Transcript How clinical trials create breakthroughs in care

Targeted Therapy: A
Giant Step Forward
Ian Krop, MD-PhD
Dana-Farber Cancer Institute
Brigham and Women’s Hospital
Harvard Medical School
May 2009
“Targeted” therapy
• Drug which inhibits a protein or molecule
that is only expressed in cancer or which
only the cancer is dependent
• Offer the promise of reduced side effects
compared to less targeted drugs
Breast cancer is family of different cancers
HER2+
GENES
Triple
Negative
TUMORS
Estrogen
receptor +
Kaplan Meier plots allow comparison of clinical
outcome over time
Percentage of women WITHOUT
recurrence
100-
Time
Breast cancer is family of different cancers
Estrogen
receptor +
Percentage of women WITHOUT recurrence
HER2+
GENES
Triple
Negative
TUMORS
Breast Cancer in the U.S.
All Breast Cancer
180,000 + cases
20% =
36,000 cases
HER 2 +
Disease
Amplification of the HER2 gene
observed in a subset of breast
cancers
FISH -
FISH +
% without recurrence
HER2 amplification impacts
prognosis
Time (months)
HER2 is a cell surface signaling protein
HER2 is a cell surface signaling protein
<10,000 HER2 proteins
on normal breast cell
HER2 gene amplification results in marked
overexpression of HER2 proteins
2,000,000 HER2 proteins on cancer cell
Herceptin (trastuzumab) is a recombinant antibody that
specifically binds to the HER2 protein
HER2 binding domain
By attaching to HER2, Herceptin prevents
HER2 proteins from binding to each
other, leading to inhibition of signaling
Herceptin given with chemotherapy improves outcome
for patients with HER2+ advanced breast cancer
Slamon, et al. NEJM 2001 (data originally presented 1998)
U.S. Adjuvant Herceptin Trials (May, 2005)
Chemo+herceptin
85%
AC T
%
Chemo alone
Romond, Perez et al, Years
NEJMFrom
2005Randomization
67%
B31/N9831
Herceptin given with chemotherapy improves outcome
for patients with HER2+ advanced breast cancer
Slamon, et al. NEJM 2001 (data originally presented 1998)
Overcoming Herceptin resistance
Her2
Her2
From Hanahan and Weinberg, 2000
HER2 is a kinase, a protein that adds
phosphate to other proteins
Lapatinib is an oral inhibitor of the
HER2 kinase
Clinical trial of lapatinib for women with HER2+
metastatic breast cancer that had progressed on
Herceptin
R
A
N
D
O
M
I
Z
E
Lapatinib
+
Capecitabine
Capecitabine alone
Lapatinib improves outcome in patients
with metastatic HER2+ breast cancer
Geyer CE et al. N Engl J Med 2006;355:2733-2743
HER2 Kinase inhibitors
– Results of first study confirm role for HER2
targeted therapy after progression on
Herceptin
– Is it better than Herceptin?
– Can it add to benefit of Herceptin
– Are there particular types of tumors that are
better treated with one or the other
– Lapatinib being tested in adjuvant setting
• Additional inhibitors in development
– HKI272
– BIBW227
Clinical trial of Herceptin and xeloda for women
with HER2+ metastatic breast cancer that had
progressed on Herceptin
R
A
N
D
O
M
I
Z
E
Herceptin
+
Capecitabine
Capecitabine alone
Trastuzumab Treatment Beyond Progression
in Locally Advanced or MBC
Von Minckwitz, G et al, SABCS 2007 and ASCO 2008
The HER Family
HER2 can dimerize with itself or other HER family members
Courtesy of Kenneth Bloom.
Intracellular
Herceptin and pertuzumab bind to
distinct epitopes on HER2 extracellular domain
Pertuzumab
Herceptin
Hubbard 2005
HSP90 is a chaperone for proteins
like HER2
Trastuzumab-DM1, a novel antibody
drug conjugate
Drug
Drug
Herceptin
DM1
Her2
• Delivers high concentrations
of drug to tumor
• Spares normal tissue from
toxicity
Trastuzumab-DM1, a novel antibody
drug conjugate
Drug
Drug
Herceptin
DM1
Her2
• Delivers high concentrations
of drug to tumor
• Spares normal tissue from
toxicity
Trastuzumab-DM1, a novel antibody
drug conjugate
Drug
Drug
Herceptin
DM1
Her2
• Delivers high concentrations
of drug to tumor
• Spares normal tissue from
toxicity
HER2  A Good ADC Target
• Tumor expression >>> Normal-tissue expression
• Absolute Expression levels very high
• Internalized without down regulation
Austin et al. (2004) Mol Biol Cell 15, 5268-82.
