277 days (95% CI 0–566). No patient had a PR,
seven had SD and fourteen PD with the erlotinib therapy. The median PFS was 31 days (95% CI 9.1–52.9). The
response rate (RR) was 0, and the disease control rate (DCR) was 35% (7/20). Cox regression analysis demonstrated
that sex (P=0.96), age (P=0.89), smoking history (P=0.78), performance status (PS) (P=0.98), gefitinib efficacy (P=0.90)
and whether chemotherapy was applied between using the two drugs (P=0.45) had no significant correlation with
erlotinib PFS. Fifteen patients had epidermal growth factor receptor (EGFR) mutation status determined. There were five
cases got SD with the erlotinib treatment in ten mutation negative (wild-type) patients. No SD was recorded in the five
mutation positive patients.
Conclusions The efficacy of erlotinib treatment after gefitinib failure was limited. However, the patients who are EGFR
mutation negative can probably benefit from erlotinib treatment after gefitinib failure.
Chin Med J 2011;124(15):2279-2283
hemotherapy is the standard treatment for advanced
non-small cell lung cancer (NSCLC), and patients
show symptom improvement and there is a survival
advantage. Gefitinib, an epidermal growth factor
receptor-tyrosine kinase inhibitor (EGFR-TKI), has
demonstrated clinical efficacy in the second or third-line
treatment of NSCLC, especially among never-smokers,
females, East Asians,
adenocarcinoma.1,2 Recently, Mok et al3 have confirmed
that gefitinib was effective as a first-line treatment for
patients with EGFR gene mutations. The target therapy
has increased the quality of life (QoL) and prolonged the
survival time in previous studies. Currently, EGFR-TKIs
are selected mainly for advanced NSCLC patients with
disease recurrence. Unfortunately, resistance to gefitinib
is a critical issue and it has been not clear which regimen
is optimal as a salvage treatment after failure of gefitinib
in current clinical practice. Erlotinib, another EGFR-TKI,
also has shown a survival benefit in second-line or
third-line treatment for advanced NSCLC.4,5 There are
somewhat different pharmacological properties between
gefitinib and erlotinib in experiments and clinic.6,7 For
example, the maximal tolerated dose (MTD) of gefitinib
is lower compared to that of erlotinib. However, the
efficacy of erlotinib after gefitinib failure in patients with
NSCLC is unclear in clinical practice. Several
retrospective and prospective trials in western countries
and patients with
showed a disease control rate that ranged from
8.6%–70.0%.8-10 Because of the existing ethnic
difference, we conducted a study to determine the
efficacy in Chinese patients and explore what patients
may benefit from erlotinib after failure of gefitinib.
Twenty consecutive, unselected NSCLC patients, who
were admitted to our institution from January 2007 to
December 2008, were included in our study. NSCLC
staging was performed for all the patients according to
the 6th TNM classification. Inclusion criteria were as
follows: (1) Pathologically proven primary stage IIIB or
IV NSCLC; (2) All the patients were supplied with
erlotinib as subsequent salvage therapy after failure of
gefitinib; (3) The disease recurrence was confirmed using
Shanghai Lung Tumor Clinical Medical Center, Chest Hospital
Affiliated to Shanghai Jiao Tong University School of Medicine,
Shanghai 200030, China (Song ZB, Yu YF, Chen ZW and Lu S)
Correspondence to: Dr. LU Shun, Shanghai Lung Tumor Clinical
Medical Center, Chest Hospital Affiliated to Shanghai Jiao Tong
University School of Medicine, Shanghai 200030, China (Tel:
86-21-62821990. Fax: 86-21-62801109. Email: lushun1964@
Chin Med J 2011;124(15):2279-2283
chest computed tomography (CT), brain MRI and bone
scan as well as ultrasound examination and/or CT of the
abdomen; (4) Without any local treatment like
radiotherapy or interventional therapy during the period
of erlotinib therapy; (5) At least one measurable lesion
and an Eastern Cooperative Oncology Group performance
status of 0 to 2.
All patients were followed up every 4 weeks (±1 week)
with imaging examination (chest X-ray or CT) during
treatment with EGFR-TKIs or were evaluated early when
significant tumor progression appeared. Objective tumor
responses were evaluated according to the Response
Evaluation Criteria in Solid Tumors (RECIST 1.1).
