US Pharm. 2007;32(10):5-13.
ABSTRACT: Non–small cell lung cancer (NSCLC)
continues to be the leading cause of cancer death in the United States, and
treatment for patients with advanced NSCLC remains an important, clinically
complex challenge. Although chemotherapy alone or in combination with
radiotherapy is considered the standard of care, overall prognosis for these
patients is poor, with a five-year survival rate of 15%. The advent of new
molecular targeted agents in the last decade has introduced a new and
interesting setting, but thus far, the results of clinical trials have not
provided the panacea scientists are seeking. This article aims to educate and
update pharmacists about the three FDA-approved agents for use in
NSCLC--gefitinib, erlotinib, and bevacizumab--as well as recent advances in
targeted pharmacology for NSCLC, including recent clinical trial data.
is the leading cause of cancer death in the United States for both men and
women. In 2003, lung cancer accounted for more deaths than breast cancer,
prostate cancer, and colon cancer combined.1 Lung cancer is divided
into two major types: small cell and non–small cell lung cancer (NSCLC). NSCLC
comprises approximately 80% of diagnosed cases and is made up of four
histological types--epidermoid, squamous carcinoma, adenocarcinoma, and large
cell carcinoma.2 Table 1 represents the American Joint
Committee on Cancer staging system for lung cancer.3,4
Despite advances in the
molecular understanding and management of lung cancer, the overall five-year
survival rate for all types of lung cancer remains about 15%. If left
untreated, most patients with NSCLC will die within one year of diagnosis.
2 Only a small number of NSCLC patients are suitable candidates for
radical curative treatment. The majority present with locally advanced or
metastatic disease at diagnosis and can obtain only a modest survival benefit
from palliative platinum-based chemotherapy with or without radiotherapy.5
Conventional treatment in NSCLC--combination chemotherapy with cisplatin or
carboplatin and third-generation agents (e.g., docetaxel, gemcitabine,
irinotecan, paclitaxel, vinorelbine)--has apparently reached a plateau of
effectiveness in improving survival.6-11
In the last decade, increased
understanding of cancer biology has revealed numerous cellular targets for
therapeutic intervention, including epidermal growth factor receptors (EGFRs),
angiogenesis inhibitors, proteasome inhibitors, and various signal
transduction inhibitors.5,12,13 This article aims to educate and
update pharmacists about the three agents approved by the FDA for use in NSCLC
(gefitinib, erlotinib, and bevacizumab), as well as the recent advances in
targeted pharmacology for NSCLC, including recent clinical trial data.
Approved Medications for NSCLC
The ErbB (human
epidermal receptor [HER]) family of transmembrane tyrosine kinase type I
receptors, also known as EGFRs, have an important role in processes such as
cell growth, proliferation, survival, and differentiation. The receptors
contain an extracellular domain and an intracellular protein tyrosine kinase
core and must form dimers to initiate signaling.14,15 The
EGFR-dependent autocrine pathway is known to have a significant impact in the
development and progression of human epithelial cancers, including NSCLC.
There are two classes of
anti-EGFR agents that have demonstrated clinical activity in NSCLC. They are
the low-molecular-weight tyrosine kinase inhibitors that inhibit the tyrosine
kinase activity of EGFR by competing with adenosine triphosphate (ATP) for the
ATP-binding site and the monoclonal antibodies directed at the extracellular
domain of the EGFR.16 The antitumor effects of EGFR inhibitors in
human cancer models include inhibition of cancer cell proliferation with cell
cycle arrest, induction of apoptosis, antiangiogenesis, inhibition of invasion
and metastasis, and potentiation of antitumor activity of cytotoxic drugs and
Tyrosine Kinase Inhibitors:
Erlotinib (Tarceva) is a HER1/EGFR tyrosine kinase inhibitor. Erlotinib
inhibits the intracellular phosphorylation of tyrosine kinase associated with
the EGFR. Erlotinib is an oral tablet approved by the FDA as monotherapy for
the treatment of patients with locally advanced or metastatic NSCLC after
disease progression with at least one prior chemotherapy regimen.18
There are three significant
clinical trials that led to the FDA approval of erlotinib. The BR.21 trial,
carried out by the National Cancer Institute of Canada, consisted of 731
patients with NSCLC whose disease had progressed after chemotherapy. There was
a statistically significant increase in the overall survival among patients
who took erlotinib, compared to the placebo group (6.7 vs. 4.7 months).19
Both the Tarceva Lung Cancer
Investigation (TALENT) trial and the Tarceva Response in Conjugation with
Paclitaxel and Carboplatin (TRIBUTE) trials were conducted in patients who
were chemotherapy-naïve. The patients first received their respective
chemotherapy regimens followed by maintenance monotherapy with erlotinib. In
both trials, erlotinib failed to show an increase in survival.20-22
Subset analysis in several clinical trials has suggested that nonsmokers,
women, and patients with adenocarcinoma have a higher response rate to
The most common adverse events
associated with erlotinib include acneiform rash and diarrhea, occurring in 9%
and 6% of patients, respectively. Other common adverse effects include
fatigue, dyspnea, cough, nausea and vomiting, stomatitis, and infection. Liver
function test abnormalities have also been reported but were usually transient
in nature. Interstitial lung disease (ILD)–like events have occurred in
approximately 0.7% of erlotinib-treated patients, including some fatalities.
