Download Chemotherapy in NSCLC

Advanced NSCLC
Management
혈액 종양 내과
Prof.김시영/R3 문수영
Chemotherapy for advanced NSCLC patients
with performance status 2

The natural history of untreated, advanced NSCLC :
- a median survival of 4–5 months &
a 1-year survival rate of less than 10%
- Treatment with cisplatin or carboplatin in combination with a thirdgeneration cytotoxic such as gemcitabine, paclitaxel, docetaxel, or
vinorelbine  median survival of 8 to 11 months &
1-year survival rate of 30–45%

PS consistently - an independent prognostic parameter

1960 patients treated with cisplatin-based chemotherapy between
1981 & 1994

The median survival times : 9.4, 6.4 & 3.3 months in patients with a
PS of 0, 1 and 2, respectively

in the ECOG 1594 trial that compared four platinum combination
regimens in over 1000 patients
median survival 4.1mon. & 1 year survival rate 19% for PS 2 pt.

Randomized trials of comparative standard platinum-based
combination CTx regimens  inferior survival rates in PS 2 pt.
compared with those with PS 0 or 1

The sideeffects of treatment outweigh the benefits ?

CTx has not been recommended as a standard of care.

Gemcitabine, vinorelbine or taxane monotherapy, dose-attenuated
platinum combination regimens, & epidermal growth factor receptor
inhibitors may provide a clinical benefit with less toxicity.

Potential with cytotoxic treatment to improve the palliative
options for PS 2 patients with advanced NSCLC

Further trials designed specifically for PS 2 patients that include
measurement of symptoms, quality of life, & survival & toxicity
are required.
CLINICAL PROGNOSTIC CHARACTERISTICS

Performance status

Weight loss - Separate from performance status, an independent
predictor of decreased survival

Inflammatory response to the tumor
- Chronic inflammation implicated in the development of airway
dysplasia & lung cancer.

Ethnicity
Novel therapeutic approaches for advanced NSCLC

Conventional treatment for patients with metastatic NSCLC
- systemic chemotherapy

The benefits of chemotherapy in patients with advanced NSCLC
- reduction in symptoms, improvement in quality of life,
prolongation of survival
Chemotherapy in NSCLC

Metastatic NSCLC - a uniformly fatal disease

Treatment is palliative

Despite being considered a relatively chemotherapy-refractory disease

Some regimens (cisplatin, or non-cisplatin combinations with gemcitabine
or paclitaxel) produce objective response rates in the range of 20 to 40
percent

The response duration generally less than six months, &
median survival is disappointingly short, usually less than 10 months

the impact of chemotherapy on survival from NSCLC
is modest an objective response to therapy accompanied
by symptomatic improvement, an important palliative endpoint.

This improvement in disease-related symptoms must be balanced
against treatment-related toxicity, particularly with regimens
containing cisplatin.

The median survival of PS 2 patients treated with best supportive
care is 2–3 months

Chemotherapy regimens associated with median survivals ranging
from 4 to 6 months

These data provide encouragement to revisit the role of CTx in this
group of patients
Therapeutic approaches & the molecular
pathogenesis of lung cancer

Major components of cell signaling pathways
- protein tyrosine kinases, protein kinase C, ras/mitogen-activated
protein kinase [ras/MAPK]

Components of the normal cell cycle
- overexpression or mutation.

Tumor-associated antigens a focus for immunotherapy approaches

Angiogenesis
Treatment of NSCLC & pharmacogenomics:
where we are and where we are going

Chemotherapy NSCLC has reached a plateau, with no evidence of
substantial improvement in survival.

Performance status of 0 is the most significant prognostic factor,
though excision repair cross-complementing 1 (ERCC1) mRNA
expression is closely linked to cisplatin resistance

The economic impact of novel targeted therapies has not yet been
evaluated & their overall benefit is still meager

Activating mutations in tyrosine kinases have emerged as a
new paradigm for predicting response and outcome.

Growing evidence indicates that epidermal growth factor
receptor (EGFR) deletions & L858R mutations are
strong predictors of dramatic responses to gefitinib &
erlotinib.
the most relevant findings in lung cancer
molecular biology

The way for individualized treatment based on predictive markers
- BRCA mRNA expression
- K-ras mutations
- ERCC1 & SEMA3B single nucleotide polymorphisms
- mutations in tyrosine kinases
- acquired resistance in sensitive EGFR mutations
- erythropoietin receptor
- estrogen & progesterone receptors
- microRNAs (miRNAs)
- Wnt signaling pathway
Predictive markers for
customized chemotherapy

Between 1993 & 1999, 1436 patients with stage IV or
IIIB NSCLC with effusion were treated with platinumbased
doublets (involving either paclitaxel, docetaxel,
vinorelbine or gemcitabine)

The response rates & median survival times were 20% & 8.2 months.
One & two-year survivals were 33% and 11%, respectively

In a multivariate analysis, lower performance status
1 versus 0 was identified as one prognostic factor.

