most drugs will work really well for only a few people in many cancers

Report
Approaching Personalized Oncology
as a Clinician and Researcher
Where are we now, and how can we
take it further?
Andrew Poklepovic MD
Massey Cancer Center
Hematology, Oncology, and Palliative Care
Associate Member
Developmental Therapeutics Program
Personalized Cancer Care
Goals and Definitions
• Individualized care for each patient
• Treatments prescribed based upon the unique nature
of that person’s cancer
– with the goal to maximize response, improve survival, and
improve the ability to cure
• Avoiding treatments that are likely to be ineffective
• Adjusting doses of medications to accommodate each
person’s own metabolism
The origins of personalized care
•
Breast Cancer
•
Estrogen Receptor (ER) /Progesterone Receptor (PR)
– ~80% of breast cancers
– Tamoxifen FDA approved in 1977 following studies showing benefits in advanced disease, but
not until over a decade later did the idea that ER was associated with response was confirmed.
– Anastrozole (Arimidex) Letrozole (Femara) Exemestane (Aromasin) Fulvestrant (Faslodex)
•
HER2 – Genetic amplification (more copies of the gene than there should be) in
15-20% of breast cancers.
– Trastuzumab (Herceptin) –
•
•
Approved 1998 for stage IV breast cancer, the first antibody specifically targeting a cancer related
protein
Approved in 2006 for adjuvant treatment of breast cancer with the intent for improving cure rates
– Lapatinib (Tykerb) – 2007 stage IV breast cancer
– Pertuzumab (Perjeta) 2012 stage IV breast cancer- seeking FDA approval 10-2013 for adjuvant
– Trastuzumab-emtansine (Kadcyla) 2013 stage IV breast cancer
•
Triple Negative: ER, PR, and HER2 negative.
– No targeted therapy identified to date.
Breast Cancer
• Oncotype DX
• Or…Do I need Chemo?
• FDA approved genomic
test for early stage ER+
breast cancer.
• Additional studies to
determine its role in
lymph node positive
(more advanced) disease
Taking it further than ER/PR/HER2 or
Oncotype
• Complete Gene Sequencing of 510 breast tumors – over 30,000 mutations found
• 4 major sub-classes of breast cancer, with variability within each sub-class.
Lung cancer
• SCLC v. NSCLC
• EGFR Mutation
– EGFR aka HER1 – the first “kinase” discovered, 1978
– Its activated role in mutations was identified much later.
• ALK/EML4 Fusion Mutation
– First identified in 2007 in a single patient in Japan, now known
to affect ~5% of all lung cancer patients (70,000 worldwide)
• Others being identified
EGFR
•
•
•
•
Epidermal
Growth
Factor
Receptor
• When mutated, sends a
continuous signal into the
cell. The cancer cell may
be dependent on this
broken signal for cell
survival
Targeting the mutant EGFR with
erlotinib
• Erlotinib superior to
chemotherapy in EGFR
mutated lung cancer
= chemotherapy
= EGFR targeted therapy
Garassino et al. Lancet 2013
Zhou et al. Lancet 2011
• Chemotherapy
superior to erlotinib in
EGFR non-mutated
(wildtype) cancer.
Open Access At: http://cancergrace.org/lung/2010/10/10/overview-ofmolecular-markers-in-lung-cancer/
Targeted ALK therapy is better than
chemotherapy
Shaw et al. NEJM 2013
Lung Cancer Mutational Landscape
The KIT example
• Kit is another protein that, when mutated,
leads to uncontrolled cancer growth (similar
concept to EGFR).
– Kit mutated cancers are generally not responsive
to chemotherapy.
– Multiple newer “targeted therapies” can inhibit
mutated Kit.
Kit mutations common in rare cancer
Gastrointestinal Stromal Tumor (GIST)
80
60
Pre-Imatinib Era
40
Imatinib
Kit Exon 11 (imatinib)
20
Kit Exon 9 (imatinib)
0
Median OS (months)
Median OS (months)
Imatinib is the standard of care for advanced, unresectable or metastatic GIST.
It has improved median overall survival from 18 to 57 months, vastly changing
the outlook for patients with this disease.
Targeted therapy with a logical biologic target changed the course of this disease.
Poklepovic et al, Gastrointenstinal stromal tumor: imatinib and beyond. InTech 2012 open access
• Targeting KIT requires
understanding what
drug fits in the pocket
to turn it off.