Objective tumor responses included complete response
(CR), partial response (PR), stable disease (SD) and
progressive disease (PD). Disease control rate (DCR) was
defined as the addition of objective response and
The toxicity profile of EGFR-TKI was assessed by
reviewing medical records including skin rash, diarrhea,
liver toxicity, and radiological evidence of interstitial
pneumonitis. Severity of adverse reactions was
determined based on the requirements of dosage
reduction or discontinuation of EGFR-TKI. All such
toxicities were evaluated according to the National
Cancer Institute Common Toxicity Criteria version 3.0
All the patients were to be evaluated for tumor response
and progression-free survival (PFS). Follow-up rate was
100%. The last follow-up date was August 31, 2009.
The chi-square was applied to elucidate the differences
between different treatment arms. PFS encompassed the
time from the first cycle of therapy to documented
progression or death from any cause, or until the date of
the last follow-up visit for patients who were still alive
and who had not progressed. Survival analysis was
conducted with a Kaplan-Meier analysis and log-rank test.
Cox regression model was done to analyze the
relationship between the influential factors and the PFS of
erlotinib. A P value of less than 0.05 was regarded as
statistically significant. All statistical tests were analyzed
using the computer software SPSS version 17.0 (SPSS
Inc, Chicago, IL, USA).
A total of 20 patients were included in the study and all of
them were assessable for response and toxicity. There
were nine males and 11 females, and the female to male
ratio was 1.2:1. Performance status (PS) 0–1 was present
in 17 patients (85%) and PS 2 accounted for 15%. The
median age of the patients was 58 years (range 35–72
years). The majority of the tumors were adenocarcinoma
(90%) and all of them were advanced stage on
presentation. Twenty-five percent (5/20) had a smoking
history. Fifteen patients had the mutation status of the
EGFR determined, and five cases were mutation positive.
Patients’ characteristics are shown in Table 1.
Table 1. Baseline characteristics of the study population (n=20)
Age at diagnosis (years)
Chemotherapy between two EGFR-TKIs
As second line
As third line
Response data and survival analysis
Response data for gefitinib and erlotinib therapy are
shown in Table 2. Five patients had a PR to gefitinib and
nine patients had SD, accounting for a disease control rate
of 70%. There were no patients with a PR to erlotinib
treatment, while seven patients had SD and thirteen
patients had PD. Median PFS during gefitinib treatment
was 277 days (95% CI 0–566, Figure 1), but only 31 days
during erlotinib treatment (95% CI 9.2%–52.5%, Figure
2). The median survival time for all patients was 18.1
Table 2. Response rate after treatment with gefitinib and erlotinib
Response Response to prior gefitinib
PR 5 (25)
SD 9 (45)
PD 6 (30)
Total 20 (100)
Toxicities of treatment
Toxicities were acceptable with grade 3 skin toxicity in
two patients that was of short duration. No dosage
reduction was necessary. Grade 1 and grade 2 skin
toxicities were seen in five and one patients, respectively,
and grade 1 diarrhea occurred in six patients. One patient
demonstrated hepatic function injuries after being treated
with erlotinib therapy.
Response to erlotinib
Chinese Medical Journal 2011;124(15):2279-2283
Figure 1. PFS in gefitinib treatment (median time 277 days).
Figure 2. PFS in erlotinib treatment (median time 31 days).
Cox regression analysis about erlotinib treatment
Cox regression analysis showed that there was no
significant correlation between erlotinib response and sex
(P=0.96), age (P=0.89), smoking (P=0.78), PS score
(P=0.98), gefitinib response (P=0.90), or the interval
from discontinuation of gefitinib to beginning erlotinib
(P=0.45) (Table 3).
Table 3. Cox regression analysis about erlotinib PFS
Variables β SE
Sex –0.034 0.68
Age –0.09 0.67
Smoking –0.19 0.68
Histology 1.169 0.97
PS score –0.015 0.68
Gefitinib efficacy 0.037 0.30
Interval* 0.457 0.61
*Whether there was interval chemotherapy between erlotinib and gefitinib.
Relationship between EGFR mutation status and
Fifteen patients had their EGFR mutation status
determined using direct sequencing (exons 18 to 21). Ten
patients had no mutations (wild-type), and mutations
were detected in five cases; three deletions in exon 19 and
two in exon 21L858R. Five patients had SD among the
ten wild type patients during the erlotinib treatment, in
contrast, no SD was seen in the positive mutation patients
(DCR rate 50% vs. 0, P=0.175).
Exp (β) 95% CI for Exp (β)
Comparison between chemotherapy and erlotinib
efficacy after gefitinib treatment
There were ten patients who received chemotherapy first
after failure of gefitinib therapy, and ten patients who
received erlotinib directly after gefitinib therapy. There
was one patient with a PR and four with SD in the
chemotherapy group. However, there were no patients
who achieved a PR during erlotinib treatment, but three
patients had SD when directly treated with erlotinib. The
ORR was higher in the chemotherapy arm (10% vs. 0).
