A randomized, double-blind, placebo-controlled Phase III study of first-line maintenance Tarceva vs Tarceva at the time of disease progression in patients with advanced non-small cell lung cancer (NSCLC) who have not progressed following 4 cycles of platinum-based chemotherapy.

The use of the single-agent EGFR tyrosine kinase inhibitor erlotinib in NSCLC
after
chemotherapy is supported by the results of the BR.21 Phase III study. In 2004,
the
FDA approved erlotinib for the treatment of patients with locally advanced or
metastatic
NSCLC after failure of at least one prior chemotherapy regimen, based on the
results of
BR.21 that showed an overall survival benefit for patients treated with
erlotinib. This was
followed by the approval in this setting in the EU and other countries.

The collective information derived from the BR.21 and SATURN trials indicates
that
erlotinib provides a PFS and OS benefit for patients with advanced NSCLC either
in the
first-line maintenance setting or at the time of disease relapse. In
particular, the data from
the SATURN trial showed that erlotinib in the maintenance setting provided a
PFS and
OS benefit compared to patients that were randomized to placebo and waited until
progression before receiving a second-line of treatment. However, because the
secondline
treatment was at the investigator*s discretion, the trial was not able to
address the
specific question of the relative benefit of *early* erlotinib maintenance
therapy versus
*late* erlotinib administration at the time of disease progression. This
present study is
designed to prospectively determine the relative survival benefit of *early*
versus *late*
erlotinib therapy in patients with advanced (Stage IIIB and not amenable for
combined
modality treatment) or metastatic (Stage IV) NSCLC.

The primary objective of this study is to compare the Overall Survival (OS) of
first-line
maintenance therapy with erlotinib versus erlotinib administered at the time of
disease
progression in patients with histologically documented, advanced or recurrent
(Stage IIIB
and not amenable for combined modality treatment) or metastatic (Stage IV) NSCLC
(according to the ISC updated Lung cancer staging criteria [44]), whose tumours
do not
harbour an EGFR activating mutation (exon 19 deletion or exon 21 L858R
mutation), and
who have not experienced disease progression or unacceptable toxicity during 4
cycles of
platinum-based chemotherapy.

Secondary objectives are:
* To compare the PFS between the treatment arms during the Blinded (first-line
maintenance) phase;
* To compare overall response rate (ORR) and disease control rate (DCR) between
treatment arms during the Blinded (first-line maintenance) phase;
* To evaluate the safety and tolerability profile of erlotinib in this patient
population.

This is a multi-centre, randomized, placebo-controlled, Phase III study. The
study will
consist of three components: (1) Screening phase, (2) Blinded phase, and (3)
Open-label
phase.

The screening phase will consist of screening patients into the chemotherapy
run-in
period with a (non-investigational) platinum based chemotherapy. In order to
reflect current
practices in the management of advanced NSCLC, bevacizumab
can be added to the first-line chemotherapy regimen in countries where it has
been
approved in this setting, and continued until disease progression in the
Blinded phase of
the study in combination with erlotinib or placebo (depending on randomization).

Patients with already known EGFR mutated tumours (exon 19 deletion or exon 21
L858R
mutation) determined by local test will not be allowed into the Screening
phase. Patients
with unknown EGFR mutation status or wild-type status determined by local test
will be
allowed into the Screening phase, and their tumour will be tested in a central
laboratory
to determine their EGFR mutational status (or confirm it as wild-type if
locally assessed).
Patients whose sample is found to harbor an EGFR activating mutation by central
laboratory test will not be randomized into the Blinded phase. In the event of
discordant
results, the central laboratory test result will overrule the local test result.
Patients whose tumours do not harbour an EGFR activating mutation (exon 19
deletion or
exon 21 L858R mutation) or have an indeterminate EGFR mutation status following
central testing, and who do not progress following 4 cycles of platinum based
chemotherapy (i.e. with documented complete response, partial response or
stable disease
according to RECIST v1.1), will be randomized into the Blinded phase of the
study (with
stratification).

The Blinded phase of the study will consist of patients being randomized to 150
mg/day
erlotinib (*early erlotinib* arm) or placebo (*late erlotinib* arm) in the
maintenance
setting until the occurrence of disease progression, death or unacceptable
toxicities.
Following randomization, patients who demonstrate disease progression
(according to
RECIST v1.1 or because of symptomatic deterioration attributed to suspected
tumour
progression), will be unblinded and will enter the Open-label phase of the
study. If the
patient was randomized to the *early erlotinib* arm, the investigator will have
the option
of providing the patient with best supportive care or an approved second line
therapy
(such as pemetrexed or docetaxel, but not EGFR-directed therapies). This
decision will
be guided by the patient*s preference and the investigator*s medical judgment.
If the
patient was randomized to the *late erlotinib* arm (first-line maintenance with
placebo),
the patient will receive second-line erlotinib provided by the sponsor until
the occurrence
of further disease progression (confirmed by the treating physician; determined
on the
basis of radiological evidence or symptomatic deterioration, according to local
practices),
death, or unacceptable toxicities.During the Blinded phase of the study, data
will be captured.

In the Open-label phase of the study, only SAEs will be captured in addition to
survival and
subsequent treatment data until PD, death or unacceptable toxicity. Only
survival and
subsequent treatment data will be collected thereafter.

Take one tablet of Tarceva or placebo oraaly every day.

Erlotinib has been shown to improve survival in patients with advanced NSCLC
without concomitant bone marrow toxicity. In NSCLC, erlotinib monotherapy has
shown a clinically relevant and statistically significant survival benefit in
the first-line maintenance, second-line and third-line settings Collectively,
data from the SATURN and BR.21 studies support the benefit of Tarceva in both
the first-line maintenance and second-line setting in NSCLC patients. The
purpose of the present study is to prospectively determine the relative
survival benefit of *early* versus *late* erlotinib therapy in patients with
advanced (Stage IIIB and not amenable for combined modality treatment) or
metastatic (Stage IV) NSCLC.
Given the demonstrated efficacy of erlotinib when administered in the
first-line maintenance and second-line setting, and its the well established
safety profile in NSCLC patients, the potential benefits to patients enrolling
in study BO25460 outweigh the potential risks.