Transcript State of the Art in Clinical Practice Targeting the Future

New Technologies and
Challenges
Targeted Therapies in Cancer
Ian Olver MD PhD
CEO The Cancer Council Australia
Changing of the Guard
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There is a paradigm shift in the treatment
of cancer
Conventional cytotoxic drugs interact with
DNA to prevent cell replication but are not
specific to cancer cells
We are moving to targeted therapies
which specifically target cancer cells as
evidenced by the many presentations at
this meeting
Side Effects of Chemotherapy
Immediate
Early
Delayed
Late
Cardiotoxicity
Lung fibrosis
P. Neuropathy
Hepatotoxicity
Nephrotoxicity
Second Cancer
Encephalopathy
Sterility
Teratogenicity
(hours - days) (days - weeks) (weeks- months) (months - yrs)
Extravasation
Emesis
Hypersensitivity
Tumour lysis
Myelosuppression
Mucositis
Alopecia
Cystitis
Targeted therapies
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With targeted therapy the specific
mechanism of action of the drug results in
an increase in its therapeutic index
However, the advantages of the specificity
and safety of the are offset by the smaller
number of susceptible tumour types
Increasing numbers of these innovative and
expensive anti-cancer drugs may exceed the
capacity of the public purse to pay for them
The Need to Identify the
Target
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Appropriate use of newly approved and
expensive targeted therapies for cancer
first depends on the pathologist identifying
the target for treatment in the tumour
sample
Currently the two major classes of
targeted therapy are the small molecule
tyrosine kinase inhibitors (TKIs) and
monoclonal antibodies (mAbs)
Potential mechanisms of
Glivec
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Glivec may inhibit tyrosine kinases in
many tumours, but this will be effective
therapy only where tumour stem cells
depend on these enzymes for survival,
growth or metastasis
Tyrosine kinases are part of the signalling
pathways of cells which tell them to grow
PET Before and after
Glivec for GIST
7/12/00
9/1/01
STI 571 (Glivec)
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Specific inhibitor for BCR-ABL, PDGF
receptor and c-kit tyrosine kinases produced
by these genes which are responsible for
growth in CML and GIST
Effective in chronic myeloid leukaemia
Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
Side effects
– Nausea, myalgia oedema, diarrhoea,
myelosuppression, LFT’s early “storm”
Monoclonal Antibodies
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of the mAbs, rituximab
(Mabthera®) for NHL and
trastuzumab (Herceptin®) for
breast cancer depend on the
targets CD20 expression and
erbB2 gene being amplified
and responsible for growth
Rituximab
Mabthera
Mabthera is an Anti-CD20
monoclonal antibody for
lymphoma
 CD20 is a protein on the surface
of malignant lymphoma cells
 CD20 expressed on 90% of B-cells
in lymphoma
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Mabthera
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Side effects include:
– Infusion related fever, chills rigors
– N + V, urticaria, pruritis, headache,
fatigue, bronchospasm, hypersensitivity
– Rare heart rhythm disturbance
– Low blood counts for up to 30 days
HER2
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HER2 gene (neu, c-erb-2) ecodes a
transmembrane gycoprotein receptor
HER 2 is over expressed by 1/4 human
breast cancer and correlates with poorer
outcome
MoAb against the receptor inhibits the
growth of overexpressing cells
HER 2
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As a single agent 15% chance of
shrinking metastatic breast cancer,
4% chance of a complete shrinkage in
heavily pretreated patients
Duration of response can be 9 months
which is at least as good as single
chemotherapy agents
Can combine with chemotherapy
Disease-Free Survival
Romond H et al. Trastuzumab plus Adjuvant Chemotherapy for
Operable HER2-Positive Breast Cancer NEJM 2005; 353:1673-1684
ACTH
87
ACT
%
%
85%
75%
67%
N Events
ACT 1679 261
ACTH 1672 134 HR=0.48,
2P=3x10-12
Years From Randomization
B31/N9831
The Paradigm Shift
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The use of these drugs is giving
clinicians a glimmer of the paradigm
shift that will occur in the treatment of
cancer
One or several new targeted therapies
offer the prospect of cancer being
treated as a chronic disease.
Brain Tumours
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The optimal use of temozolomide
chemotherapy for the treatment of
primary brain tumours may depend on
knowing the DNA repair enzyme status of
the tumour
Hegi ME et al. MGMT gene silencing and benefit from temozolomide
in glioblastoma. New Engl J Med 2005; 352:997-1003
Dramatic response in female,
non-smoking patient with
Broncho-Alveolar Carcinoma
Courtesy Dr T. Lynch, MGH
Patient demographic factors
associated with outcome in Gefitinib
Phase II studies
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Gender
– Females ORR 25% (CI 19-33%)
– Males ORR 8% (CI 5-12%)
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Ethnicity
– Japanese ORR 27% (CI 19-37%)
– Caucasian ORR 11% (CI 6-19%)
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Smoking history
– Non-smokers ORR 31% (CI 23-40%)
– Smokers ORR 8% (CI 5-12%)
Patient demographic factors
associated with outcome in
Gefitinib Phase II studies
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Histology
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Adenocarcinoma
Squamous
Undifferentiated
Mixed
Large cell
Unrecorded
n=275
n=75
n=35
n=26
n=11
n=3
ORR 19%
ORR 7%
ORR 3%
ORR 4%
ORR 9%
ORR 0%
EGFR Mutations and
Response
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Lynch TJ et al New Engl J Med 350, May 20 2004
Hypothesis was that a mutation of EGFR
accounts for the response of some patients
with NSCLC to gefitinib
They sequenced the entire coding region of
EGFR in tumors from patients with a
response to gefitinib and in tumors from
those without a response
Use of Molecular Methods
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Increase diagnostic accuracy and thereby
improve prognostication
Identify clinically distinct patient subsets to
facilitate rational clinical trial design
Help to optimize current treatments by
increasing their specificity and improving their
safety
Identify signaling pathways that define cancer
vulnerabilities and thus create drug targets
Brown M, Buckley M, Rudzki B, Olver I. How can we turn cancer into
a chronic disease that we can afford to treat? J Intern Med 2006 in
press
Practical Uses of Molecular
Pathology and Targeting
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The decision to treat metastatic breast cancer
depends on the state of the disease
The need for additional treatment after surgery
relies on predicting its behavior, which still relies on
anatomic staging
– Tumor size
– Nodal status
These are prognostic but not predictive of
treatment outcome
However hormone status and HER2 status have
been shown to be both prognostic and predictive
and we have had targeted hormonal therapy for
decades
Molecular Classification
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With technology that can rapidly
measure multiple gene expression
profiles it has been found that:
– They correlate with microscopic observed
difference e.g. one pattern of genes
correlates with grade (Perou CM et al
Nature, 2000, 406: letter 749-52, 2000)
– They differ across tumors defined by
hormone and HER2 status
– Breast Cancer can be subtyped
Sorlie T et al Proc Natl
Acad Sci U S A. 2001,
98:10869–10874.
85 samples gene
expression patterns
analyzed by
hierarchical clustering.
Green is normal breast,
red is the basal poor
prognosis group
Can use to predict
prognosis and
outcome of therapy
and can target the
therapy
Conclusions
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Targeted therapies which improve
the therapeutic index are the future
of anti-cancer therapy
Advances in molecular pathology will
provide the means to identify the
targets and will be used to subtype
tumours and will provide predict
response to therapy and provide
prognostic information