harold j burstein md phd dana farber cancer institute harvard medical school boston ma
Download
Skip this Video
Download Presentation
Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

Loading in 2 Seconds...

play fullscreen
1 / 58

Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA - PowerPoint PPT Presentation


  • 59 Views
  • Uploaded on

Strategic use of available agents through multiple lines of therapy for advanced ER/PR-negative disease: A discussion of 9 Things to Know About Metastatic Breast Cancer Beyond 1 st Line Chemotherapy. Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA' - africa


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
harold j burstein md phd dana farber cancer institute harvard medical school boston ma
Strategic use of available agents through multiple lines of therapy for advanced ER/PR-negative disease:A discussion of 9 Things to Know About Metastatic Breast Cancer Beyond 1st Line Chemotherapy

Harold J. Burstein, MD, PhD

Dana-Farber Cancer Institute

Harvard Medical School

Boston, MA

slide4
Approximately how many total lines of chemotherapy were received by the last 5 patients you treated who died of metastatic breast cancer (average of the 5 patients)?

NLove, Research to Practice, 2008

slide5
Duration of Chemotherapy for Advanced Breast Cancer

45

Overall

40

ER+

HER2+

35

TN

30

25

Average Weeks on Treatment

20

15

10

5

0

1st

2nd

3rd

4th

5th

6th

7th

Burstein, Litsas 2010

Unpublished data

Line of Therapy

slide6
Duration of Chemotherapy for Advanced Breast Cancer

45

Overall

40

ER+

HER2+

35

TN

30

25

Average Weeks on Treatment

Median # of regimens: 4

20

15

10

5

0

1st

2nd

3rd

4th

5th

6th

7th

Burstein, Litsas 2010

Unpublished data

Line of Therapy

slide7

2. Tumor biology / tumor subset governs outcomes –Triple negative tumors stand out as having a different trajectory

slide8
Duration of Chemotherapy for Advanced Breast Cancer

45

Overall

40

ER+

HER2+

35

TN

30

25

Average Weeks on Treatment

Median # of regimens: 4

20

15

10

5

0

1st

2nd

3rd

4th

5th

6th

7th

Burstein, Litsas 2010

Unpublished data

Line of Therapy

slide9
Duration of Chemotherapy for Advanced Breast Cancer

45

Overall

40

ER+

HER2+

35

TN

30

25

Average Weeks on Treatment

20

15

10

5

0

1st

2nd

3rd

4th

5th

6th

7th

Burstein, Litsas 2010

Unpublished data

Line of Therapy

gem carbo bsi 201 in triple negative metastatic breast cancer
Gem/Carbo +/- BSI-201 in Triple Negative Metastatic Breast Cancer

Gemcitabine 1000 mg/m2 d 1,8

Carbo AUC 2 d 1,8

MBC

Triple Negative

Prior Chemo

N=120

CYCLES EVERY 21 DAYS

Gemcitabine 1000 mg/m2 d 1,8

Carbo AUC 2 d 1,8

BSI-201 5.6 mg/kg d 1,4,8, 11

RESTAGE EVERY 2 CYCLES

O’Shaugnessy et al, ASC0 2009

slide13
Chemotherapy+/- iniparib for triple-negative breast cancer: phase II

O'Shaughnessy J et al. N Engl J Med 2011;364:205-214

schema
Schema

Study Design: Multi-center, randomized open-label Phase III Trial

N = 519

Gem/Carbo (GC)

(N= 258)

Gemcitabine 1000 mg/m2 IV d 1, 8

Carboplatin AUC2 IV d 1, 8

21-day cycles

Crossover allowed

to GCI following

Disease Progression*

(central review)

  • Study Population:
  • Stage IV TNBC
  • ECOG PS 0–1
  • Stable CNS metastases allowed
  • 0-2 prior chemotherapies for mTNBC
  • Randomization stratified by prior chemo in the metastatic setting:
    • 1st-line (no prior therapy)
    • 2nd/3rd-line (1-2 prior therapies)

