Trial Information

A Phase III Study to Investigate the Differential Influence of Prior Chemotherapy on the Efficacy of Erlotinib in Patients With Advanced Non-small Cell Lung Cancer (IIIB, IV) With or Without EGFR Gene Mutation

The clinical management of advanced non-small cell lung cancer (NSCLC) remains challenging.
Initial therapies for advanced NSCLC with platinum-based regimens have shown consistent
overall response rates of 30% to 40% with progression-free intervals of 4-5 months and
1-year survival rates of 35% to 40% [1-3]. First line doublet chemotherapy commonly used in
daily practice includes Gemcitabine, vinorelbine, paclitaxel and docetaxel those have proven
efficacy with platinum against best supportive care, prolonging survival for approximately 3
months. Recently, pemetrexed, a multi-target antifolate agent, has been introduced into the
1st line doublet chemotherapy with platinum-based regimen to have similar efficacy and a
better safety profile compared to docetaxel or gemcitabine [4]. Although those agents seem
to have equivalent efficacy, tolerability tends to be a concern for docetoxel.

Myelosuppression with the standard docetaxel schedule of 75 mg/m2 administered once every 3
weeks is extremely frequent and severe; neutropenia occurs in 54% to 67% of patients and
febrile neutropenia occurs in 1.8% to 8.0% of patients [5, 6]. Moreover, non-hematologic
toxicities, such as grade 3-4 asthenia (12% to 18%), and nausea and vomiting (1% to 3.6%),
are not uncommon [5, 6]. To increase tolerability of docetaxel, alternative schedules have
been extensively studied. Accumulating evidence suggests that a weekly schedule of docetaxel
(35 mg/m2) reduces severe and febrile neutropenia without decreasing antitumor activity
[7-10]. Nevertheless, no significant differences were observed for anemia, thrombocytopenia,
and non-hematologic toxicity [7]. For the same reason, a lower dose of docetaxel (60 mg/m2
every 3 weeks) has been recommended in Japan [11, 12]. However, recent large scale trials
with such a dose of docetaxel still revealed high incidences of grade 3 and 4 neutropenia
(up to 82.9%) [12-14]. Different schedules of low dose docetaxel have not been studied, nor
has a comparison been made between low dose docetaxel and the less toxic agent, pemetrexed.

Currently, the investigators have been following a schedule of weekly low dose docetaxel (30
mg/m2 on days 1 and 8 every 3 weeks; 60 mg/m2 accumulated dose for each cycle) at our
hospital in an effort to achieve better tolerability (in press-chemotherapy 2010). The
investigators therefore perform an exploratory study, by prospective analysis, to
investigate the efficacy and toxicity of such a low dose docetaxel schedule compared to that
of pemetrexed in patients with NSCLC who are chemotherapy naive.

Erlotinib, an orally-available epidermal growth factor receptor (EGFR) tyrosine-kinase
inhibitor (TKI), significantly prolongs survival and produces significant symptom and
quality-of-life benefits compared with best supportive care in unselected patients with
relapsed non-small-cell lung cancer (NSCLC) [15, 16]. In a large, phase III,
placebo-controlled study (BR.21), erlotinib produced a survival benefit across all patient
sub-groups studied [15].