Cisplatin resistance is associated with increased expression
of the ERCC1 gene. Cancer tissues from ovarian
cancer patients whose tumors were clinically resistant
therapy showed greater levels of ERCC1 mRNA
BRCA1 levels and cisplatin resistance

BRCA1 overexpressed in the cisplatin-resistant breast cancer cell
line MCF7

BRCA1 - a component of multiple DNA repair pathways & functions
as a molecular determinant of response to a range of cytotoxic
chemotherapeutic agents.

BRCA1 abrogates the apoptotic phenotype induced by a range of
DNA-damaging agents, including cisplatin, etoposide & bleomycin,
induces dramatic responses to a range of antimicrotubule agents,
paclitaxel & vinorelbine.

BRCA1 mRNA expression closely correlates with ERCC1 mRNA
expression

BRCA1 mRNA expression predicts outcome in locally advanced
NSCLC patients treated with neoadjuvant gemcitabine plus cisplatin
followed by surgery.

Median survival has not been reached in patients with the lowest
BRCA1 mRNA levels, while survival was very poor in patients with
the highest levels.
K-ras mutations

Adjuvant vinorelbine plus cisplatin increased survival in
patients with stage II NSCLC

Adjuvant Chemotherapy , did not confer survival advantage
in patients whose tumors had ras mutations

Pooled data on K-ras mutations indicate that it is mutated in 20% of
NSCLC, mainly in adenocarcinoma & linked to poor prognosis
Single nucleotide polymorphisms in ERCC1
& SEMA3B

Single nucleotide polymorphisms (SNPs) found in nearly all human
DNA repair genes that have been investigated.

The repair genotype can be very complex in an individual, resulting
in several variant peptides between the respective repair complexes.

DNA repair function & cancer risk are significantly modulated by
additive & even multiplicative effects of various variant allele

Two common SNPs of ERCC1, codon 118 C/T & C8092A,

The codon 118 C/T SNP - associated with differential mRNA levels.
The C8092A SNP - may affect ERCC1 mRNA stability

A significant observation has been observed between C8092A SNP
& survival in cisplatin-treated NSCLC patients.

Median survival was 22.3 months for patients with the C/C genotype
versus 13.4 months for those with C/A or A/A (P ¼ 0.006)
 any copy of the A allele is associated with poor outcome

SEMA3B belongs to a large family of secreted, transmembrane
& membrane-associated semaphoring proteins characterized by a
conserved, cysteine-rich, 500 amino-acid ‘sema’ domain.

SEMA3B is located in the LUCA region of chromosome 3p21.3,
which is frequently deleted in human lung cancer.

Protein homology between the sema domain of SEMA3B &
the MET and RON oncogenes  SEMA3B can antagonize the
VEGF pathway.

An SNP has been reported at codon 415 of SEMA3B, leading to a
substitution of Thr Ile (T415I).

The variant Ile allele occurs in African-American and LatinoAmerican control subjects but not in Caucasian subjects

Possessing either the heterozygous or homozygous variant
genotype  greater than 40% reduced relative risk of lung cancer
in Latino-Americans, controlling for other lung cancer risk
factors
CELL SIGNALING PATHWAYS:
TYROSINE KINASES

the largest family of dominant oncogenes that are altered in lung

Two major types: receptor tyrosine kinases (RTKs) & nonreceptor
TKs

Tumor growth & progression depends largely upon the activity
of cell surface membrane receptors
( control the intracellular signal transduction pathways regulating
proliferation, apoptosis, angiogenesis, adhesion, & motility)

RTKs  EGFR (HER1 or erbB-1), erbB-2 ( HER-2/neu)
erbB-3 (HER-3) erbB-4 (HER-4).
Gene mutations as predictive markers for
molecular therapy

Inhibition of tyrosine kinases by selective small molecule inhibitors
emerging as a new strategy for treatment of hematologic
malignancies & solid tumors, including leukemias, gastrointestinal
stromal cell tumors & NSCLC.

The identification of somatic mutations in the tyrosine kinase domain
of the EGFR gene represents the most important molecular marker
of sensitivity to EGFR tyrosine kinase inhibitors

The EGFR is overexpressed in a variety of solid tumors, including
NSCLC
- EGFR overexpression correlates with advanced disease stage
poor prognosis in many but not all studies

The protein phosphorylation  activation of the EGFR promotes
pathways  tumor growth and progression, including cell
proliferation, inhibition of apoptosis, invasion/metastasis, and
upregulation of angiogenesis

Mutations in the EGFR observed in some tumors (eg, brain, lung,
breast, prostate &stomach cancers)  a constitutively activated TK
with a truncated ligand binding domain, whose activation is
independent of ligand binding

Several agents that block the activation of EGFR
 potential therapies for NSCLC, including small molecule TK
inhibitors, monoclonal antibodies, & antisense oligonucleotides
MicroRNAs

MiRNAs & short interfering RNAs (siRNAs)
- processed by the type III double-stranded RNase Dicer
 function in an RNA-based mechanism of gene silencing

MiRNA genes expressed as primary transcripts (pri-miRNAs)

PrimiRNAs trimmed into 70 nucleotide pre-miRNA
forms, mainly in the nucleus.