R

Gem/Carbo + Iniparib (GCI)

(N= 261)

Gemcitabine - 1000 mg/m2 IV d 1, 8

Carboplatin - AUC2 IV d 1, 8Iniparib - 5.6 mg/kg IV d 1,4,8,11

21-day cycles

*Prospective central radiology review of progression required prior to crossover

96% (n=152) of progressing patients crossed over to GCI at time of primary analysis

NCT00938652

efficacy endpoints itt population
Efficacy Endpoints – ITT population

1.0

1.0

0.9

0.9

0.8

0.8

Pre-specified alpha = 0.01

Pre-specified alpha = 0.04

0.7

0.7

0.6

0.6

0.5

Probability of Survival

0.5

Probability of Progression Free Survival

0.4

0.4

0.3

0.3

0.2

0.2

0.1

0.1

0

0

0

2

4

6

8

10

12

14

16

0

2

4

6

8

10

12

14

16

Months

Months Since Study Entry

overall response rate itt population
Overall Response Rate* – ITT Population

* Independent central review, RECIST 1.1 + confirmation of response

17

what s going on
What’s going on?
  • Not all exploratory studies stand up to validation in larger experience
  • Iniparib probably is NOT a PARP inhibitor
what s going on1
What’s going on?
  • Not all exploratory studies stand up to validation in larger experience
  • Iniparib probably is NOT a PARP inhibitor

That is to say, inadequate preliminary science

goals of chemotherapy for advanced breast cancer
Goals of Chemotherapy for Advanced Breast Cancer
  • Relieve symptoms associated with advanced cancer, such as pain, fatigue, or dyspnea
  • Prevent symptomatic progression of tumor
  • Prolong survival
  • Enhance quality of life
  • To make advanced breast cancer a “chronic” condition
does chemotherapy palliate refractory breast cancer
Does Chemotherapy Palliate Refractory Breast Cancer?
  • 3rd line chemotherapy:
    • 30% had improvement in emotional status
    • 34% had major improvement in HRQL scores
    • 6% had objective clinical response
  • Tumor response correlated with more energy, diminished distress, and functional improvement
  • Not all “benefit” was seen in responders, and not all “responders” benefit

McLachlan SA, Pintilie M, Tannock IF. Breast Cancer Res Treatment 1999;54:213

slide23
Cumulative Incidence of Adverse Symptom Events over Time as Reported by Patients versus Clinicians at Successive Office Visits.

Clinical teams under-report

symptoms relative to patients

Survey of consecutive office

visits among 467 cancer patients

at MSKCC

Basch E. N Engl J Med

2010;362:865-869.

trade offs
Trade-offs
  • Cancer-related symptoms
  • Benefits of chemotherapy
  • Side effects of chemotherapy, especially chronic side effects (fatigue, neuropathy, GI discomfort)
  • The tyranny of the infusion room
  • The hope that comes with doing something
slide25

5. There are a lot of choices once you get beyond 1st or 2nd line,but there really aren’t much data

overview mechanism of action of microtubule targeting drugs
Overview: Mechanism of action of microtubule-targeting drugs

Vinca alkaloids / eribulin

Taxanes / epothilones

Destabilizers

Stabilizers

 Polymerization

 Polymerization

ixabepilone epothilone b analog
Ixabepilone: Epothilone B Analog
  • Furthest developed agent in a new class of antineoplastics, the epothilones
  • Epothilones bind to microtubules resulting in polymerization and apoptosis
  • Novel microtubule-stabilizing agent with tubulin-binding mode distinct from other agents

S.cellulosum

Epothilone B

Ixabepilone

Lee JJ, Swain SM. Semin Oncol. 2005;32(suppl 7):S22-S26; Kamath K et al. J Biol Chem. 2005;280:12902-12907; Mozzetti S et al. Clin Cancer Res. 2005;11:298-305.

