Annals of Oncology 19: 2039–2042, 2008
Published online 21 July 2008
Phase II study of erlotinib as a salvage treatment for
non-small-cell lung cancer patients after failure of
D. H. Lee, S.-W. Kim, C. Suh*, D. H. Yoon, E. J. Yi & J.-S. Lee
Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
Received 14 May 2008; revised 11 June 2008; accepted 12 June 2008
Background: Both gefitinib and erlotinib are reversible epidermal growth factor receptor tyrosine kinase inhibitors,
but they have somewhat different pharmacological properties. We conducted a phase II study of erlotinib after failure
of gefitinib treatment in patients with non-small-cell lung cancer (NSCLC).
Patients and methods: Patients with advanced/metastatic NSCLC who had shown disease progression on
gefitinib treatment were treated with erlotinib 150 mg/day until disease progression or intolerable toxicity.
Results: Between September 2006 and January 2008, a total of 23 patients were enrolled and all were assessable
for response and toxicity. All patients were never smokers and all but one had adenocarcinoma. Of these 23 patients,
one had a partial response and one stable disease, resulting in an objective response rate of 4.3% and a disease
control rate of 8.7%. These two patients benefited from erlotinib for 6.2 months and 7.8 months, respectively; both
had also benefited from prior gefitinib therapy. The most common toxic effects were skin rash and diarrhea.
Conclusion: Erlotinib should not be given routinely after failure of gefitinib treatment, but can be an option for more
highly selected subsets, especially those who had benefited from prior gefitinib treatment. Identification of molecular
markers in tumors is important to understand and overcome acquired resistance to gefitinib.
Key words: erlotinib, gefitinib, non-small cell lung cancer
Erlotinib and gefitinib are oral epidermal growth factor
receptor (EGFR) tyrosine kinase inhibitors (TKIs) widely used
to treat patients with advanced or metastatic non-small-cell
lung cancer (NSCLC). Although their similar structures and
mechanism of action suggest that erlotinib and gefitinib should
have similar efficacies, the agents have somewhat different
pharmacological properties. For example, erlotinib is less
susceptible than is gefitinib to metabolism by the cytochrome
P450 pathway and therefore has a lower clearance rate and
inhibits the activity of wild-type EGFR at lower concentrations
than gefitinib [1, 2]. In addition, because the maximum-
tolerated doses of gefitinib and erlotinib are 1000 and 150 mg,
respectively [3, 4], the usual dose of erlotinib 150 mg may be
a higher biological dose than the usual dose of gefitinib 250 mg.
These differences may account at least in part for the
contradictory results of the two phase III studies, in which
erlotinib, but not gefitinib, was found to prolong survival in
previously treated patients [5, 6]. These findings suggested that
salvage treatment with erlotinib may be an option for patients
who fail gefitinib treatment. We therefore carried out
a prospective phase II study of erlotinib in patients with
advanced or metastatic NSCLC who showed disease
progression on gefitinib treatment.
patients and methods
Patients with advanced or metastatic NSCLC who had documented
progressive disease on gefitinib treatment were eligible for inclusion if they
had at least one unidimensionally measurable lesion, an Eastern
Cooperative Oncology Group performance status of zero to three, and
adequate organ functions [white blood cell 3000/ll, platelets 100 000/ll,
hemoglobin 9.0 g/dl, serum creatinine 1.5· the upper limit of normal
(ULN), bilirubin 1.25· ULN, and serum aminotransferases 2.5· ULN].
Prior chemotherapy or radiotherapy was allowed. Brain metastases were
also allowed if they were asymptomatic or controlled by supportive care.
However, those patients with unresolved chronic toxicity from prior
therapy, other active malignancies, uncontrolled brain metastases, or
severe comorbid conditions were excluded. The study was approved by
the institutional review board of the Asan Medical Center, and written
informed consent was obtained from all enrolled patients. The study was
carried out in accordance with the Declaration of Helsinki and Good
Clinical Practice guidelines.
