New treatment options in lung cancer

download report

Transcript New treatment options in lung cancer

New treatment options for
lung cancer
• Lung cancer is a
•
•
•
leading cause of
death world wide
90% of lung cancer is
caused by smoking
20% of patients are
suitable for surgery
5% of all cases have
5 year survival
• Most of the patients are in
•
•
advanced stages and have very
poor prognosis
Only 20% of patients are
operable and only 5% of all
cases survive 5 years
In general, patients with
untreated lung cancer survive 8
months
• Lung cancer is classified
•
•
•
•
•
based on TNM system
Tumor, Node, Metastasis)
The most common
among lung cancers is
non-small cell lung
carcinoma (NSCLC)
Diagnosis by history and
x-ray
Spiral CT screening
Surgery is a treatment of
choice. (Chemotherapy,
radiation)
Cure is rare
New treatment options
•
•
To survive and replicate cancer cells have very complex molecular
pathways. Many epithelial tumors have abnormally activated epidermal
growth factor (EGF). Several mechanisms lead to the activation of
epidermal growth factor receptor (EGFR). This activation promotes series
of reactions.
Two classes of EGFR anti-cancer agents:
1. Erlotinib
2. Cetuximab
Erlotinib (Tarceva)
Erlotinib (Tarceva)
• Erlotinib is an anti – EGFR tyrosine kinase inhibitor. This drug has
been approved for treatment of the patients with locally advanced
or metastatic non – small cell lung cancer after failure at least one
prior chemotherapy regimen. It was approved in U.S. in November
2004.
• Erlotinib is the only EGFR TKI therapy that have shown to improve
the survival for NSCLC patients (6.7 months vs. 4.7 months for
erlotinib and placebo respectively)
• Erlotinib has proved to be safe for patients. Only 5% of patients had
to discontinue treatment because of toxicity.
Erlotinib (Tarceva)
• Some groups of patients may
benefit more from this drug.
They are: female patients,
nonsmokers, patients of Asian
decent, and patients with
adenocarcinoma.
• The most recent research of
2006 made a discovery of
EGFR mutations in tumor cells.
This mutant EGFR is required
for tumor maintenance.
Surprisingly, Erlotinib was
found to be more efficacious in
mutant EGFR (Mendelsohn,
2006)
Iressa (Gefitinib)
• Iressa (Gefitinib) is very similar to Erlotinib. It was the first
selective EGFR inhibitori. Iressa reseived accelerated approval
based on the data from phase II study. However, Iressa failed to
improve a survival advantage in confirmatory trials requested by
FDA.
• Some scientists have speculated that Iressa and Tarceva had
different interactions depending on the type of mutations in EGF
receptors in human lung cancer. There are at least twenty
different mutations in EGFR and scientists do not know if the
same drug has the same effect for every mutation.
• Another issue that has been discussed by research community
was the use of different doses, suggesting that higher dose of
Iressa was still probably effective (Twombly, 2006).
Cetuximab
• The second class of EGFR
•
agents is represented by
Cetuximab.
It is a MONOCLONAL
ANTIBODY that binds to
EGFR and inhibits
intracellular
phosphorylation of EGFR
and its signaling
pathways.
• Cetuximab is less
potent than
Erlotinib/Gefinib, it
has its definite
advantages.
Cetuximab
demonstrated to be
effective on Gefitinib
resistant mutant
EGFR
Bevasizumab
Bevasizumab
Angiogenesis is one of the hallmarks
of tumor formation. Majority of
NSCLC tumors express vascular
endothelial growth factor (VEGF).
Studies proved that the higher
expression of VEGF correlate
with poor prognosis for lung
cancer patients (Herbst, 2006).
Bevasizumab is a recombinant
humanized monoclonal antibody
against VEGF

Molecular pathways involved
in stimulation and
proliferation of cancer cells
are involved in multiple
levels. If one molecular
target is blocked by anticancer agent, the others can
be an escape routes for
cancer cell stimulators.

This concept brought the
next step in exploring
possibilities of anti-cancer
research. Combining drugs
that affect different pathways
can have additional clinical
benefits (Sandler, 2006)
Combined therapy

Based on this concept, some investigators have
speculated that the use of EGFR TKI with new
agiogenesis inhibitors can be more efficacious.
Preliminary data has shown no pharmacokinetic
interaction between Erlotinib and Bevasizumab. The
median overall survival for the treated patients was 12.6
months vs. 4 months for control group, with
progression free survival of 6.2 months vs. 2.5 months
for untreated controls.
Statins


Lovastatin is inhibitor of 3-NMG CoA
reductase. It leads to the inhibition
of EGF-induced EGFR
autophosphorylation and its
signaling cascade within 24 hours.
Studies of combining Lovastatin and
Erlotinib showed inhanced inhibition
and cytotoxisity in a variety of cell
lines. However, combinig Lovastatin
and Erlotinib is contraindicated
because of high risk of toxicity (both
drugs are metabolized by CYP3A4).
Rosuvastatin + Erlotinib