Erlotinib is listed as a category D agent in pregnancy.18
Gefitinib (Iressa) was the
first EGFR tyrosine kinase inhibitor approved by the FDA. Gefitinib inhibits
the intracellular phosphorylation of numerous tyrosine kinases associated with
transmembrane cell surface receptors, including the tyrosine kinases
associated with the EGFR. Gefitinib is as an oral tablet and is FDA approved
as monotherapy for the continued treatment of patients with locally advanced
or metastatic NSCLC who are benefiting or have benefited from gefitinib after
failure with both platinum-based and docetaxel chemotherapies.23
In phase II trials, the Iressa
Dose Evaluation in Advanced Lung Cancer trials (IDEAL 1, IDEAL 2) included 210
and 221 stage III and IV NSCLC patients, respectively, comparing gefitinib 250
or 500 mg/day versus placebo. The patients had previously failed one or two
platinum-based chemotherapy regimens. The objective tumor response rate for
both the 250- and 500-mg doses were 8% to 19%, respectively, and a median
survival benefit of six to seven months was seen. In addition, 35% to 43% of
patients showed symptom improvement.22,24
Phase III trials included the
Iressa NSCLC Trial Assessing Combination Treatment (INTACT 1, INTACT 2) and
the Iressa Survival Evaluation in Lung Cancer study (ISEL). The INTACT 1 and
INTACT 2 trials included 2,130 stage III and IV chemotherapy-naïve NSCLC
patients. Patients were randomized to receive 250 mg/day, 500 mg/day, or
placebo in combination with platinum-based chemotherapy regimens (gemcitabine
plus cisplatin in INTACT 1 and carboplatin plus paclitaxel in INTACT 2).
Gefitinib failed to show any increase in tumor response rates, time to
progression, or overall survival in comparison to placebo. In the ISEL trial,
1,692 advanced-stage NSCLC patients received either gefitinib 250 mg/day plus
best supportive care or placebo plus best supportive care. The patients
previously had one or two unsuccessful chemotherapy regimens. Gefitinib failed
to demonstrate any significant increase in survival compared to placebo.
Common adverse events
associated with gefitinib include diarrhea, nausea and vomiting, rash, acne,
and dry skin. In approximately 1% of patients, ILD has been reported; one
third of these cases have been fatal. ILD was seen in patients who received
prior radiotherapy and chemotherapy and in patients who had no previous
Due to the lack of overall
survival benefit in the aforementioned clinical trials, the FDA issued a
public health advisory for gefitinib on June 17, 2005.27 In the
advisory, the FDA stated that they have partnered with AstraZeneca to create
the Iressa Access Program, which allows the limited distribution of gefitinib
to the following patient populations:
currently receiving and benefiting from gefitinib;
• Patients who
have previously received and benefited from gefitinib; and
enrolled or new patients in non-Investigational New Drug (IND) clinical trials
approved by an investigational review board prior to June 17, 2005.
