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

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TUMORS

Breast cancer is family of different cancers

Time

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Kaplan Meier plots allow comparison of clinical outcome over time

HER2+ Estrogen receptor +

Triple Negative

GE

NE

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TUMORS

Breast cancer is family of different cancers

Per

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20% =36,000 cases

HER 2 + Disease

Breast Cancer in the U.S.

All Breast Cancer

180,000 + cases

Amplification of the HER2 gene observed in a subset of breast

cancers

FISH -

FISH +

HER2 amplification impacts prognosis

Time (months)

% w

ith

ou

t re

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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

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

Overcoming Herceptin resistance

Her2

From Hanahan and Weinberg, 2000

Her2

HER2 is a kinase, a protein that adds phosphate to other proteins

Lapatinib is an oral inhibitor of the HER2 kinase

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

HSP90 is a chaperone for proteins like HER2

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

PI3-kinase may be an important target in breast cancer

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

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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 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

Redundant Mechanisms of DNA Repair

Base excision repairHomologous RecombinationX

Base excision repair requires PARP

Huber et al.DNA Repair 3 (2004) 1103–1108

Redundant Mechanisms of DNA Repair

Base excision repairHomologous RecombinationX

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

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

Miller KD ASCO 2005

• Patients enrolled Dec. 2001- March 2004• First interim analysis with data cut-off Feb. 2005 with 355 events

Progression Free Survival

Miller KD ASCO 2005

*Benefit the same in ER+ and ER- patients

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

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