This was an open-label, single-institution, phase II study. Patients received
erlotinib 150 mg once daily. One dose reduction per patient was permitted
*Correspondence to: Dr C. Suh, Department of Oncology, University of Ulsan College of
Medicine, Asan Medical Center, 388-1 Pungnap-2 dong, Songpa-gu, Seoul 138-736,
South Korea. Tel: +82-2-3010-3209, Fax: +82-2-3010-6961; E-mail: email@example.com
ª The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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from 150 to 100 mg and erlotinib treatment could be interrupted for
a maximum of 21 days. Therapy was continued until disease progression,
intolerable toxicity, or withdrawal of consent. Baseline evaluations
included a complete medical history, physical and radiologic examinations,
complete blood cell count, and biochemistry. The primary efficacy end
point of this study was objective tumor response rate. Response
assessments were carried out 4 6 1 weeks after commencement of erlotinib
therapy and then after every 8 6 1 weeks unless clinically indicated,
according to the Response Evaluation in Solid Tumors criteria; complete
response (CR) is defined as the disappearance of all target lesions; partial
response (PR) is defined as at least a 30% decrease in the sum of the longest
diameter of target lesion, taking as reference the baseline sum longest
diameters and/or the persistent of one or more nontarget lesion(s);
progressive disease (PD) defined as at least a 20% increase in the sum of the
longest diameter taking as reference the smallest sum longest diameter
recorded since treatment started or the appearance of one or more new
lesions and/or unequivocal progression of existing nontarget lesions; and
stable disease (SD) defined as neither sufficient shrinkage to qualify the
partial response nor sufficient increase to qualify for progressive disease,
taking as reference the smallest sum longest diameter since the treatment
started. For patients with documented CR or PR, a confirmatory.
Progression-free survival (PFS) was defined as the interval between the
date treatment started and the date of documented disease progression or
death from any cause. Overall survival (OS) was defined as the interval
between the date treatment started and the date of death from any cause.
Patients lost to follow-up were censored at the last date of contact. Adverse
events were graded according to the National Cancer Institute Common
Terminology Criteria for Adverse Event version 3.0.
A Simon two-stage optimal design was chosen for definition of the total
number of patients required for the phase II study. We set a response rate of
15% as the target activity level and 5% as the lowest response rate (objective
response rate) of interest. The study was designed to have 80% power to
accept the hypothesis and 5% significance to reject the hypothesis. For
a total of 56 patients, 23 would be accrued during the first stage and 33
during the second stage. If one or no response was observed during the first
stage, the study would be stopped early. If five or fewer responses were
observed by the end of the study, no further investigation of the drug would
Between September 2006 and January 2008, a total of 23 patients entered into
the study and all were assessable for response and toxicity. All patients were
never smokers and all but one had adenocarcinoma histology. Before starting
therapy, we knew the mutation status of exons 18–21 of the EGFR gene in 10
patients (43.5%); three had exon 19 deletions, two had exon 18 substitutions,
and five had no mutations. Fifteen patients (65.2%) had benefited from prior
gefitinib therapy. Patients’ characteristics are shown in Table 1.
response and survival outcome
Out of 23 patients, one had PR and one had SD, giving an overall
response rate of 4.3% and a disease control rate of 8.7% (Table 2). These two
patents were female never smokers with adenocarcinoma histology and both
had a best response of OR to prior gefitinib treatment. In the patient with
a PR to erlotinib treatment, an interval from discontinuation of gefitinib to
administration of erlotinib was 7.4 months, her PFS during gefitinib
treatment was 3.9 months, and her PFS during erlotinib treatment was 6.2
months, while in the patient with SD, the corresponding values were 1.4,
12.0, and 7.8 months, respectively. The remaining 21 patients showed PD to
erlotinib treatment within 3 months.
The most common toxic effects were skin rash recorded in 14 patients
(60.9%) and diarrhea in seven patients (30.4%). Two patients (8.7%)
experienced grade 3 skin rash. Only one patient required a dose reduction
of erlotinib due to grade 3 hyperbilirubinemia.
Table 1. Patient characteristics
ECOG performance score
EGFR mutations in exons 18–21
No. of prior chemotherapy, not including
Best response to gefitinib therapy
Interval from discontinuation of gefitinib
to commencement of erlotinib
aThree had a mutations in exon 19 and 2 had a mutations in exon 18.
bAll patients except two received at least one platinum-doublet.
ECOG, Eastern Cooperative Oncology Group; PR, partial response; SD,
stable disease; PD, progressive disease.
Table 2. The tumor responses
4.3% (95% CI, <1% to 22%)
8.7% (95% CI, 1% to 28%)
PR, partial response; SD, stable disease; PD, progressive disease; ORR,
objective response rate; DCR, disease control rate; CI, confidence interval.