New patients may also be able
to obtain gefitinib if AstraZeneca decides to make it available through an IND
trial and the patients meet the criteria for enrollment according to the IND
Similar to erlotinib, there
were certain subsets of patients who showed an increased response to gefitinib
therapy. Among those patients with relapsing NSCLC, Asian patients, women,
nonsmokers, patients with adenocarcinoma, and patients who maintained normal
activity or were slightly bedridden had the highest response rates from
gefitinib treatment.22 Kato and colleagues have created a list of
clinical and molecular factors that are predictive of response to the small
molecule EGFR tyrosine kinase inhibitors (see Table 2).7
Vascular Endothelial Growth
Factor (VEGF) Inhibitors
Angiogenesis is the
formation of new blood vessels and is therefore an important mechanism leading
to tumor cell proliferation and metastasis in human malignancies. This is a
process prompted by various enzymes.28-34 Among these, VEGF is
known to be the most important proangiogenic factor, necessary for the
development of novel tumor vessels. VEGF mediates its effects by interaction
with two high-affinity kinase receptors: VEGFR-1 and VEGFR-2. Clinically
active agents against VEGF include the monoclonal antibodies (bevacizumab and
VEGF-Trap) and oral small molecule VEGF tyrosine kinase inhibitors (ZD6474,
sunitinib, and sorafenib).6,35,36
Bevacizumab (Avastin) is a recombinant, human monoclonal antibody that binds
to and inhibits the biologic activity of human VEGF. Once bevacizumab binds to
VEGF, it prevents the interaction of VEGF to its receptors. This leads to
decreased endothelial cell proliferation, new blood vessel formation, and
inhibition of metastatic disease progression. The FDA has approved bevacizumab
in combination with carboplatin and paclitaxel as first-line treatment for
patients with unresectable, locally advanced, recurrent, or metastatic
In an initial phase II trial,
patients with previously untreated stage IIIb/IV NSCLC were randomized to
receive 7.5 mg/kg bevacizumab or 15 mg/kg bevacizumab plus
carboplatin/paclitaxel or chemotherapy alone. The 15 mg/kg arm demonstrated a
better response rate (31.5% vs. 18.8%), longer time to progression (7.4 months
vs. 4.2 months), and a slight increase in survival (17.7 vs. 14.9), compared
to patients taking chemotherapy alone. Bleeding episodes were the main serious
adverse event in this trial; of six patients who developed hemoptysis or
hematemesis, four patients died. Squamous cell histology was determined to be
an independent risk factor for bleeding.
Subsequent trials evaluated
nonsquamous cell NSCLC patients.38-40 In the largest of these
trials, 878 chemotherapy-naïve patients with locally advanced, metastatic, or
recurrent nonsquamous NSCLC were randomized to receive a combination of
carboplatin/paclitaxel plus bevacizumab or carboplatin/paclitaxel alone.
Overall survival was significantly higher among patients receiving
carboplatin/paclitaxel plus bevacizumab (12.3 months vs. 10.3 months),
compared to patients on chemotherapy alone. Although these findings are
statistically significant, detailed analysis showed that women, patients ages
65 and older, and patients with 5% or more weight loss at study entry did not
have as robust of a response.41
The most serious adverse
reactions in patients treated with bevacizumab included gastrointestinal
perforations (0.9%), wound-healing complications (0.8%), hemorrhage (fetal
hemoptysis in 31% of squamous histology and 2.3% in nonsquamous histology),
arterial thromboembolic events (4.4%), hypertensive crisis (8-18%), reversible
posterior leukoencephalopathy syndrome (<0.1%), nephrotic syndrome (0.5%), and
congestive heart failure (1.7%). Common adverse events included mild to
moderate rash, diarrhea, and proteinuria.37
Agents Currently Under
Investigation for Use in NSCLC
currently being used or evaluated for NSCLC, along with approved indications,
dosages, route of administration, and significant adverse effects, can be
found in Table 3.