New possible alternative is mevolanate
pathway inhibitor Rosuvastatin. The
studies of combining Erlotinib and
Rosuvastatin are proposed for a phase
I/II in advanced non-small cell lung
cancer.
COX-2 inhibitors
• Lung tumors induce very immunosuppressive
microenvironment. This may explain a very high
unresponsiveness to immunological-based
therapies. To enhance immunotherapy the use
of COX-2 inhibitors was suggested. Although this
mechanism is poorly understood, it has shown
some effect on improvement in immunotherapy.
Blocking arginase I through careful use of COX-2
inhibitors promoted better outcomes of
immunotherapy of lung cancer (Rodriguez,
2006).
Lung cancer blood test
• A team of University of Kentucky
•
•
Chandler Medical Center
researchers has been working on
developing the blood test to
detect lung cancer in early stages.
The blood test identifies body’s
own immune response to tumors.
This test is 90 % accurate and
diagnostic for lung cancer at early
stages in the patients with high
risk factors such as smoking,
family history and age. This test
can correctly predict NSCLC years
before CT scan can detect it.
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
References
Auberger J, Loeffler-Ragg J, Wurzer W, Hibe W. Targeted therapies in non-small cell lung cancer: proven concepts and unfulled promises. Curr Cancer
Drug Targtes. 2006 Jun 6(4):271-94.
Bandyopadhyay A, Agyin JK, Wang L, Tang Y, Lei X, Story BM, et al. Inhibition of pulmonary and skeletal metatstasis by a transforming growth factorbeta type I receptor kinase inhibitor. Cancer Res. 2006 Jul 1;66(13)6714-21.
Belvedere O, Grossi F. Lung cancer highlits from Asco 2005. Oncologist. 2006 Jan;11(1):39-50.
Bezjak A, Tu D, Seymour L, Clark G, Trajkovic A,Zukin M, et al. Symptom improvement in lung cancer patients treated with erlotinib: quality of life
analysisnof the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol. 2006 Aug 20;24(24):3831-7.
Blackhall F, Ranson M, Thatcher N. Where next for gefitinib in patients with lung cancer? Lancet Oncol. 2006 Jun;7(6):499-507.
Comis RS. The current situation: Erlotinib (Tarceva) and Gefitinib (Iressa) in non-small cell lung cancer. Oncologist. 2006 2005;10:467-470.
Dalwadi H, Krysan K, Heuze-Vourch N, Dohadwala M, Elashaff D, Sharma S, Casalano N, Lichenstein A, Dubinett S. Cyclogenase-2-dependent activation
of signal transducer and activator of transcription 3 by interleukin-6 in non-small cell lung cancer. Clin. Cancer. Res. 2005 Nov 1; 11 (21): 7674-82.
Dimitroulakos J, Lorimer IA, Goss G. Strategies to enhance epidermal growth factor inhibition: targeting the mevalonate pathway. Clin. Cancer. Res.
2006 Jul 15;12(14 Pt 2):4426s-4413s.
Dy GK, Adjei AA. Angiogenesis inhibitors in lung cancer: a promice fulfilled. Clin Lung Cancer.2006 May;7 Suppl 4:S 145-9.
Fang LC, Komaki R, Allen P, Guerrero T, Mohan R, Cox JD. Comparison of outcomes for patients with medically inoperable Stage I non-small-cell lung
cancer treated with two dimensional vs. three dimensional radiotherapy. Int J Radiat Oncol Biol Phys. 2006 Sep 1;66(1):108-16.
Heymach JV, Nilsson M, Blumenschein G, Papadimitrakopoulou V, Herbst R. Epidermal growth factor receptor inhibitors in development for the
treatment of non-small cell lung cancer. Clin Cancer Res. 2006 Jul 15;12(14 Pt 2):4441s-4445s.
Ji H, Zhao X, Yuza Y, Shimamura T, Li D, Protopopov A, et al. Epidermal growth factor receptor variant III mutations in lung tumorigenesis and
sensitivity to tyrosine kinase inhibitors. Proc Natl Acad Sci USA. 2006 May 16;103(20):7817-22.
Johnson BE, Janne PA. Rationale for a phase II trial of Pertuzamub, a HER-2 dimerization inhibitor, in patients with non-small cell lung cancer. Clin
Cancer Res. 2006 Jul 15;12(14 Pt 2):4436s-4440s.
Kris MG. How taday’s developments in the treatment of non-smalllung cancer will change tomorrow’s standards of care. Oncologist. 2005 Oct;10 Suppl
2:23-9.
Maione P, Gridelli C, Troiani T, Ciardiello F. Combining targeted therapies and drugs with multiple targets in the treatment of NSCLC. Oncologist. 2006
Mar;11(3):274-84.
Mendelsohn J, Baselga J. Epidermal growth factor receptor targeting in cancer. Semin Oncol. 2006 Aug;33(4):369-85.
Politi K, Zakowski MF, Fan PD, Schonfeld EA, Pao W, Varmus HF. Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung
cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev. 2006 Jun 1;20(11):1496-510
Potti A, Mukherjee S, Petersen R, Dressman HK, Bild A, Koontz J, et al. A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer.
N Engl J Med. 2006 Aug 10;355(6):570-60.
Sandler A, Herbst R. Combining targeted agents: blocking the epidermal growth factor and vascular endothelial growth factor pathways. Clin Cancer
Res. 2006 Jul 15:12(14Pt 2):4421s-4425s.
Swanton C, Futreal A, Eisen T. Her2-targeted therapies in non-small cell lung cancer. Clin Cancer Res. 2006 Jul 15;12 (14 Pt2):4733s-4383s.
Twombly R.Failing survival advantage in crucial trial, future of Iressa is in jeopardy. J Nat Cancer Institute. 2005 Feb 16(97):249-250.
Zhong L, Coe S, Stromberg A, Khattar N, Jett J, Hirschowitz E. Profiling tumor-associated antibodies for early detection of non-small cell lung cancer.
Journal of Thoracic Oncology. 2006 July 1 (16): 513-519.