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Current Approaches in Metastatic Breast Cancer Edgardo Rivera, MD Chief, Breast Medical Oncology Section The Methodist Hospital/Weill Cornell University Houston, TX. 1 in 4 Deaths CANCER. Leading cause of death among women aged 40 to 79 years

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slide1

Current Approaches in Metastatic Breast CancerEdgardo Rivera, MDChief, Breast Medical Oncology SectionThe Methodist Hospital/Weill Cornell UniversityHouston, TX

slide3

Leading cause of death among women aged 40 to 79 years

  • Leading cause of death among men aged 60 to 79 years
slide4

Abnormal

GROWTH

slide7

Estimated New Cases*-------------------------------------------------------------------------------------------------------------------------------

Males Females

Ten Leading Cancer Types for the Estimated New Cancer Cases, by Sex, US, 2007

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Estimates are rounded to the nearest 10.

slide8

1,444,920

Estimated New Cancer Cases

slide9

Estimated Deaths-------------------------------------------------------------------------------------------------------------------------------

Males Females

Ten Leading Cancer Types for Estimated Deaths, by Sex, US, 2007

slide10

U.S.A.

70

1950-2001

60

Lung

Breast

50

Uterus

40

Annual cancer mortality / 100,000 women, ages 35 - 69*

Breast

30

20

Stomach

Colon & rectum

10

Uterus

Lung

Stomach

0

1950

1960

1990

1970

1980

2000

2010

EBCTCG Lancet 2005

declining u s mortality
Declining U.S. Mortality
  • Behavior Modification
  • Early detection
  • Improvements in treatment
impact of chemotherapy
Impact of Chemotherapy

Ross et al., Cancer 55:341-346, 1985

slide13

Survival after Recurrence

Giordano et al, Cancer 100:44-52, 2004

impact of new therapies
Impact of New Therapies

Giordano et al, Cancer 100:44-52, 2004

slide15

Historical Changes in Overall Survival (OS)

_______________________________________

Median OS (days)

GONOBritish Columbia Cancer Agency

(NCI, Genoa, Italy)

N =790 N = 2152

Cohort 1 (1983–86) 546 Cohort 1 (1991–92) 438

Cohort 2 (1987–89) 522 *Cohort 2 (1994–95) 450

Cohort 3 (1992–94) 584 ▼Cohort 3 (1997– 98) 564

*Cohort 4 (1995–97) 793 ■ Cohort 4 (1999–01) 667

Cohort 5 (1998–2001) 713

_______________________________________________________________

* Inclusion of paclitaxel in MCB regimen

▼Release of docetaxel and AI’s

■ Release of capecitabine and trastuzumab

Chia, SKL. Proc ASCO, #22, 2003

Gennari, A. Proc ASCO, #634, 2004

recently fda approved drugs for metastatic breast cancer
Recently FDA-Approved Drugs for Metastatic Breast Cancer
  • Paclitaxel 1994
  • Goserelin 1995
  • Anastrozole 1995
  • Toremifene 1996
  • Docetaxel 1996
  • Pamidronate 1996
  • Letrozole 1997
  • Capecitabine 1998
  • Trastuzumab 1998
  • Exemestane 1999
  • Fulvestrant 2002
  • Gemcitabine 2004
  • Abraxane 2005
  • Lapatinib 2007
slide17

Staging

The process of finding out how widespread the cancer is and whether it has spread to other parts of the body

AJCC

Stages I – IV

T-N-M

metastatic breast cancer
Metastatic Breast Cancer
  • 3 – 5% of women present with metastases at time of diagnosis
  • 5 yr survival 5 – 15%
  • Therapy targeted at metastatic disease
  • Local therapy historically reserved for palliation for those with local progression of tumor
goals of therapy in mbc
Goals of therapy in MBC
  • Palliate or delay onset of symptoms
  • Improve quality of life
  • Prolong life
  • ?? Cure
advanced breast cancer is treated based on the biology of the tumor
Advanced Breast Cancer Is TreatedBased on the Biology of the Tumor_______________________________________
characteristics of the long term disease free survivors
Characteristics of the Long-Term Disease-Free Survivors
  • Limited metastatic disease (one organ site involved)
  • Young age
  • Excellent performance status
  • Normal organ function
  • Absence of significant co-morbidity