ixabepilone in mbc summary of single agent phase ii trials
Ixabepilone in MBC: Summary of Single-Agent Phase II Trials

100

90

83

77

80

70

26

57

60

53

35

SD

Percentage (%)

50

RR

40

35

41

30

57

42

20

22

10

12

N=65

N=23

N=37

N=49

0

After Adjuvant Anthracycline1 (40 mg/m2 q3w)

Taxane Pretreated MBC3

(6 mg/m2 daily X 5)

Taxane Resistant MBC4

(40 mg/m2 q3w)

Taxane Naïve MBC2

(6 mg/m2 daily X 5)

  • Roche H et al. J Clin Oncol. 2007;23:3415-3420. 3. Low et al. J Clin Oncol 2005;23:2726–2734.
  • 2. Denduluri N et al. J Clin Oncol. 2007;23:3421-3427. 4. Thomas E et al. J Clin Oncol. 2007;23:3399-3406.
slide33
Capecitabine +/- ixabepilone after anthracyclines and taxanes

.

Thomas E S et al. JCO 2007;25:5210-5217

©2007 by American Society of Clinical Oncology

slide34
Time to resolution of neuropathy

Thomas E S et al. JCO 2007;25:5210-5217

©2007 by American Society of Clinical Oncology

slide35
.

Ixabepilone After Anthracyclines, Taxanes and Capecitabine

Perez E A et al. JCO 2007;25:3407-3414

©2007 by American Society of Clinical Oncology

slide36
Ixabepilone After Anthracyclines, Taxanes and Capecitabine

Perez E A et al. JCO 2007;25:3407-3414

©2007 by American Society of Clinical Oncology

capecitabine ixabepilone in triple negative mbc
Capecitabine ± Ixabepilone in Triple Negative MBC

37

Pooled triple negative subgroup (n = 443)

Rugo H, et al. SABCS 2008. Abstract 3057.

eribulin mesylate e7389
Eribulin mesylate (E7389)
  • Synthetic analogue of halichondrin B
  • Binds to unique site on tubulin
    • Suppresses microtubule polymerization
    • Sequesters tubulin into nonfunctional aggregates
    • Creates irreversible mitotic block
  • Inhibition of breast cancer cell line growth in vitro

MCF7

Jordan M A et al. Mol Cancer Ther 2005;4:1086-1095

slide40
Eribulin: Phase II Results in A- and T-Treated MBC

Dosing

1.4 mg/m2 days 1, 8, 15 q28d

or days 1,8 q21 days

Response rate (n=103)

Overall 11%

ER+ 15%

TN 7%

HER2+ 8%

Grade 3 or 4 side effects

neutropenia 64%

febrile neutropenia 4%

fatigue 5%

neuropathy 5%

Vahdat, L. T. et al. J Clin Oncol; 27:2954-2961 2009

slide41
EMBRACE study design
  • Global, randomized, open-label Phase III trial (Study 305)

Eribulin mesylate

1.4 mg/m2, 2-5 min IVDay 1, 8 q21 days

Patients (N=762)

Primary endpoint

  • Locally recurrent or MBC
  • 2-5 prior chemotherapies
  • Progression ≤6 months of last chemotherapy
  • Neuropathy ≤grade 2
  • ECOG ≤2
  • Overall survival
  • ≥2 for advanced disease
  • Prior anthracycline and taxane

Randomization 2:1

Secondary endpoints

Treatment of Physician’s Choice (TPC)

Any monotherapy (chemotherapy, hormonal, biological)* or supportive care only†

  • PFS
  • ORR
  • Safety
  • Stratification:
    • Geographical region, prior capecitabine, HER2/neu status

* Approved for treatment of cancer

†Or palliative treatment or radiotherapy administered according to local practice, if applicable

