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Prospective Evaluation of Small Molecule EGFR-1 Tyrosine Kinase Inhibition as a First-Line Treatment in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) Harbouring a Mutant EGFR Gene

Phase 2
18 Years
Open (Enrolling)
Lung Neoplasms, Non-Small Cell Lung Cancer, Adenocarcinoma, Bronchiolo-Alveolar

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Trial Information

Prospective Evaluation of Small Molecule EGFR-1 Tyrosine Kinase Inhibition as a First-Line Treatment in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) Harbouring a Mutant EGFR Gene

Patients with stage IV NSCLC and some patients with advanced locoregional disease (stage
III) are in general incurable and have a low probability for long-term survival.

Current systemic treatment in good PS patients (PS 0-1) consists of a cisplatin doublet
(e.g. cisplatin plus a second drug: vinorelbine, gemcitabine, paclitaxel, docetaxel). The
median and one year survival obtained with this treatment ranges between 8-10 months and 25
- 35 % respectively (1,2). Progression-free survival is a median of 5 month or less in
randomized studies (3). Response rates obtained are less than 25% in metastatic disease and
up to 75% in advanced locoregional disease.

Receptor tyrosine kinase inhibitors (RTKI's) are active drugs in patients with NSCLC
pre-treated with cisplatin and/or docetaxel containing chemotherapy (2,4). Recently it has
been shown that the EGFR1 kinase inhibitor erlotinib added to best supportive care (BSC)
prolonged survival compared to BSC alone in patients with advanced NSCLC failing 1st or 2nd
line chemotherapy (5).

A small number of preliminary reports have indicated that the objective response rate with
these RTKI's as first line treatment in some patient populations with advanced NSCLC could
be around 20 % (6), The objective (mainly partial) response in the phase II studies with
pre-treated patients ranges from 10 - 15 % according to the level of pre-treatment but the
control of the disease (stable disease) and improvement of symptoms without demonstrated
objective response has been reported to be as high as 40 to 50 % (2,4). The addition of
RTKI's or placebo to the current standard doublets (e.g. cisplatin, gemcitabine or
taxol/carboplatin) has not been shown to impact on response rate, time to treatment failure
or survival in large phase III randomised trials in advanced NSCLC patients not selected for
EGFR expression (7,8).

Recently, mutations in the intracellular EGFR kinase domain that increase sensitivity of the
receptor to RTKI's have been discovered (9,10). These studies suggest that the
response/resistance to treatment could be strongly correlated to the presence/absence of
such mutations. It is presently unclear whether patients who achieve stable disease under
RTKI treatment do have receptor mutations, of which nature such mutations could be or what
other biological pathways modulate the responsiveness/resistance.

Mutations have been observed in about 10 % or less of the tumours examined. Most mutations
in the EGFR kinase domain have been found in adenocarcinoma of non-smokers or minimal

Recent data have established that an EGFR mutation can be found in 30% of adenocarcinoma of
the lung if the smoking history is maximally 15 years. The probability of finding a mutation
is approximately 50% in never-smokers with adenocarcinoma (11).

In contrast to the rather low objective response rate, the clinical benefit rate of
treatment with RTKI is around 40 % in a general population of non-small lung cancer (9,10),
more than can be accounted for by mutational analysis. EGFR gene amplification might be
another determinant for sensitivity, but the biological factors leading to disease
stabilisation in some patients with non-activated EGFR are presently unknown.

Several humanized monoclonal antibodies (huMoAb) that can inhibit the EGFR-1 receptor have
been developed as well. Of these, cetuximab (ErbituxÒ) has been developed most extensively,
especially in head and neck (12) and colorectal cancer (13,14), but other, fully humanized
antibodies (huMoAb) (ABX-EGF, EMD 72000) are under development.

Cetuximab has been assessed in NSCLC, especially in combination with first-line and
second-line chemotherapy (15), but no data are currently available with respect to single
agent activity.

The two types of currently available drugs targeting the EGFR-1, the RTKI's such as
gefitinib and erlotinib and huMoAb such as cetuximab and ABX-EGF, are generally well
tolerated and devoid of significant grade 3-4 toxicity.

While there are strong indications that the major responses obtained with RTKI’s could
strongly correlate with the presence of tyrosine kinase domain mutations in addition to the
known mechanism of action of these drugs (16,17), this is at present yet not so clear for
the monoclonal antibodies directed against the extracellular domain of the receptor.

Some recent data suggest that EGFR gene amplification might also correlate with response to
TKI (18).

Patients with Stage IV and some advanced stage III NSCLC are at present incurable and
first-line chemotherapy has had only a palliative and a life prolonging effect at a cost of
variable toxicity.

On the other hand the response rate to TKI in patients with a NSCLC carrying a mutant
receptor is probably high as can be inferred from the comparison of the prevalence of such
mutations and the response rate to these agents in an unselected population (16).

It seems therefore reasonable to explore in a first-line setting the potential of EGFR-1
targeted therapy, as these drugs have a very favourable toxicity profile and might induce
prolonged palliation.

There are currently no data that would suggest that delaying chemotherapy in this patient
population in well controlled conditions and for a limited time period (sufficient to
evaluate the efficacy of more novel first-line treatments) might affect the efficacy of
subsequent chemotherapy. There are also no data that suggest that prior administration of
drugs targeted at the EGFR-1 will induce resistance to subsequent chemotherapy. The distinct
respective mechanisms of action of these drugs and chemotherapy also do not suggest this to
be likely.

In other diseases such as prostate cancer and oestrogen receptor-positive breast cancer, the
availability of hormonal treatments permits prolonged and at times long-term disease control
with limited discomfort. It is possible that a similar scenario could be obtained with an
anti-EGFR treatment in NSCLC carrying a mutant EGFR.