Lapatinib (Tykerb) is an orally available dual inhibitor of the intracellular
tyrosine kinase domains of both the EGFR and HER2. Lapatinib is presently
approved for use in combination with capecitabine for the treatment of
advanced or metastatic breast cancer.42 Because of its dual
mechanism of action, it has been studied in a variety of cancers, including
NSCLC. Data from these trials are not yet published.28
Cetuximab (Erbitux) is a recombinant, human/mouse chimeric monoclonal
antibody that binds specifically to the extracellular domain of the human
EGFR. Cetuximab is composed of the Fv regions of a murine anti-EGFR antibody
with human immunoglobulin G1 (IgG1) heavy and kappa light-chain constant
regions. Binding of cetuximab to the EGFR, by competitively inhibiting the
binding of epidermal growth factor and other ligands, blocks phosphorylation
and activation of receptor-associated kinases, resulting in inhibition of cell
growth, induction of apoptosis, and decreased matrix metalloproteinase and
vascular endothelial factor production.43 Currently, cetuximab is
FDA approved for use in colorectal, head, and neck cancers. It is currently
being investigated in phase III trials for use in NSCLC, based on encouraging
results from phase II studies.
Two phase II trials tested the
combination of cetuximab with standard platinum-based doublets in
EGFR-positive patients with previously untreated advanced NSCLC. Time to
progression of 4.5 and 5.5 months, median survival of 11 and 10.3 months, and
a one-year survival rate of 45% were seen in these trials. These results
compared favorably to previous trials using chemotherapy alone, and no
enhancement in toxicity was noted. A European phase II trial compared
cisplatin and vinorelbine with or without cetuximab as first-line therapy in
patients with advanced NSCLC. Objective response rates were 35% for cetuximab
plus chemotherapy versus 28% in the chemotherapy-only arm. Time to progression
was not statistically different between the two groups. Median survival was
8.3 months, with a one-year survival of 32% in the patients treated with
cetuximab plus chemotherapy, whereas the chemotherapy-only patients showed a
median survival of seven months and a one-year survival of 26%. At two years,
14% of patients in the cetuximab arm were still alive, but there were no
survivors in the control arm.44-47
The most frequent side effects
with cetuximab include acneiform skin rash (76%), asthenia (45%), fever (29%),
anorexia (27%), and diarrhea (19%). ILD is a rarely reported (<0.5%)
complication of cetuximab therapy. There are currently two black box warnings
for cetuximab--infusion reactions and cardiopulmonary arrest. Approximately 3%
of patients develop allergic or anaphylactic reactions, usually during the
first infusion. Also, 2% of patients with squamous cell carcinoma of the head
and neck developed cardiopulmonary arrest while being treated with cetuximab
plus radiation therapy.43
Currently, cetuximab is FDA
approved for use only in colorectal, head and neck cancers. Preliminary data
from the above phase II trials suggest that cetuximab lends itself to
combination chemotherapy and radiation therapy without excessive toxicity and
with promising antitumor activity. However, only phase III trial data will
determine cetuximab's appropriate place in the treatment of NSCLC.
Trastuzumab (Herceptin) is a
recombinant DNA-derived humanized monoclonal antibody that selectively binds
to the extracellular domain of the human EGFR-2 protein (HER2). Trastuzumab is
FDA approved for use in HER2-overexpressing breast cancer. Utility in NSCLC
has been studied in several phase II trials. Overall survival benefit was not
seen in the general NSCLC patient population of these studies. Only those
patients who were HercepTest 3+ positive showed an increase in
progression-free survival time. These data suggest that a very specific small
subgroup of NSCLC patients (2-5%) showing HercepTest 3+ positive might indeed
benefit by the addition of trastuzumab. In addition, trastuzumab carries black
box warnings for cardiomyopathy and infusion reactions.28,48-50
is a composite, soluble decoy receptor based on VEGFR-1 and VEGFR-2 fused to a
Fc segment of IgG1. It has been shown to block outgrowth of new vessels and is
capable of disrupting the preexisting vasculature of established metastases.