ECOG, Eastern Cooperative Oncology Group; IV, intravenous; PFS, progression-free survival;HER2/neu, human epidermal growth factor receptor 2

embrace trial
EMBRACE Trial

OS PFS

RR: Eribulin 12%, TPC 5%

Cortest, et al. 2011:377; 914-923

slide44
Progression-free Survival Overall Survival

Miller K et al. N Engl J Med 2007;357:2666-2676

ribbon 2 trial design
RIBBON-2 trial design

Investigator’s choice of chemotherapy

Treat to disease progression; crossover after progression permitted

HER2-negative LR/mBC, one prior line of CT, no prior anti-VEGF therapy

(n=684)

2:1

BEV + CT

Taxane or gemcitabine or capecitabine or vinorelbine

R

PLA + CT

  • Taxane (paclitaxel 90 mg/m2 d1, 8, 15 q4w or paclitaxel 175 mg/m2, nab-paclitaxel 260 mg/m2, or docetaxel 75–100 mg/m2 q3w)
  • Gemcitabine (1250 mg/m2 d1, 8 q3w)
  • Capecitabine (1000 mg/m2 bid d1–14 q3w)
  • Vinorelbine (30 mg/m2 d1, 8, 15 q3w)
  • BEV or PLA (15 mg/kg q3w or 10 mg/kg q2w, depending on CT regimen)
  • Stratification factors: CT regimen; interval from LR/MBC diagnosis to 1st progression; ER and PgR status

ER = estrogen receptor; PgR = progesterone receptor; PLA = placebo; R = randomization

summary of efficacy in ribbon 2 all patients
Summary of efficacy in RIBBON-2 (all patients)

aStratified analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression, ER/PgR receptor status)

bNot significant at prespecified α=0.01

Brufsky et al. SABCS 2009

tnbc population pfs
TNBC population: PFS

Estimated probability

1.0

0.8

0.6

0.4

0.2

0

aStratified analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression)

2.7

6.0

0 5 10 15 20 25

Time (months)

No. at risk:

BEV + CT 112 65 26 8 4

Placebo + CT 47 11 4 2

tnbc population interim os
TNBC population: Interim OS

Estimated probability

1.0

0.8

0.6

0.4

0.2

0

aStratified analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression)

12.6

17.9

0 5 10 15 20 25 30

Time (months)

No. at risk:

BEV + CT 112 92 73 27 14 5

Placebo + CT 47 38 25 14 4 2 1

tnbc population orr a
TNBC population: ORRa

Patients (%)

Difference: 23% (95% CI 7–39%)

p=0.0078

41 (95% CI 31–51)

18 (95% CI 8–34)

PLA + CT (n=47)

BEV + CT (n=112)

aStratified analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression)

triple negative breast cancers potential therapeutic targets
Triple-Negative Breast Cancers: Potential Therapeutic Targets

Cetuximab

EGFR Tyrosine Kinase

C-KIT tyrosine kinase

Dasatinib Sunitinib

MAP Kinase Pathway

Akt Pathway

MAPK inhibitors; NOTCH inhibitors

Transcriptional Control

PARP inhibitors; Trabectedin

Anti-Angiogenesis

Cell Cycle

DNA Repair pathways

Bevacizumab

After Cleator S et al. Lancet Oncol. 2006:8:235-244

Cell Death

egfr inhibitors in breast cancer
EGFR Inhibitors in Breast Cancer

In unselected metastatic breast cancer, single agent EGFR inhibitors have not shown great activity:

  • Phase II ZD1839 (Robertson) 2/27 PR 6/27 SD
  • Phase II ZD1839 (Baselga) 0/31 PR 12/31 SD
  • Phase II OSI-774 (Dickler, Winer) 1/69 PR 3/69 SD
  • Phase II ZD1839 (Albain) 1/63 PR 7/63 SD

Summary RR: 2%

platinum egfr inhibition in triple negative breast cancer
Platinum & EGFR Inhibition in Triple-negative Breast Cancer

TBCRC01: Carey LA, et al. ASCO 2008

BALI-1: Baselga et al. SABCS 2010

ad