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
Gefitinib
Gefitinib (Iressa, AstraZeneca), which gained accelerated
approval in May 2003 for the treatment of advanced
NSCLC, is also a selective EGFR TKI.Initial studies using
this agent were very promising. Recently, ISEL (Iressa
Survival Evaluation in Lung Cancer), a placebocontrolled,
randomized phase III trial of more than 1,600
patients, reported no statistically significant difference in
survival between patients treated with gefitinib and those
given placebo. Gefitinib is therefore no longer recommended
in the treatment of NSCLC.
Cetuximab
Cetuximab (Erbitux, ImClone Systems/Bristol-Myers
Squibb), a promising monoclonal antibody targeting
the EGFR, has been approved for use in colorectal
cancer and recently in head/neck squamous cell cancer.
Studies examining cetuximab as a treatment for patients
with NSCLC are on-going. In first-line treatment of
patients with metastatic disease, the addition of
cetuximab to PC, gemcitabine/carboplatin (GCb),VC
are currently under way. In the setting of second-line
treatment of NSCLC, a recent study reported on the
use of docetaxel plus cetuximab in patients with
EGFR-positive tumors. The results were encouraging,
with a response rate of 25–30% in this chemotherapyrefractory
patient population. A phase III trial is ongoing
in this patient population with docetaxel or
pemetrexed +/- cetuximab.
VEGF Signaling Pathway
Angiogenesis plays an important role in the growth and
metastasis of solid tumors. vascular endothelial growth
factor (VEGF), its isoforms, and its receptor (VEGFR)
are important in regulating angiogenesis. Multiple
strategies have been developed to target this pathway.
One approach to the modulation of VEGF-mediated
angiogenesis is to use antibodies targeted against the
VEGF protein itself,or to its receptor.Encouraging results
have been reported with the addition of bevacizumab to
PCb (ECOG 4599) in patients with advanced, metastatic,
or recurrent non-squamous cell NSCLC. A phase II
randomized second-line trial of chemotherapy + placebo,
chemotherapy with bevacizumab, and erlotinib with
bevacizumab was reported at American Society of
Clinical Oncology (ASCO) this year. The results
demonstrated improved PFS (primary endpoint) in favor
of both bevacizumab arms and a better response rate with
the bevacizumab and erlotinib combination. This
combination of erlotinib and bevacizumab is being
studied in a large phase III randomized study in the
second-line setting.
ZD6474 (AstraZeneca) is an oral agent with dual
kinase inhibitor activity which targets both VEGFR-2
and EGFR TKs. ZD6474 has shown activity in
NSCLC and other solid tumor types. This small
molecule inhibitor therefore affects two distinct
processes involved in tumor growth and survival: cell
proliferation and angiogenesis. Phase I studies with
ZD6474 have been completed and demonstrated good
tolerability at an oral dose =300mg, and manageable
side effects. Although phase II studies with ZD 6474
are currently on-going, preliminary data from two
studies appear promising.
Other compounds are actively being studied in
NSCLC. These include BAY 43-9006 (Sorafenib,
Bayer), a potent inhibitor of both Raf kinase signaling
pathway (involved in cell proliferation), as well as
VEGFR2 and platelet derived growth factor receptor
(PDGFR)-ß (involved in angiogenesis). BAY 43-9006
has demonstrated promising anti-tumor activity in a
number of tumor types including renal cell carcinoma
(RCC), sarcoma, melanoma, and pancreatic, thyroid,
and colorectal cancers. Sunitinib (Sutent) is an oral
multi-kinase inhibitor (VEGFR, PDGFR-a, PDGFR-
ß,RET,KIT, FLT-3) and is approved for use in renal cell
cancer and imatinib-refractory GIST. Sunitinib has
been studied in NSCLC with response rates of about
10%. Further studies are planned in combination.
Conclusion
The treatment of advanced lung cancer remains an
exciting area that reflects a sobering challenge.
Cytotoxic chemotherapy doublets have modestly
improved survival, and research is now emphasizing
QOL issues. Agents targeting VEGF and EGFR have
become critical weapons in the treatment of NSCLC.
Bevacizumab and erlotinib are the first biologic agents
to demonstrate a survival advantage when added to
standard chemotherapy. Other strategies are being
evaluated including earlier detection, predictive
markers, and chemoprevention.As research on genomic
and proteomic techniques continues, therapy tailored to
specific tumors may offer an opportunity for improved
efficacy and disease control with the use of both
cytotoxic and biologic compounds.