It is currently being tested in phase I and II trials, but no trial data are
available at this time.28,51,52
VEGF Tyrosine Kinase
(Zactima): ZD6474 is
an oral, small molecule inhibitor of VEGFR and EGFR kinase activity. By
targeting both pathways, ZD6474 can inhibit VEGF-dependent tumor angiogenesis
and EGFR-dependent cell proliferation and survival.28,53
In phase I studies, the drug was
generally well tolerated, but dose-dependent diarrhea, rash, and asymptomatic
QT prolongation were observed.54
Sorafenib is an oral, multikinase inhibitor targeting several
serine/threonine and receptor tyrosine kinases. It has been shown to interact
with multiple intracellular and cell surface kinases, including VEGFR-2 and
VEGFR-3. Sorafenib is FDA approved for use in patients with advanced renal
cell carcinoma. Due to its effects on the VEGFR, it has been studied as an
option in NSCLC. To date, no clinical data have been published for outcomes
related to NSCLC patients.55,56
Common adverse events are
hand-foot skin reaction and rash. Hypertension, hemorrhage, and wound-healing
complications have also been reported as serious adverse events associated
with sorafenib use.55
Sunitinib is an orally available, small molecule that inhibits multiple
receptor tyrosine kinases, some of which are implicated in tumor growth,
angiogenesis, and metastatic progression of cancer. It has shown activity at
VEGFR-1, VEGFR-2, and VEGFR-3. In vivo, sunitinib has been shown to cause
inhibition of tumor growth or tumor regression and/or inhibited metastases.
Sunitinib is indicated for the treatment of gastrointestinal stromal tumor
after disease progression or intolerance to imatinib and for the treatment of
advanced renal cell carcinoma.57 Due to actions on multiple VEGF
receptors, sunitinib is currently being evaluated for use in NSCLC. The trials
are still ongoing as of September 1, 2007.
Similar to other drugs in this
category, such as sorafenib, sunitinib has caused hypertension, hemorrhagic
events, QT interval prolongation, and diarrhea. A larger percentage of
patients receiving sunitinib compared to patients who received placebo or
interferon-alpha had a decline in left ventricular ejection fraction.
Discontinuation of sunitinib is recommended in those patients who develop
clinical manifestations of congestive heart failure.57
The proteasome pathway has a central
role in the selective degradation of ubiquitinated proteins involved in cell
cycle regulation, apoptosis, and angiogenesis. It has been shown that
proteasome inhibitors can stabilize numerous cell cycle inhibitory proteins
and cause cell cycle arrest and apoptosis through multiple mechanisms. The
discovery that tumor cells appear to be more sensitive to the proapoptotic
effects of proteasome inhibitors than normal cells has led to the clinical
evaluation of proteasome inhibitors in NSCLC.28,58-61
Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the
26S proteasome. The 26S proteasome is a large protein complex that degrades
ubiquitinated proteins. Inhibition of the 26S proteasome prevents targeted
proteolysis, which can affect multiple signaling cascades within cells. This
disruption of normal homeostatic mechanisms can lead to cell death. Currently,
bortezomib is approved for use in patients with multiple myeloma and patients
with mantle cell lymphoma.62
Due to its novel mechanism of
action, bortezomib has been evaluated for use in NSCLC as monotherapy and in
combination therapy. In a phase II study comparing bortezomib versus
bortezomib plus docetaxel in 155 previously treated patients with advanced
NSCLC, an 8% response rate for bortezomib versus a 9% response rate for
bortezomib plus docetaxel was reported. The time to disease progression was
1.5 months in the bortezomib group, compared to four months in the combination
group.63,64 A phase II trial of 114 chemotherapy-naïve patients
were given bortezomib plus carboplatin and gemcitabine. A response was seen in
20% of patients, with 45% reporting stable disease. Progression-free survival
was five months, and overall survival was 11 months.63,65 While
these results are promising, phase III trials are currently being conducted
and will further determine bortezomib's place in the treatment of NSCLC.
hypotension, congestive heart failure, acute respiratory distress syndrome,
thrombocytopenia, and neutropenia have all been reported during bortezomib use.
NSCLC continues to
be the leading cause of cancer death in the U.S., and the treatment for
patients with advanced NSCLC remains an important, clinically complex
challenge. Although chemotherapy alone or in combination with radiotherapy is
considered the standard of care, overall prognosis for these patients is poor,
with a five-year survival rate of 15%. The advent of new molecular targeted
agents in the last decade has led to a new and interesting setting. Yet, so
far, the findings of clinical trials have not provided the panacea scientists
are seeking. Among the new agents, the EGFR inhibitors, VEGF inhibitors, and
proteasome inhibitors have shown promise in certain subsets of NSCLC patients.
