ian krop, md-phd dana-farber cancer institute brigham and women’s hospital harvard medical school...
TRANSCRIPT
Ian Krop, MD-PhD
Dana-Farber Cancer Institute
Brigham and Women’s Hospital
Harvard Medical School
May 2009
Targeted Therapy: A Giant Step Forward
“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
HER2+ Estrogen receptor +
Triple Negative
GE
NE
S
TUMORS
Breast cancer is family of different cancers
Time
Per
cen
tag
e o
f w
om
en W
ITH
OU
T
recu
rren
ce100-
Kaplan Meier plots allow comparison of clinical outcome over time
HER2+ Estrogen receptor +
Triple Negative
GE
NE
S
TUMORS
Breast cancer is family of different cancers
Per
cen
tag
e o
f w
ome
n W
ITH
OU
T r
ecur
renc
e
HER2 gene amplification results in marked overexpression of HER2 proteins
2,000,000 HER2 proteins on cancer cell
HER2 binding domain
Herceptin (trastuzumab) is a recombinant antibody that specifically binds to the HER2 protein
By attaching to HER2, Herceptin prevents HER2 proteins from binding to each
other, leading to inhibition of signaling
Slamon, et al. NEJM 2001 (data originally presented 1998)
Herceptin given with chemotherapy improves outcome for patients with HER2+ advanced breast cancer
U.S. Adjuvant Herceptin Trials (May, 2005)
85%
67%%
Chemo+herceptin
ACT
Years From Randomization B31/N9831Romond, Perez et al, NEJM 2005
Chemo alone
Slamon, et al. NEJM 2001 (data originally presented 1998)
Herceptin given with chemotherapy improves outcome for patients with HER2+ advanced breast cancer
Lapatinib+
Capecitabine
Capecitabine alone
RANDOMIZE
Clinical trial of lapatinib for women with HER2+ metastatic breast cancer that had progressed on
Herceptin
Geyer CE et al. N Engl J Med 2006;355:2733-2743
Lapatinib improves outcome in patients with metastatic HER2+ breast cancer
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
Herceptin+
Capecitabine
Capecitabine alone
RANDOMIZE
Clinical trial of Herceptin and xeloda for women with HER2+ metastatic breast cancer that had
progressed on Herceptin
Trastuzumab Treatment Beyond Progression in Locally Advanced or MBC
Von Minckwitz, G et al, SABCS 2007 and ASCO 2008
The HER Family
Courtesy of Kenneth Bloom.
HER2 can dimerize with itself or other HER family members
Intracellular
Herceptin and pertuzumab bind to distinct epitopes on HER2 extracellular domain
Hubbard 2005
Herceptin
Pertuzumab
Trastuzumab-DM1, a novel antibody drug conjugate
DrugDrug
Herceptin
Her2
DM1
• Delivers high concentrations of drug to tumor
• Spares normal tissue from toxicity
Trastuzumab-DM1, a novel antibody drug conjugate
DrugDrug
Herceptin
Her2
DM1
• Delivers high concentrations of drug to tumor
• Spares normal tissue from toxicity
Trastuzumab-DM1, a novel antibody drug conjugate
DrugDrug
Herceptin
Her2
DM1
• 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.
• 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
Trastuzumab-DM1, a novel antibody drug conjugate
Burstein, H. J.N Engl J Med 2005;353:1652-1654
Targeting HER2+ Tumors
InhibitKinaseactivity
InhibitDimerization
Inhibitdownstream
effects
Antibodyconjugates
Moderatereceptor
expression
HER2+ Estrogen receptor +
Triple Negative
GE
NE
S
TUMORS
Breast cancer is family of different cancers
Per
cen
tag
e o
f w
ome
n W
ITH
OU
T r
ecur
renc
e
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
04-183 Preoperative Cis-Platinum in Triple Negative
Breast Cancer
Women with newly
diagnosed ER-/PR-
/HER2- breast cancer
CisPlatinum x 4 doses
SURGERY
Standard Treatment
Research Biopsy, Blood
Tissue for Research
Hereditary ovarian cancer summary
Total number of patients
No. of evaluable patients
Platinum resistant
Ongoing response
GCIG CA125 and/or RECIST
radiological response
13 11 7/11 5/11 6/11
AZD2281 – PARP inhibitor
Next Step
Women with newly
diagnosed ER-/PR-/HER2
- breast cancer
CisPlatinum/PARP
INHIBITOR x 4 doses
SURGERY
Standard Treatment
Research Biopsy, Blood
Tissue for Research
ECOG 2100: Trial Design
Miller KD ASCO 2005
• Patients enrolled Dec. 2001- March 2004• First interim analysis with data cut-off Feb. 2005 with 355 events
Cancer stem cell model of therapeutic resistance
Drugs thatkill cancer cellsbut not CSCs
CSCs regenaratetumor
Drugs that killcancer stem cells
Tumor looses itsability to generatenew cells
Tumor degenerates,patient is cured
CSCCSC
CSCCSC
CSCCSC
Tumor regresses
Tumor recurs
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
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