Hortobagyi GN, et al, 1996

slide25

Selection of Chemotherapy for MBC

  • Activity
  • Prior therapy
  • Performance status
  • Co-morbidities
    • CHF, peripheral vascular disease, diabetes
  • Patient Considerations
    • Convenience vs compliance vs control
    • Toxicities affecting normal functioning • Peripheral neuropathy • Mucositis • Diarrhea
    • Patient appearance • Alopecia • IV Port
chemotherapy for mbc simultaneous or sequential the issue
Chemotherapy for MBC:Simultaneous or Sequential?The Issue
  • Patients with metastatic breast cancer receive multiple cytotoxic agents during their clinical course
  • Do combinations of two or more drugs given simultaneously give better results than each single agent given until progression and then the others given sequentially?
simultaneous vs sequential combinations advantages and disadvantages
Simultaneous

Higher response rate

Higher complete response rate

Longer time to progression

Covers multiple mechanisms of resistance

Exploits synergistic interactions

Generates more adverse events

Sequential

Avoids additive or overlapping toxic effects

Simpler scheduling

Lower response rate

Shorter time to progression

Equivalent median survival

Simultaneous vs Sequential Combinations: Advantages and Disadvantages
slide28

Arm B

Arm C

Arm A

DOX

60 mg/m2

q 3 w x 8

TAX

175 mg/m2

q 3 w

DOX

50 mg/m2 x 8

TAX

150 mg/m2

GCSF

PD

PD

PD

TAX

DOX

5 mg/kg d 3-12

E1193 Schema

Randomize

e1193 results
E1193: Results

Sledge G, et al, JCO 21:588-592, 2003

chemotherapy for mbc simultaneous or sequential conclusions
Chemotherapy for MBC:Simultaneous or Sequential?Conclusions
  • Both simultaneous and sequential administration of combinations of drugs represent a standard of care for different clinical situations.
  • Research should continue to develop more effective, potentially curative approaches for MBC
  • Simultaneous combinations based on potential synergy should be explored as new agents are developed
ixabepilone a novel antineoplastic agent
New antineoplastic class

Semisynthetic analog of epothilone B

Specifically designed to overcome tumor resistance mechanisms

MRP-1 and P-gp efflux pumps

b (III) tubulin overexpression

b tubulin mutations

Ixabepilone: A Novel Antineoplastic Agent
ixabepilone preclinical antitumor activity

Tumor response (log cell kill)

2500

250 mg/kg (MTD)

2000

10 mg/kg (MTD)

1500

Median tumor weight (mg)

1000

500

(P=0.0001)

Control

Ixabepilone

0

Combination

Capecitabine

10

30

50

Days post-tumor implant

Ixabepilone: Preclinical Antitumor Activity
  • In vitro and in vivo activity in taxane-resistant tumors1,2
  • Synergy with capecitabine in preclinical and phase I/II settings2

1. Jordan MA, et al. Proc Amer Assoc Cancer Res. 2006;47:abstr LB280. 2. Lee FY, et al. J Clin Oncol. 2006;24(18s):abstr 12017.

ixabepilone single agent activity in metastatic breast cancer
Ixabepilone Single-Agent Activity in Metastatic Breast Cancer

ORR (%)

Roché1

After adjuvant anthra

Low2

Taxane-pretreated MBC

Conte3

Taxane-resistant MBC

Thomas4

Multiresistant(anthra / tax / cape) MBC

Baselga5

Neoadjuvant T2-4, N0-3, M0

1. Roché H et al. International Union Against Cancer World Cancer Congress, 8-12 July 2006; abstr 96-3. 2. Low et al. J Clin Oncol. 2005;23:2726–2734. 3. Conte P et al. J Clin Oncol. 2006;24(18S):abstr 10505. 4. Thomas E et al. J Clin Oncol. 2006;24(18S):abstr 660. 5. Baselga J et al. Breast Cancer Res Treat. 2005;94(Suppl 1):S31:abstr 305.

phase iii study design
Phase III Study Design

N=375

Ixabepilone 40 mg/m2 IV over 3h d1 q3wk

Capecitabine 2000 mg/m2/dayPO

BIDd1-d14 q3wk

+

N=752

Stratification

  • Visceral liver/lung metastases
  • Anthracycline resistance
  • Prior chemo for MBC
  • Study site