Currently, erlotinib (Tarceva), gefitinib (Iressa), and bevacizumab (Avastin)
are approved by the FDA for use in NSCLC. Recently, the combination of
bevacizumab and erlotinib has been evaluated in phase II studies. Authors
concluded that this combination is well tolerated and active in NSCLC. Further
investigation into the efficacy and tolerability of combined erlotinib and
bevacizumab is ongoing in phase III trials.66 These novel agents
also have varying toxicities that can mimic common diseases or conditions such
as respiratory illness, bleeding, congestive heart failure, and
As pharmacists, it is
extremely important to be educated on the latest therapies for NSCLC, which
patients may benefit most from them, and their associated toxicities. Of
course, the promotion of smoking cessation--the only proven prevention strategy
for lung cancer--cannot be overlooked.
1. Centers for
Disease Control and Prevention. Lung cancer statistics. Available at:
www.cdc.gov/cancer/lung/statistics. Accessed August 15, 2007.
2. Depiro JT, Talbert
RL, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed.
New York, NY: McGraw Hill; 2005;126:2365-2367.
3. Kurtzweil A, Sheetal
S. Treatment options for lung cancer. US Pharm. 2005;30:10.
4. Mountain CF.
Revisions in the International System for staging lung cancer. Chest.
5. Cascone T, Gridelli
C, Ciardiello F. Combined targeted therapies in non-small cell lung cancer: a
winner strategy? Curr Opin Oncol. 2007;19:98-102.
6. Gridelli C, Rossi A,
Maione P. Treatment of non-small cell lung cancer: state of the art and
development of new biologic agents. Oncogene. 2003;22:6629-6638.
7. Kato T, Nishio K.
Clinical aspects of epidermal growth factor receptor inhibitors: benefit and
risk. Respirology. 2006;11:693-698.
8. Schiller JH,
Harrington D, et al. Comparison of four chemotherapy regimens for advanced
non-small cell lung cancer. N Engl J Med. 2002;346:92-98.
9. Kelly K, Crowley J,
et al. Randomized phase III trial of paclitaxel plus carboplatin versus
vinorelbine plus cisplatin in the treatment of patients with advanced
non-small cell lung cancer: a Southwest Oncology Group Trial. J Clin Oncol
10. Scagliotti GV, De
Marinis F, et al. Phase III randomized trial comparing three platinum-based
doublets in advanced non-small cell lung cancer. J Clin Oncol.
11. Kubota K, Nishiwaki
Y, et al. The Four-Arm Cooperative Study (FACS) for advanced non-small cell
lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2004;23:7006.
12. Molina JR, Adjei
AA, et al. Advances in chemotherapy of non-small cell lung cancer. Chest
13. Sandler AB, Gray R,
et al. Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C)
with or without bevacizumab in patients with advanced non-squamous cell,
non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group
(ECOG) Trial E4599. J. Clin Oncol. 2005;23:2s.
14. Johnston JB,
Navaratnam S, et al. Targeting the EGFR pathway for cancer therapy. Curr
Med Chem. 2006;13:3483-3492.
15. Brown JG, Gibson
SB. Growth factors, receptors, and kinases: their exploration to target
cancer. In: Apoptotic Pathways as Target for Novel Therapies in Cancer and
Other Diseases. Los M, Gibson SB, eds. Springer Science+Business Media,
16. Gridelli C,
Bareschino MA, et al. Erlotinib in non-small cell lung cancer treatment:
current status and future development. Oncologist. 2007;12:840-849.
17. Normanno N, Bianco
C, et al. Target-based agents against ErbB receptors and their ligands: A
novel approach to cancer treatment. Endocr Relat Cancer. 2003;10:1-21.
18. Tarceva (erlotinib)
[package insert]. San Francisco, CA: Genentech, OSI Oncology; 2007.
19. Shepherd FA,
Rodrigues PJ, et al. Erlotinib in previously treated non-small-cell lung
cancer. N Engl J Med. 2005;353:123-132.
20. Gatzemeier U,
Pluzanska A, et al. Results of a phase III trial of erlotinib (OSI-774)
combined with cisplatin and gemcitabine (GC) chemotherapy in advanced
non-small cell lung cancer (NSCLC). J Clin Oncol. 2004;22:617.