The DCR was similar in the chemotherapy arm and in the
erlotnib arm (50% vs. 30%). The overall survival time
after failure of gefitnib treatment in the chemotherapy and
erlotinib treatment arms were 8.5 months and 4.2 months
(P=0.146, Figure 3).
Figure 3. The overall survival after failure of gefitinib between
chemotherapy and erlotinib treatment arm (8.5 months vs. 4.2
With case reports since 200511-13 claiming that erlotinib
has efficacy after the failure of gefitinib treatment, there
has been discussion of the potential of using erlotinib as a
salvage treatment. There have been a few prospective
phase II trials and retrospective reviews that have
addressed the debate.8-10,14-18 Table 4 lists all the studies
recently published with more than 10 cases, showing that
there are conflicting results to erlotinib treatment and the
DCR ranged from 8.6% to 70%. The overall disease
control rate of the eight studies was 33.3%. The DCR was
35% in our series, which was consistent with that in
Both gefitinib and erlotinib have the same activity of
EGFR blockade. Preclinical models indicated that the two
most common mechanisms of acquired resistance to
gefitinib, the EGFR T790M mutation and the MET
amplification, also confer resistance to erlotinib.19 So the
patients who failed on gefitinib were not expected to
respond to erlotinib. However, the molecular mechanisms
behind this double sensitivity do not yet completely
explain the clinical outcome.20
Difference in tumor sensitivity, especially tumors with
Chin Med J 2011;124(15):2279-2283
Table 4. Articles published about erlotinib as a salvage treatment after failure of gefitinib in recent years
Patients number Year Study type
21 2007 Prospective
23 2008 Prospective
16 2009 Retrospective
14 2008 Retrospective
13 2008 Retrospective
25 2007 Retrospective
10 2008 Retrospective
21 2010 Retrospective
wild-type EGFR, might be associated with the
concentration of EGFR TKIs. Six out of twenty-one
patients had SD after erlotinib and were regarded as
salvaged after gefitinib failure in Cho et al’s study,8 and
four of the six SD patients had a wild-type EGFR.
Erlotinib has shown a certain efficacy in patients with
wild type EGFR in clinical trials.21 Five patients got SD
with erlotinib out of the 10 patients without EGFR
mutations, but there were no SD in mutation positive
patients in our series. Our outcome is consistent with Cho
et al’s result. Another explanation for tumor sensitivity
may be that there are some differences in the
pharmacological equivalent dosage of the two drugs. The
IC50 value of erlotinib is much lower than that of
gefitinib.4 Low dosage gefitinib may not inhibit tumor
growth, while the same dose of erlotinib can inhibit the
Usually, for most patients with advanced NSCLC, we
cannot get sufficient tissue to detect the mutation, so
many of the previous studies used clinical characteristics
when choosing patients. Several of these studies showed
that erlotinib might be considered as a salvage treatment
for those who demonstrated initial disease control with
gefitinib. Eighteen (85.7%) patients had disease control
with gefitinib and 12 (57.1%) patients with salvage
erlotinib in Wong et al’s study.18 There was an association
between the disease control with gefitinib and erlotinib
(P = 0.031). The conclusion was confirmed by Wong et
al’s14 and Lee et al’s9 studies. Multivariate analysis
showed that there was no association of erlotinib response
in our patients with sex (P=0.96), age (P=0.89), smoking
(P=0.78), PS score (P=0.98), gefitinib response (P=0.90),
or with the interval after discontinuation of gefitinib
(P=0.45) (Table 3).
Direct sequencing was used to analyze the EGFR
mutations in our patients. It has a lower sensitivity than
amplification refractory mutation system (ARMS) and
other techniques, and may increase the false-negative in
the EGFR mutation result.22 It has also been reported that
chemotherapy may partly change the EGFR mutation
status.23,24 All of these may influence our clinical analysis,
however, with few cases even in limited previous clinical
trials, our retrospective study can also be considered to be
In conclusion, the efficacy after gefitinib failure with
Gefitinib efficacy (DCR, %)
Erlotinib efficacy (DCR, %)
erlotinib treatment was limited and the mechanisms have
not been completely clarified. EGFR mutation negative
patients may benefit more from the erlotinib treatment
after failure of gefitinib therapy. It is necessary to explore
new target treatment drugs to treat the patients with
EGFR-TKIs induced resistance.
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(Received November 7, 2010)
Edited by WANG Mou-yue and LIU Huan