Trastuzumab-DM1, a novel
antibody drug conjugate
• Results of early studies of TDM1
encouraging
– Response rate ≈40% in patients whose
tumors had progressed on Herceptin
– Side effects minimal (validates strategy of
antibody–drug conjugate)
• Larger trials are underway
PI3-kinase may be an important
target in breast cancer
Targeting HER2+ Tumors
Inhibit
Dimerization
Inhibit
Kinase
activity
Antibody
conjugates
Moderate
receptor
expression
Inhibit
downstream
effects
Burstein, H. J.
N Engl J Med 2005;353:1652-1654
Breast cancer is family of different cancers
Estrogen
receptor +
Percentage of women WITHOUT recurrence
HER2+
GENES
Triple
Negative
TUMORS
The link between BRCA1 associated breast
cancer and basal like cancers
• Inherited mutations in the BRCA1 gene account
for a small percentage of breast cancers
• 80% of BRCA1 associated breast cancers are
basal like (triple negative)
The link between BRCA1 associated breast
cancer and basal like cancers
• BRCA1 associated breast cancers have a
fundamental defect in DNA repair
– Evolving data suggest that spontaneous TN
breast cancers share this defect
Basal-like Tumors Show DNA
Damage Sensitivity
NATURE REVIEWS | GENETICS
VOLUME 2 | JUNE 2001 | 447
Platinum Damages DNA
04-183 Preoperative CisPlatinum in Triple Negative
Breast Cancer
Women with
newly
diagnosed
ER-/PR/HER2- breast
cancer
CisPlatinum
x 4 doses
Research
Biopsy, Blood
S
U
R
G
E
R
Y
Tissue for
Research
Standard
Treatment
Redundant Mechanisms of
DNA Repair
X
Homologous Recombination
Base excision repair
Base excision repair requires
PARP
Huber et al.
DNA Repair 3 (2004)
1103–1108
Redundant Mechanisms of
DNA Repair
X
Homologous Recombination
Base excision repair
AZD2281 – PARP inhibitor
Hereditary ovarian cancer summary
Total
number of
patients
13
No. of Platinum Ongoing GCIG CA125
evaluable resistant response
and/or
patients
RECIST
radiological
response
11
7/11
5/11
6/11
Next Step
Women with
newly
diagnosed
ER-/PR/HER2- breast
cancer
CisPlatinum/
PARP
INHIBITOR
x 4 doses
Research
Biopsy, Blood
S
U
R
G
E
R
Y
Tissue for
Research
Standard
Treatment
Cancers are dependent on new blood
vessel growth (angiogenesis)
Blocking VEGF with Avastin leads to
loss of tumor vasculature and tumor
regression
Blocking VEGF may also lead to
“normalization” of blood vessels
ECOG 2100: Trial Design
• Patients enrolled Dec. 2001- March 2004
• First interim analysis with data cut-off Feb. 2005 with 355 events
Miller KD ASCO 2005
Progression Free Survival
*Benefit the same in ER+ and ER- patients
Miller KD ASCO 2005
Cancer stem cell model of
therapeutic resistance
Drugs that kill
cancer stem cells
Tumor looses its
ability to generate
new cells
CSC
Drugs that
kill cancer cells
but not CSCs
Tumor regresses
CSC
Tumor degenerates,
patient is cured
CSCs regenarate
tumor
Tumor recurs
CSC
Novel strategies for estrogen receptor
expressing cancers
• Hormonal therapy + therapies targeting
growth factor receptors
• Avastin and other anti-angiogenic drugs
seem to work well in ER+ breast cancer
• Currently, major advance is observation
that for many women, prolonged adjuvant
therapy (>5yr) can offer additional benefit
How long does it take?
Conclusion
• The number of new drugs in development
is increasing quickly
• Targeted therapy’s promise of improved
effectiveness and decreased side effects
is being fulfilled
• If a good target is identified, the drugs will
come
• Participation in clinical trials in needed to
accelerate the pace of drug development