N=377

Capecitabine 2500 mg/m2/day PO BID

d1-d14 q3wk

Vadhat et al ASCO 2007 abstract #1006

patient eligibility
Inclusion Criteria

Women ≥18 years

Locally advanced or MBC

Anthracycline-resistant or minimum cumulative dose

Taxane-resistant

KPS 70–100

Life expectancy ≥12 wk

Exclusion Criteria

>3 prior chemo regimens (metastatic)

≥G2 motor/sensory neuropathy

Reduced hematologic/renal function

≥G2 liver function tests*

No CNS metastases

Patient Eligibility

*Protocol amendment excluded patients with ≥G2 liver function tests regardless of liver metastases; 377 patients (33 with ≥G2 liver function tests) had been enrolled before amendment.

Vadhat et al ASCO 2007 abstract #1006

results progression free survival

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0

4

8

12

16

20

24

28

32

36

40

Results: Progression Free Survival

Ixabepilone + Capecitabine 5.8 mo (95% CI 5.5-7.0)

Capecitabine 4.2 mo (95% CI 3.8-4.5)

HR: 0.75 (95% CI 0.64-0.88)*

Proportion Not Progressed

P=0.0003

Months

Vadhat et al ASCO 2007 abstr 1006

*Adjusted for interim analysis.

results response rate
Results: Response Rate

Vadhat et al ASCO 2007 abstr 1006

enhanced anti tumor activity of abi 007 vs taxol in mice
Enhanced Anti-tumor Activity of ABI-007 vs Taxol in Mice

Human MX-1 Mammary Carcinoma (n = 5/group); Dose: 5  Daily

Control

nab-Paclitaxel 30 mg/kg/dose

Cremophor®-EL Paclitaxel 30 mg/kg/dose*

Tumor Volume (mm3)

Days Post-implant

*30 mg/kg/day of Cremophor®-EL paclitaxel causes 20% mortality; no death with nab paclitaxel.

Hawkins, et al.,AACR. 2003; Abstract Poster # A3

abi 007 q3w regimen in mbc
ABI-007 Q3W regimen in MBC
  • No routine premedication required
  • DLTs at 375 mg/m2: keratitis, neuropathy-sensory, stomatitis
  • MTD: 300 mg/m2
  • Bi-exponential distribution, linear PK

PHASE I

DOSE- FINDING STUDY

N=19

PHASE II

300 MG/M2 DOSE STUDY

N=63

PHASE II

175 MG/M2 DOSE STUDY

N=41

  • Overall Response Rate 40%
  • 1st Line Response 45%
  • Well Tolerated Without Steroids
  • 0% Grade ¾ Neuropathy
  • Overall Response Rate 48%
  • 1st Line Response 64%
  • Well Tolerated Without Steroids
  • 11% Grade ¾ Neuropathy

PIVOTAL PHASE III STUDY

260 MG/M2 ABI-007 DOSE VS 175MG/M2 TAXOL DOSE N=460 (3,4)

Ibrahim,et al.,Clin Cancer Res. 2002;8:1038-1044.

O’Shaughnessy, et al., SABCS. 2003; Abstract #44

phase iii trial design abi 007 versus taxol
Phase III Trial Design ABI-007 versus Taxol

ABI-007 260 mg/m2 paclitaxel

IV over 30 min q 3 wk

No Premedication

Randomization (1:1)N = 460

Taxol® 175 mg/m2 paclitaxel

IV over 3 hrs q 3 wk Standard Premedication with Dexamethasone and Anti-histamines

O'Shaughnessy, et al., SABCS 2003. Abstract #44

phase iii trial abi 007 versus taxol study objectives
Phase III Trial ABI-007 versus Taxol Study Objectives

PRIMARY ENDPOINTS:

  • Objective response rates (RR)
    • All treated patients and first line (planned analysis)
    • RECIST criteria
  • Safety and tolerability

SECONDARY ENDPOINTS:

  • Time to tumor progression (TTP)
  • Overall survival (OS)

O’Shaughnessy, et al., SABCS. 2003; Abstract #44.

phase iii overall response rates orr abi 007 vs taxol
Phase III Overall Response Rates (ORR): ABI-007 vs Taxol

*Cochran-Mantel-Haenszel test.