21. Herbst RS, Prager
D, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774)
combined with carboplatin and paclitaxel chemotherapy in advanced
non-small-cell lung cancer. J Clin Oncol. 2005;23:5892-5899.
22. Eyben FE. Epidermal
growth factor receptor inhibition and non-small cell lung cancer. Crit Rev
Clin Lab Sci. 2006;43:291-323.
23. Iressa (gefitinib)
[package insert]. Wilmington, DE: AstraZeneca; 2004.
24. Fukouka M, Yano S,
et al. Multi-institutional randomized phase II trial of gefitinib for
previously treated patients with advanced non-small-cell lung cancer (the
IDEAL 1 trials). J Clin Oncol. 2003;21:2237-2246.
25. Giaccone G, Herbst
RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin
in advanced non-small-cell lung cancer: A phase III trial–INTACT 1. J
Clin Oncol. 2004;22:777-784.
26. Herbst RS, Giaccone G, Schiller
JH, et al. Gefitinib in combination with paclitaxel and carboplatin in
advanced non-small-cell lung cancer: A phase III trial–INTACT 2. J
Clin Oncol. 2004;22:785-794, 2004
27. Gefitinib (marketed
as Iressa) information. Food and Drug Administration Web site. Available at:
www.fda.gov/cder/drug/infopage/gefitinib. Accessed August 15, 2007.
28. Auberger J,
Loeffler-Ragg J, et al. Targeted therapies in non-small cell lung cancer:
proven concepts and unfulfilled promises. Curr Cancer Drug Targets.
29. Willett CG, Boucher
Y, et al. Direct evidence that the VEGF-specific antibody bevacizumab has
antivascular effects in human rectal cancer. Nat Med. 2004:10;145-147.
30. Ferrara N. Role of
vascular endothelial growth factor in the regulation of angiogenesis.
Kidney Int. 1999;56:794-814.
31. Asahara T,
Takahashi T, et al. VEGF contributes to postnatal neovascularization by
mobilizing bone marrow-derived endothelial progenitor cells. EMBO J.
32. Lyden D, Hattori K,
et al. Impaired recruitment of bone-marrow derived endothelial and
hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med
33. Li CY, Shan S, et
al. Initial stages of tumor cell-induced angiogenesis: evaluation via skin
window chambers in rodent models. J Natl Cancer Inst. 2000:92;143-147.
34. Obyrne KJ,
Koukourakis MI, et al. Vascular endothelial growth factor, platelet-derived
endothelial cell growth factor and angiogenesis in non-small cell lung cancer.
Br J Cancer. 2000;82:1427-1432.
35. Cacone T, Troiani
T, et al. Antiangiogeneic drugs in non-small cell lung cancer treatment.
Curr Opin Oncol. 2006;18:151-155.
36. Takahashi Y,
Kitadai Y, et al. Expression of vascular endothelial growth factor and its
receptor, KDR, correlates with vascularity, metastasis, and proliferation of
human colon cancer. Cancer Res. 1995;18:3964-3968.
(bevacizumab) [package insert]. South San Francisco, CA: Genentech Inc.; 2006.
38. Ranieri G, Patruno
R, et al. Vascular endothelial growth factor (VEGF) as a target of bevacizumab
in cancer: from the biology to the clinic. Curr Med Chem.
39. Johnson DH,
Fehrenbacher L, et al. Randomized phase II trial comparing bevacizumab plus
carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously
untreated locally advanced or metastatic non-small-cell lung cancer. J Clin
40. Herbst RS, Johnson
DH, et al. Phase I/II trial evaluating the anti-vascular endothelial growth
factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal
growth factor receptor tyrosine kinase inhibitor erlotinib for patients with
recurrent non-small-cell lung cancer. J Clin Oncol. 2005;23:2544-2555.
41. Sandler A, Gray R,
et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small cell
lung cancer. N Engl J Med. 2006;355:2542-2550.
42. Tykerb (lapatinib)
[package insert]. Research Triangle Park, NC:GlaxoSmithKline; 2007.
43. Erbitux (cetuximab)
[package insert]. Princeton, NJ: Imclone Systems Incorporated, Bristol-Myers
Squibb Co.; 2006.