Therefore it seems justified to expand previous second-line phase II experience with
anti-EGFR strategies to patients with incurable stage III-IV NSCLC without prior therapy and
a mutant EGFR. The informed consent towards these patients before entry in the study will
clearly state that until now the first-line standard of care has been chemotherapy, which
leads to a small overall survival benefit compared to the supportive treatment only and that
participation in the current study will delay this treatment within a tightly controlled

In the current trial the RTKI erlotinib will be used. Prior experience with this drug has
been obtained in phase II and III studies. In the phase II setting, in an unselected
pretreated population, a response rate of 12.3% and a median survival of 8.4 months could be
obtained (19). In phase III, placebo-controlled studies, combination of erlotinib with
concurrent chemotherapy does not provide a survival advantage (gemcitabine and cisplatin in
TALENT (20) and paclitaxel and carboplatin in TRIBUTE (21). Several hypotheses can explain
these results: lack of selection of patients; antagonism between cytostatic and cytotoxic
agents (negative interaction with chemotherapy when given concurrently); chemotherapy and
EGFR inhibitors target the same cell population since chemotherapy directly or indirectly
affects EGFR function/expression and thereby reducing the effects of EGFR inhibitors. These
results are in contrast to the significant survival benefit seen in the phase III randomized
placebo-controlled study in NSCLC following failure of 1st or 2nd line chemotherapy (BR21).
The response rate was 9% in the erlotinib treated patients, with significant increase in
progression free survival (from 8 to 9,7 wks) and increased survival (from 4.7 mth to 6.7
mth, p< 0.001). In that study the biological parameters that correlate with response
(mutation status, EGFR gene amplification and EGFR immunohistochemistry) are still under

Survival benefit correlated best with the presence of EGFR expression by
immunohistochemistry and EGFR gene polysomy (22).

Inclusion Criteria:

- Histological or cytological diagnosis of inoperable, locally advanced, recurrent or
metastatic (Stage IIIB or Stage IV) adenocarcinoma of the lung in a patient with a
smoking history of < 15 years and quit smoking > 1 year before diagnosis.

- Evidence of disease but measurable disease is not mandatory.

- 18 years of age or older.

- ECOG performance status of 0 – 3.

- Patients not eligible for standard curative-intent treatment with surgery or

- Life expectancy ³ 3 months.

- Prior therapy for NSCLC allowed for primary disease: surgery and radiotherapy and
adjuvant or proto-adjuvant chemotherapy completed > 6 months before inclusion

- Adequate bone marrow, hepatic and renal function:

Granulocyte count > 1.5 x 109/L and platelet count > 100 x 109/L Serum bilirubin must be <
1.5 upper limit of normal (ULN). If alkaline phosphatase is > 2.5 x ULN, SGOT (AST) and
SGPT (ALT) must be < 1.5 x ULN.

Serum creatinine < 1.5 ULN or creatinine clearance > 60 ml/min.

- Ability for giving informed consent for participating in the study and filling out
FACT-L quality of life scales.

- Able to comply with study and follow-up procedures.

- Availability of tumour biopsy sample (fixed in formalin and, if possible, also snap
frozen tumour sample). If frozen samples are available, these will be collected by
central data management.

- Signed Informed Consent for performing mutation analysis and subsequent biomarker

- Separate signed Informed Consent for participation in the treatment phase of the

- Ability to take oral medication.

- For all females of childbearing potential a negative pregnancy test must be obtained
within 48 hours before starting therapy.

Exclusion Criteria:

- Patients for whom urgent chemotherapy or radiotherapy is deemed necessary (e.g.
rapidly progressive disease).

- Current symptomatic central nervous disorder, brain or leptomeningeal metastasis.

- Pre-existing symptomatic interstitial lung disease, not related to the current

- Patients with a history of other malignancies, except patients with basal cell
carcinoma of the skin or in situ carcinoma of the cervix with a disease free interval
of ³ 5 years. Patients with a prior history of other good prognosis malignancies more
than 5 years since end of treatment and in un-maintained complete remission also can
be considered for inclusion

- Prior therapy with systemic anti-tumour therapy with HER1/EGFR inhibitors (small
molecule or monoclonal antibody) or chemotherapy

- Significant malabsorption syndrome or disease affecting the gastrointestinal tract

- Pregnant or breast-feeding women; for women in reproductive condition, a negative
pregnancy test is required.

- Concomitant food or drug intake which potentially impairs absorption and
metabolisation of RTKI's.

- Participation in another clinical trial with any investigational drug within 30 days
prior to study screening.

- Any unstable systemic disease (including active infection, grade 4 hypertension,
unstable angina, congestive heart failure, hepatic, renal or metabolic disease).

- Any significant ophthalmological abnormality, especially severe dry eye syndrome,
keratoconjunctivitis sicca, Sjögren syndrome, severe exposure keratitis or any other
disorder likely to increase the risk of corneal epithelial lesions.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Establish clinical benefit (progression free survival) of first line RTKI in patients with stage IV and stage IIIB NSCLC not eligible for curative-intent treatment (chemo-radiotherapy) carrying a mutant EGFR-1.

Principal Investigator

Jacques De Grève, MD PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:



Belgium: The Federal Public Service (FPS) Health, Food Chain Safety and Environment

Study ID:




Start Date:

January 2006

Completion Date:

Related Keywords:

  • Lung Neoplasms
  • Non-Small Cell Lung Cancer
  • Adenocarcinoma, Bronchiolo-Alveolar
  • Non-small cell lung cancer
  • tyrosine kinase inhibition
  • first-line treatment
  • mutant EGFR-gene
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Neoplasms
  • Adenocarcinoma, Bronchiolo-Alveolar
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms