The Latest is the Greatest… Future Directions in the ...Background • Metastatic breast cancer...

City Wide Medical Oncology Rounds Friday Sept. 21st, 2007

Mark ClemonsHead, Breast Medical Oncology Group

Princess Margaret HospitalCampbell Family Institute for Breast Cancer Research

The Latest is the Greatest…

Future Directions in the Management of Patients with Bone Metastases from Breast Cancer

Conflict of interest• Clinical Research Protocols

– Roche (ibandronate)

• Lab studies– Amgen (denosumab), Novartis (zoledronic acid)

• Talks– AstraZeneca (zactima), Novartis (zoledronic acid),

Roche (ibandronate)

• Bone Metastases Program at PMH– Novartis (zoledronic acid)

Preventing metastasesPreserving bonemineral density

Treating bone metastases

How does bone, “health” affect my patients?

Background

• Metastatic breast cancer• Bone metastases

– incidence– consequences

• Why does breast cancer go to bone?• Are current management strategies the, “best”?• Clinical Trials• The Future

1. Ferlay J, et al. IARC Globocon 2000. Cancer Incidence, Mortality, and Prevalence.2. Coleman RE. Cancer Treat Rev. 2001;27:165-176.3. Coleman RE. Cancer. 1997;80:1588-1594.4. Zekri J et al. Int J Oncol. 2001;19:379-382.

5-year world prevalence,thousands1

Incidence of BM

in cancers2Median survival,

Months2-4

Myeloma 144 70 - 95 6 - 54Renal 480 20 - 25 12Melanoma 533 14 - 45 6Bladder 1,000 40 6 - 9Thyroid 475 60 48Lung 1,394 30 - 40 6 - 7Breast 3,860 65 - 75 19 - 25Prostate 1,555 65 - 75 12 - 53

Mor

e ly

tic

Mor

e bl

astic

Metastatic Bone Disease is Common

Bone metastases are common and important!

• Over 5,000 Canadian women will die of breast cancer this year

• Majority either presented with or subsequently developed bone metastases (BM)

• Two-thirds of patients with BM will subsequently develop skeletal related events (SRE)

What do I do for Mrs J?

• Confirm that she has metastatic breast cancer• Tell her it is incurable• Consider radiotherapy for pain in back (or US trial)• Change tamoxifen (or trial)• Start a bisphosphonate (or trial)

What do I do for Mrs J?

• She then says,

“What does the future hold for me with all these bone metastases?”

Consequences of bone metastases in breast cancer: Mortality

• Median overall survival of patients with– bone only or dominant disease: 2–3 years– pathologic fracture: 12 months– spinal cord compression: 4 months– hypercalcemia: 3 months

The Bisphosphonates

• Inhibitors of osteoclast-mediated bone resorption

• BPs plus to chemo or hormonal therapy significantly– Reduce and delay SREs

• An integral part of clinical practice of patients newly diagnosed with BM

The bisphosphonates are not a panacea!

• Still need analgesia, surgery, radiotherapy, chemo / endocrine therapy

• Even with IV BP around 50% will not have a symptomatic response

• Absolute reduction in number and rate of SREs 13%

• Even with the most “potent” BP zoledronic acid therapy 30% of patients will have SREs in the following 2 years

• Maximisation of BP benefit is needed either:– Some patients do not need a BP– BPs are ineffective in some patients– Route and schedule of administration are not optimal

Can we use bisphosphonates more effectively i.e. why is the absolute benefit so small?

• When should we START bisphosphonates?– practice guidelines: initiate BPs at diagnosis of bone

metastases

• Breast cancer trials contain highly selected patients i.e. the one size fits all model does not work!– majority bone-only disease (61–70%)

– overall 13% reduction in SREs: population with a relatively favorable prognosis

– eligibility criteria include a prognosis of >6 months survival

Percentage of patients with bone only disease

Study N Bone only disease

S&W 190 29%

Hortobagyi 1996 380 60-62%

Theriault 1999 372 66-72%

Body 2003 466 65-68%

Tripathy 2004 435 NA

Kohno 2005 228 49%

Percentage of patients with bone only diseaseStudy N Bone only disease

James 267 32%

Plunkett 859 25-35%

The incidence of fractures

- highest in pts with bone only metastases- lowest in those with co-existing liver disease.

James et al. Bone metastases from breast carcinoma: histopathological - radiological correlations and prognostic features. British Journal of Cancer (2003) 89, 660-665.

Plunkett TA, Smith P, Rubens RD. Risk of complications from bone metastases in breast cancer: implications for management. EurJ Cancer. 2000;36:476-482.

There are essentially 3 groups of patients:

Worst risk group– what ever you do they will

continue to have SREs, need new treatment strategies

Probably over treated

High risk group – who with appropriate

therapy can move to the (and hopefully stay there)

Lower risk group– where SREs are not a great issue

Correctly treated

Need to be better treated

Increased Bone Resorption is the Hallmark of Metastatic Bone Disease

0 10 20 30 40 50

0-50

50-100

>100

Prostate (n=611) Breast (n=744) Myeloma (n=318)

NTX excretion (nmol/mmol creatinine)

%

Coleman et al - J Clin Oncol 2005

Normal young women/men

Pathological

Postmenopausal women /older men

Can N-telopeptide be used to guide more effective treatment strategies for patients

with bone metastases?

