Current Strategies in the Treatment of Advanced Non-small Cell Lung Cancer
Edward S Kim Assistant Professor, Department of Thoracic and Head and Neck Medical Oncology,
M.D. Anderson Cancer Center
Salvage Therapy
Treatment of NSCLC has changed dramatically over the
past several years as more drugs have been introduced for
treating patients who have failed priory chemotherapy. In
a phase III study comparing docetaxel to best supportive
care, TTP was significantly longer for the patients who
received docetaxel (10.6 vs 6.7 weeks, respectively;
p<.001), as was median (7.0 vs 4.6 months) and one-year
survival (37% vs 11%). In the TAX 320 trial, two different
doses of docetaxel (100mg/m2 and 75mg/m2) were
compared against vinorelbine or ifosfamide. Although
response rates to docetaxel were low (11% for the high
dose and 7% for the low dose), they were significantly
higher than the vinorelbine or ifosfamide arms (1%).
Patients receiving either docetaxel regimen demonstrated
a QOL benefit. Furthermore, the one-year survival was
significantly greater with docetaxel 75mg/m2 compared
with the ifosfamide or vinorelbine treatment (32% vs
19%; p=.025).
The antifolate agent, pemetrexed, has also been approved
for salvage therapy in NSCLC, after previously being
approved for mesothelioma with cisplatin. In a 571-
patient phase III study comparing pemetrexed to
docetaxel, outcomes did not reach significance between
the two groups, with ORR approximately 9%, median
progression-free survival (PFS) of 2.9 months for each
arm, median survival time of 8.3 versus 7.9 months for
pemetrexed and docetaxel, respectively, and one-year
survival rate of 29.7% for each arm.However, pemetrexed
was associated with significantly fewer side effects.
In view of poor outcomes with cytotoxic chemotherapy
in salvage treatment, EGFR tyrosine-kinase inhibitors
(TKIs) were investigated in second-line therapy for
NSCLC. Initial phase II studies with gefitinib appeared
promising; however, further studies failed to show a
significant survival difference compared with placebo
and best supportive care. In contrast, erlotinib has shown
efficacy in second-line NSCLC therapy similar to that
noted with cytotoxic agents. Shepherd et al. conducted
a 731-patient randomized placebo controlled trial of
erlotinib versus placebo in second or third line therapy.
Significant differences in outcomes, including response
rate (8.9% vs <1%), PFS (2.2 months vs 1.8 months),
overall survival (6.7 months vs 4.7 months) and QOL,
were noted, all favoring the erlotinib arm; only 5% of
patients discontinued erlotinib because of toxic effects.
Docetaxel, pemetrexed, and erlotinib are the three
currently approved single-agents in the salvage therapy
of NSCLC.
Molecular Targeted Therapies
Because of the discouraging survival statistics associated
with NSCLC, additional approaches to treatment have
been pursued diligently, including the use of targeted
agents alone or in combination with chemotherapy.
Epidermal Growth Factor Receptor
EGFR is a tansmembrane glycoprotein receptor
composed of an extracellular ligand-binding domain, a
transmembrane domain, and an intracellular domain with
a TK region.Altered or increased expression of EGFR has
been observed in 60–80% of patients with lung cancer
and has been linked to disease progression, poor survival,
poor response to therapy, development of resistance to
cytotoxic agents, advanced tumor stage, and increased risk
for metastasis. Overexpression of EGFR is most
commonly found in squamous cell (84%), followed by
large cell (68%) and adenocarcinoma (65%). The
inhibition of EGFR can therefore be accomplished
upstream by blocking the ligand-binding domain with
monoclonal antibodies (i.e. cetuximab) or downstream by
interfering with signal transduction via TK by using small
molecule TKIs (i.e. erlotinib and gefitinib).
Erlotinib
Erlotinib, an orally active quinazoline, is a potent selective
inhibitor of EGFR TK.The National Cancer Institute of
Canada Clinical Trials Group (NCIC CTG) conducted
the BR.21 trial which evaluated erlotinib in the setting
of second- or third-line therapy for advanced NSCLC.
This study was the first to demonstrate a statistically
significant survival benefit associated with the use of a
biologic agent. In BR.21, Shepherd et al. randomized
731 patients with previously treated advanced NSCLC
to receive erlotinib 150mg per day or placebo.The ORR
and overall survival with erlotinib were 8.9% and 6.7
months, respectively, compared with <1% and 4.7
months for the patients receiving placebo (p=0.001).PFS
was 2.2 months in the erlotinib group, compared with
1.8 months in the placebo group (p<0.001), and QOL
measurements also significantly favored the erlotinib
group. In addition, all subgroups benefited from therapy
with erlotinib, including men, women, and those with
squamous as well as adenocarcinoma. On the basis of this
study, erlotinib was approved by the US Food and Drug
Administration (FDA) in November 2004 for the
treatment of locally advanced or metastatic NSCLC that
has failed to respond to at least one prior chemotherapy
regimen. In view of its activity in the salvage setting, a large adjuvant study with erlotinib based on tumor
profile is planned to further evaluate its role in the
treatment of NSCLC.