Annals of Oncology
2040 | Lee et al.Volume 19| No. 12|December 2008
Both erlotinib and gefitinib are currently available in Korea and
are used to treat patients with advanced or metastatic NSCLC
in second- or third-line setting or sometimes in first-line setting
for a specific subset of patients [7, 8]. Most patients treated
with these agents, however, had progressive disease even after
showing an initial dramatic response. Although gefitinib and
erlotinib are thought to exhibit cross-resistance, their
pharmacological differences as well as their distinct clinical
outcomes suggest that erlotinib may be effective after failure
of gefitinib treatment [9–12]. Two studies have shown that
erlotinib after failure of gefitinib treatment yielded disease
control rates of 35.7% (5 of 14) and 28.6% (6 of 21),
respectively, [11, 12], although other studies, including ours,
have shown contradictory results . Of interest, most
patients who benefit from erlotinib had also benefited from
prior gefitinib treatment (Table 3) [9–12, 14], including the two
patients in our study who benefited from erlotinib. In our
study, of the 15 patients who benefited from gefitinib, two
benefited from erlotinib treatment, yielding a disease control
rate of 13.3% (2 of 15), which, however, was rather lower than
those of 55.5 % (5 of 9) and 50.0% (5 of 10) in the prior two
studies [11, 12]. This finding suggested that as a salvage
treatment after failure of gefitinib treatment, erlotinib should
be chosen very carefully in a more highly selective subset of
Several explanations could be possible for the responsiveness
to erlotinib after failure of gefitinib. Difference in tumor
sensitivity, especially wild-type EGFR tumors might be
associated with the relative concentration of EGFR TKIs. The
IC50value of erlotinib is much lower than that of gefitinib 
and 8 of 10 patients benefiting from erlotinib had wild-type
EGFR . Most of these patients, however, had also benefited
from prior gefitinib. In contrast, most patients who did not
benefit from prior gefitinib treatment did not respond to
subsequent erlotinib treatment. Another possibility may be that
tumors may possess both EGFR TKI-sensitive and -resistant
clones at the beginning of gefitinib treatment. During
gefitinib treatment, only EGFR TKI-resistant clones can grow,
but after discontinuation of gefitinib therapy and/or during
subsequent chemotherapy, sensitive clones may grow faster or
survive better than do resistant clones. Thus, subsequent
erlotinib therapy could kill such TKI-sensitive clones, similar
to the effectiveness sometimes observed following
readministration of gefitinib . However, most of our
patients had short time intervals from discontinuation of
gefitinib to commencement of erlotinib, with some patients
Table 3. Patient characteristics associated with benefits from erlotinib after failure of gefitinib treatment
HistologyGefitinib therapyNo. of prior
Garfield , case report
Gridelli et al. ; case report
Wong et al. ;
Cho et al. [12, 13];
Lee et al. (current);
aDuration of disease control
DC, disease control = CR/PR + SD; PFS, progression-free survival; M, male; F, female; Adeno, adenocarcinoma; BAC, bronchioloalveolar carcinoma; SQCC,
squamous cell carcinoma; NOS, not other wise specified; NR, not reported.
Annals of Oncology
Volume 19|No. 12| December 2008doi:10.1093/annonc/mdn423 | 2041
starting erlotinib immediately after progression on gefitinib
treatment. In addition, response to subsequent
chemotherapy was also poor [12, 15]. Finally, some of
acquired gefitinib-resistant clones might be nonresistant or
incompletely cross-resistant to erlotinib. Among the
mechanism of acquired resistance to EGFR TKIs, T790M
secondary mutation or amplification of the MET oncogene was
reportedly common [16, 17]. However, other secondary
mutations have also been reported [18, 19]. Of note, unlike
T790M secondary mutation, some mutations, such as L748S
or E884K mutation, may result in different sensitivities to
gefitinib and erlotinib, resulting in different tumor responses
to these two agents [14, 20]. Therefore, although half of
patients could overcome the resistant T790M secondary
mutation by empirical use of irreversible EGFR TKIs,
identification of the mechanism of acquired resistance in
each patient could guide the proper use of these two
different EGFR TKIs.
In conclusion, our finding suggested that erlotinib should
not be given routinely after failure of gefitinib treatment, but
may be an option for a more highly selected subset of patients,
especially those who had already benefited from prior gefitinib
treatment. However, identification of molecular markers in
tumors is important to understand and overcome molecular
mechanisms of resistance.
Asan Institute for Life Science, Seoul, South Korea (07-432 and
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Annals of Oncology
2042 | Lee et al. Volume 19| No. 12|December 2008