After this initial processing, the pre-miRNAs are exported to the
cytoplasm and are cleaved to generate the final products of 22
nucleotides by Dicer.

The miRNAs originally described as miR-1 to miR-33

miR-15 and miR-16 : commonly downregulated in CLL

The Caenorhabditis elegans let-7 miRNA is highly preserved
through the species, and reduced let-7 expression has been
associated with shorter survival in resected NSCLCs

Dicer expression levels were reduced in a fraction of NSCLCs,
especially in non-squamous histologies, conferring poor
prognosis in completely resected patients
Small molecule TK inhibitors

gefitinib (Iressa®) & erlotinib (Tarceva®)
approved for use in NSCLC by the FDA as salvage therapy
ISEL: no advantage for gefitinib compared
with best surpportive care in Pt
with advanced NSCLC
with one or two CTx
Subgrup analysis
: Female , Asian, never smoker
 survival advantage

The international TALENT and TRIBUTE trials assessing the effects
of erlotinib, confirmed the negative results for the combination of
chemotherapy & EGFR inhibitors.

Unlike gefitinib, however, erlotinib showed a survival advantage in
previously treated patients with NSCLC as compared with best
supportive care alone
(6.7 months compared with 4.7 months for erlotinib and placebo
respectively; P ¼ 0.001) in a large phase III randomized trial

Biological markers predictive of response for the EGFR inhibitors
gefitinib & erlotinib
- EGFR protein expression by immunohistochemistry,
- EGFR gene copy detected by fluorescence in situ hybridization
- EGFR mutation
- pAkt expression
Anti-EGFR MoAb

Monoclonal antibodies (MoAbs) bind to the extracellular domain of
EGFR.

The MoAb prevents the receptor from interacting with its ligand
EGF blocks the dimerization of receptors on the cell surface,
 block initiation of the intracellular signal transduction pathways
involved in tumorigenesis

Cetuximab, the prototype MoAb targeted against EGFR
- synergistic with CTx & small molecule TK inhibitors in human lung
cancer cell lines

In a study of 31 patients treated with cetuximab plus the combination
of paclitaxel & carboplatin
 treatment was well tolerated & a slight improvement in response
rate & median survival suggested compared to historical controls
Estrogen and progesterone receptors
in NSCLC

significant number of NSCLCs overexpress estrogen &
progesterone receptors and that crosstalk between estrogen
receptors & EGFR pathways is common

EGFR protein expression was downregulated in response to
estrogen and upregulated in response to fulvestrant (an estrogen
receptor antagonist) the EGFR pathway is activated when
estrogen is depleted in NSCLC

Clinical trials of EGFR tyrosine kinase inhibitors with aromatase
inhibitors.
Wnt signaling in NCLC

Ectopic wingless (Wnt) signaling is involved in breast
cancer stem cells

Wnt signaling is required for stem cell maintenance
emerging as a critical pathway in lung carcinogenesis.

In NSCLC, the Wnt pathway is activated upstream of b-catenin.

Overexpression of Wnt effectors such as disheveled & repression of Wnt
antagonists like Wnt inhibitory factor 1 play a crucial role

The components of the Wnt pathway have been characterized &
represent key targets for potential therapeutic agents.

Recently, overexpression of Wnt-1 observed in NSCLC cell lines
& primary cancer tissues

Blockade of Wnt signaling with siRNA or a specific monoclonal
antibody induced apoptosis in vitro.

The monoclonal anti-Wnt-1 antibody suppressed tumor
growth in vivo
Vascular endothelial growth factor (VEGF)
an endothelial-specific mitogen
& a potent angiogenic factor
- expressed in wide array of tumors
- In NSCLC, high levels of VEGF
associated with a poor prognosis
Anti VEGF monoclonal antibodies

Inhibiting VEGF : bevacizumab (Avastin®),
a recombinant humanized monoclonal antibody  binds VEGF

Phase III trial :
docetaxel + carboplatin
vs same CTx + avastin
as first-line Tx in patients
with advanced or metastatic NSCLC
adding avastin
significant improvement in survival
small-molecule
inhibitors of VEGF signalling



Interesting new oral drugs,
currently unde investigation
ZD6474, ZD2171  shows some activity against EGFR thymidine
kinase promising results
Novel vaccine

Targeting the exposed core peptide of the MUC1 tumour-associated
mucin, which is overexpressed in NSCLC

Prolonged survival for patients with stage IIIB NSCLC treated with
the vaccine & combined chemo-radiotherapy has been reported.

A large phase III randomized trial to define the role of this
new therapeutic approach is ongoing.