O’Shaughnessy, et al., SABCS. 2003; Abstract #44.

phase iii time to disease progression all patients

1.00

ABRAXANETM (n=229)

TAXOL® (n=225)

0.75

Proportion not progressed

0.50

Median = 23.0 weeks

(95% CI = 19.4 -26.1)

0.25

Median = 16.6 weeks

(95% CI = 15.1 – 20.1)

0

0

8

16

24

32

40

48

56

64

72

80

88

96

104

112

120

Week

Phase III:Time to Disease Progression (All Patients)

P=value=0.002

HR = 0.726 (95% CI 0.589 – 0.895)

O’Shaughnessy, et al., SABCS. 2003; Abstract #44.

phase iii randomized trial survival all patients

1.00

ABRAXANETM (n=229)

TAXOL® (n=225)

0.75

P = 0.322

HR = 0.899 (95% CI 0.728 –1.110)

Median = 65.0 weeks

(53.4 – 76.9)

Probability of survival

0.50

Median = 55.3 weeks

(48.0 – 66.4)

0.25

0

16

0

32

48

64

80

96

112

128

144

8

24

40

56

72

88

104

120

136

Week

Phase III Randomized Trial:Survival (All Patients)

Note: P-value from log-rank test.American BioScience, Inc., Data on file, 2005.

.

lapatinib targeting egfr and her 2
Lapatinib: Targeting EGFR and HER-2
  • Lapatinib oral tyrosine kinase inhibitor of ErbB1 and ErbB2
    • Blocks signaling through EGFR and HER-2 homodimers and heterodimers
    • May also prevent signaling between ErbB1/ErbB2 and other ErbB family members

Phospholipid cell membrane

Lapatinib

PTEN

Ras

Shc

P13K

Grb2

Raf

So8

pAkt

pErk

Rusnak DW, et al. Mol Cancer Ther. 2001;1:85-94; Xia W, et al. Oncogene. 2002;21:6255-6263.

egf100151 lapatinib capecitabine in advanced breast cancer
EGF100151: Lapatinib + Capecitabine in Advanced Breast Cancer

Lapatinib 1250 mg daily +Capecitabine 2000 mg/m2 dailyfor days 1-14, 3-week cycles(n=160)

Refractory, progressive metastatic or locally advanced HER-2+ breast cancer previously treated with anthracycline, taxane, or trastuzumab

(N=528 planned*)

Follow-up:until progressionor unacceptabletoxicity

Capecitabine 2500 mg/m2 dailyfor days 1-14, 3-week cycles(n=161)

*Study enrollment terminated early by IDMC due to superiority of combination arm in primary endpoint; Geyer CE, et al. ASCO 2006. Clinical Science Symposium.

lapatinib capecitabine vs capecitabine alone in her2 mbc
Lapatinib + Capecitabine Vs Capecitabine Alone in HER2+ MBC

* Exploratory Analysis

Cameron et al. ASCO 2007 Abstract 1035

agents targeting vegf
Agents Targeting VEGF

*Approved in RCC and GIST. **Approved in RCC

bevacizumab and paclitaxel in metastatic breast cancer
Bevacizumab and Paclitaxel in Metastatic Breast Cancer

Miller KD, et al. SABCS 2005. Abstract 3.

sunitinib
Sunitinib
  • SU11248 is an oral TKI of:
    • VEGFR
    • PDGFR
    • Kit
    • Flt-3
  • Phase II study in heavily pretreated MBC
  • 50 mg: 4 weeks on, 2 weeks off
  • Toxicity
    • 34% grade 3 NTP
    • 16% grade 2 thrombocytopenia
    • Fatigue, diarrhea, anorexia, mouth pain
    • 38% dose reduction, 53% dose interruption

Miller et al, SABCS 2005

conclusions
Conclusions
  • Understanding of breast cancer as a molecular disease is leading to novel therapies
    • Improved survival and response rate in early stage and metastatic breast cancer
  • However, newer therapies have led to newer toxicity issues that require further evaluation as well as longer follow up
slide55

ControlofDisease

QualityofLife

The Balancing Act