44. Lilenbaum RC. The
evolving role of cetuximab in non-small call lung cancer. Clin Cancer Res
. 2006;12(14 Suppl):4432s-4435s.
45. Kelly K, Hanna N,
et al. Multicenter phase II study of cetuximab in combination with paclitaxel
and carboplatin in untreated patients with stage IV non-small cell lung
cancer. Pro Am Soc Clin Oncol. 2003;22:644.
46. Robert F,
Blumenschein, et al. Phase Ib/IIa study of anti-epidermal growth factor
receptor (EGFR) antibody, cetuximab, in combination with
gemcitabine/carboplatin in patients with advanced non-small cell lung cancer.
Pro Am Soc Clin Oncol. 2003;22:643.
47. Rosell R, Daniel C,
et al. Randomized phase II study of cetuximab in combination with cisplatin
and vinorelbine versus CV alone in the first line treatment of patients with
EGFR-expressing advanced non-small cell lung cancer. Proc Am Soc Clin Oncol
48. Rosell R. Toward
customized trastuzumab in Her-2/neu-overexpressing non-small cell lung
cancers. J Clin Oncol. 2004;22:1171-1173.
49. Tan D, Deeb G, et
al. Her-2/neu protein expression and gene alteration in stage I-IIIA non-small
cell lung cancer: a study of 140 cases using a combination of high throughput
tissue microarray, immunohistochemistry, and fluorescent in situ
hydridization. Diagn Mol Pathol. 2003;12:201-211.
(trastuzumab) [package insert]. South San Francisco, CA: Genentech Inc.; 2006.
51. Holash J, Davis S,
et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl
Acad Sci. 2002;99:11399-11404.
52. Huang J, Frischer
JS, et al. Regression of established tumors and metastases by potent vascular
endothelial growth factor blockade. Proc Natl Acad Sci.
53. AstraZeneca press
release. AstraZeneca to start phase III trials with Zactima™ (ZD6474)–a novel
targeted lung cancer treatment. Available at: www.astrazeneca.
com/pressrelease/4988.aspx. Accessed August 15, 2007.
54. Heymach JV. ZD6474:
clinical experience to date. Br J Cancer. 2005;92(Suppl 1): S14-S20.
55. Nexavar (sorafenib)
[package insert]. West Haven, CT: Onyx Pharmaceuticals, Bayer Pharmaceuticals
56. Verhoef C, de Wilt
JHW, Verheul HMW. Angiogenesis inhibitors: persepectives for medical, surgical
and radiation oncology. Curr Pharm Des. 2006;12:2623-2630.
57. Sutent (sunitinib) [package
insert]. New York, NY:Pfizer Corp.; 2006.
58. Richardson PG,
Barlogie B, et al. A phase 2 study of bortezomib in relapsed, refractory
myeloma. N Engl J Med. 2003;348:2609-2617.
59. Elliot PJ, Zollner
TM, Boehncke WH. Proteasome inhibition: a new anti-inflammatory strategy. J
Mol Med. 2003;81:235-245.
60. Hochstrasser M.
Protein degradation or regulation: Ub the judge. Cell. 1996;84:813-815.
61. Adams J, Palombella
VJ, et al. Proteasome inhibitors: a novel class of potent and effective
antitumor agents. Cancer Res. 1999;59:2615-2622.
(bortezomib) [package insert]. Cambridge, MA: Millenium Pharmaceuticals Inc.;
63. Davies AM, Lara PN,
et al. Incorporating bortezomib into the treatment of lung cancer. Clin
Cancer Res. 2007;13(15 Suppl):4647s-4651s.
64. Fanucchi M,
Fossella F et al. Randomized phase II study of bortezomib alone and bortezomib
in combination with docetaxel in previously treated advanced non-small cell
lung cancer. J Clin Oncol. 2006;24:5025-5033.
65. Davies AM, McCoy J,
et al. Bortezomib plus gemcitabine/carboplatin results in encouraging survival
in advanced non-small cell lung cancer (NSCLC): results of a phase II
Southwest Oncology Group (SWOG) trial (S0339). Proc Am Soc Clin Oncol.
66. Sandler A, Herbst
R. Combining targeted agents: blocking the epidermal growth factor and
vascular endothelial growth factor pathways. Clin Cancer Res.
To comment on this article,