• NTX is correlated with:

– Presence of bone mets– Symptoms– Response to treatment – Progression– Survival

Use of Bone Resorption Markers to Direct Zoledronic Acid Therapy - BISMARK

• 1400 patients with bone metastases from breast cancer• Bone resorption assessed every 16 weeks- Urinary NTX• Primary endpoint: Risk of skeletal events (SRE) with time • Non-inferiority design

RANDOMI SE

Bone marker (NTX) directed therapy

Q 4, 8 or 16 weeks

Zoledronic acid 4mg iv 3-4 weekly

Worst Pain Score

±1.96*Std. Err.±1.00*Std. Err.Mean

Box & Whisker Plot: Worst Pain Score

1.5

2.5

3.5

4.5

5.5

6.5

Baseline Week 1 Week 2 Week 3 Week 4 Week 8

±95%CI±1.00*Std. Err.Mean

Worst Pain Score

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

Baseline Wk 1 Wk 2 Wk 3 Wk 4 Wk 8 Wk 12

Zoledronic Acid Oral Ibandronate

*p = 0.081 and 0.028P < 0.001

±1.96*Std. Err.±1.00*Std. Err.Mean

Box & Whisker Plot: Number of Pain Sites Reported

0.6

1.0

1.4

1.8

2.2

2.6

3.0

3.4

Baseline Week 4 Week 8 Week 12

±95%CI±1.00*Std. Err.Mean

Number of Pain Sites Reported

0.8

1.4

2.0

2.6

3.2

3.8

Baseline Wk 1 Wk 2 Wk 3 Wk 4 Wk 8 Wk 12

*p = 0.037 and 0.004

Number of Pain Sites

P < 0.001

p= 0.008 *p < 0.01

Urinary NTX Levels

±1.96*Std. Err.±1.00*Std. Err.Mean

Box & Whisker Plot: Log NTX (corrected for Cr) Over Time

2.8

3.0

3.2

3.4

3.6

3.8

4.0

4.2

Baseline Week 1 Week 2 Week 3 Week 4 Week 8 Week 12

±95%CI±1.00*Std. Err.Mean

Log Urinary NTX (corrected for Cr) Over Time

2.6

2.8

3.0

3.2

3.4

3.6

3.8

4.0

4.2

Baseline Wk 1 Wk 2 Wk 3 Wk 4 Wk 8 Wk 12

Bone Biopsy Program

Activated Osteoclast

CFU-M

Pre-Fusion Osteoclast

MultinucleatedOsteoclast

RANK/RANKL PathwayMechanism of action of AMG 162 – RANKL is a critical mediator of OC differentiation, function and survival

BONEBONEOB

Growth Factors Hormones Cytokines

RANKRANKL

AMG 162

So what’s new?

AMG 162 (Denusomab)

• Fully human monoclonal

antibody to RANKL

• Opposes osteoclast

differentiation and

activation by binding to

RANK-Ligand

Breast Cancer Phase 1: Inhibition of Bone Turnover in AMG 162 vs. Pamidronate

Time (day)

0 14 28 42 56 70 840

20

40

60

80

100

120

140

160

180

200

0.1 mg/kg (n=5-7)0.3 mg/kg (n=5-7)1.0 mg/kg (n=6-7)3.0 mg/kg (n=3)pamidronate 90 mg

Urin

ary

NT x

/Cre

atin

ine

% o

f B

asel

i ne

(Mea

n ±

SD)

Peterson MC, et al. Proc. ASCO 2004

A Randomized, Double-Blind, Multicenter Study of Denosumab Compared With Zoledronic Acid

(Zometa®) in the Treatment of Bone Metastases in Subjects with

Advanced Breast Cancer (20050136)

Status:Recruiting

Purpose:The purpose of this study is to determine if denosumab is non-inferior to zoledronic acid in the treatment of bone metastases in subjects with advanced breast cancer

Phase 3

Summary

• Bone is the most common site of recurrence of breast cancer

• Presence of bone metastases and the occurrence of skeletal related events affects both morbidity and mortality

• Despite the widespread use of BPs it remains unclear– Magnitude of individual benefit?

– Which BP to use?

– Who to treat?

– When to treat?

– For how long?

• Biomarkers of bone destruction now exist and will hopefully enable improved targeting of patients in the future

So…

Is The Latest the Greatest?

Future Directions in the Management of Patients with Bone Metastases from Breast Cancer

010203040

5060708090

0 16 32 48 64 80 96 112

NTX

Weeks

26 treatmentsOver 112 weeks

1 SRE

Fixed Schedule Treatment

NTX level Bisphosphonate treatments

Durable endocrine response? Over-treated

SRE

Aromatase Inhibitor

Rob Coleman

0

20

40

60

80

100

120

140

160

0 16 32 48 64 80 96 112

NTX level

Weeks

NTX level Bisphosphonate treatments

15 treatmentsOver 112 weeks

3 SRE

Sequential response and progression

Marker Directed Treatment

SRE

Non-steroidal AI

Exemestane

Docetaxel

Rob Coleman

SREs

So…

These agents are not without side effects – that may become increasingly important if

bisphosphonates move into the adjuvant setting

Is The Latest the Greatest?

Future Directions in the Management of Patients with Bone Metastases from Breast Cancer