The KIT protein
Imatinib
KIT in other cancers
• GIST – 85-90% of a rare disease
• Melanoma 5%
– up to 35% of mucosal melanoma, a rare subtype of
melanoma
• Rare with unclear frequencies
– Acute Myelogenous Leukemia
– Clear cell sarcoma
– Seminoma
Patient Example
• Mucosal melanoma patient
– Multiple sites of disease in the mouth and throat.
– Surgically removed, but likely residual disease
• KIT exon 11 mutation positive.
– Same as dominant mutation in the GIST group.
KIT exon 11 mutated melanoma
• Clinical trial evidence of
significant effect in a
melanoma patient when
targeting known KIT mutation
with a drug with activity
against that specific mutation.
• Unable to get insurance
coverage for imatinib because
drug was not FDA approved
for melanoma.
• Despite peer to peer.
• Only option was a research
trial, at least 5 states away.
JCO 2011
Other cancers with similar problems
• BRAF mutation = 40-50% melanoma
• BRAF mutation – <1-3% of lung cancer
• BRAF mutation – never previously reported in
case of small cell neuroendocrine carcinoma of
the intestine- an already exceedingly rare tumor.
• BRAF mutation – present in GIST in very low
frequencies of non KIT mutated cancer (1-2%)
How do you design the trial?
• In unselected patients
(not chosen based upon
EGFR status), therapy
against the EGFR was
no better than a sugar
pill.
– This trial led the FDA to
revoke approval for this
agent in the US in 2005.
How do you design the trial?
• Be wary of trying to hit a home run in a big ballpark. Low frequency
events will be lost in the noise of the high frequency events.
• Development of companion biomarkers or targets is easier in concept
than in practice.
How are we trying to do this?
•
Only 30% of GBM has the PDGFR
•
Our trial will test first in all GBM, if no
positive result, shrink the ballpark
and only include PDGFR+ GBM
*
*
60
*
*
40
VEH
PDGFR +
PDGFR -
VAL (1)
VEH
SOR 1
SOR 2
SOR 3
SOR 6
SOR 1
SOR 2
SOR 3
SOR 6
VEH
VEH
0
VEH
20
SOR 1
SOR 2
SOR 3
SOR 6
In the lab, the presence of PDGFR
was associated with the greatest
tumor cell kill
GBM5, 48h
GBM5, 24h
VEH
•
MCC 14816 looks at triple therapy in
patients who have progressed on
primary treatment.
Figure 3
80
SOR 1
SOR 2
SOR 3
SOR 6
•
In Glioblastoma (GBM) a rare and
deadly brain tumor, there are very
few treatment options.
Percentage cell death
•
VAL (1)
Diagnostic tests may identify if a
treatment is effective early on.
•
On MCC-13874, the preclinical
science suggests that the
combination of pemetrexed &
sorafenib causes a new type of
cancer cell death, toxic autophagy.
– This trial is in the stages of becoming a
collaborative effort with University of
Virginia
•
We are using circulating tumor cell
technology (capturing cancer cells
from the blood of cancer patients
with a regular blood draw) to test
early on if the combination of drugs
causes toxic autophagy.
•
This may help doctors one day know
early on if the drugs they administer
are working the way they should be,
and can help tailor patient
treatments
How do you help?
• Support the funding for development of, and
ultimately reimbursement of, genetic testing of
patient tumors.
– Supporting the tests that will find the targets the
drugs can be used on, or developed for.
– Build a repository of tumor information, to find the
rare events that can generate new treatment ideas.
• Also identify gene signatures in patients in which a
treatment was remarkably successful, to generate new
ideas.
How do you help?
• Support the idea that there are scientific reasons for using drugs in
personalized cancer care. Not every drug will work for everybody,
and it may be that most drugs will work really well for only a few
people in many cancers.
•
Insurance coverage should support logical use of known targeted
drugs against the mutations they are active on, once at least some
efficacy is shown.
– The cost is generally not substantially different from an approved
standard therapy.
– FDA approval combining a mutation requirement (melanoma with
BRAF mutation to get vemurafenib) but also histology (melanoma, not
small cell cancer), can make it hard to get therapy for individual
patients with rare diseases or low frequency mutations.
• It can be traumatic for a patient to know that they have a rare disease, with a
druggable target, but no ready access to the drug.
Thank You
Please help to continue the fight,
you have been doing.
It makes a difference, every day.
as

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