Harold j burstein md phd dana farber cancer institute harvard medical school boston ma
Download
1 / 58

Strategic use of available agents through multiple lines of therapy for advanced ER - PowerPoint PPT Presentation


  • 58 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 'Strategic use of available agents through multiple lines of therapy for advanced ER' - 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



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


Duration of Chemotherapy for Advanced Breast Cancer received by the last 5 patients you treated who died of metastatic breast cancer (average of the 5 patients)?

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Unpublished data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


Duration of Chemotherapy for Advanced Breast Cancer received by the last 5 patients you treated who died of metastatic breast cancer (average of the 5 patients)?

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


2. Tumor biology / tumor subset governs outcomes – received by the last 5 patients you treated who died of metastatic breast cancer (average of the 5 patients)?Triple negative tumors stand out as having a different trajectory


Duration of Chemotherapy for Advanced Breast Cancer received by the last 5 patients you treated who died of metastatic breast cancer (average of the 5 patients)?

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


Duration of Chemotherapy for Advanced Breast Cancer received by the last 5 patients you treated who died of metastatic breast cancer (average of the 5 patients)?

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


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

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


Iniparib data oral presentation vs publication results
Iniparib Data phase IIOral Presentation vs Publication Results


Schema
Schema phase II

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 phase II

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 phase II

* Independent central review, RECIST 1.1 + confirmation of response

17


What s going on
What’s going on? phase II

  • 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? phase II

  • 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 disease?

  • 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? disease?

  • 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


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 Reported by Patients versus Clinicians at Successive Office Visits.

  • 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


5. There are a lot of choices once you get beyond 1 Reported by Patients versus Clinicians at Successive Office Visits.st or 2nd line,but there really aren’t much data


Chemotherapy Outcomes in Refractory Breast Cancer Reported by Patients versus Clinicians at Successive Office Visits.


Typical clinical outcomes with single agent chemotherapy for advanced breast cancer
Typical Clinical Outcomes Reported by Patients versus Clinicians at Successive Office Visits.with Single-agent Chemotherapy for Advanced Breast Cancer


6 newer options ixabepilone

6. Newer options: ixabepilone Reported by Patients versus Clinicians at Successive Office Visits.


Overview mechanism of action of microtubule targeting drugs
Overview: Mechanism of action of microtubule-targeting drugs Reported by Patients versus Clinicians at Successive Office Visits.

Vinca alkaloids / eribulin

Taxanes / epothilones

Destabilizers

Stabilizers

 Polymerization

 Polymerization


Ixabepilone epothilone b analog
Ixabepilone: Epothilone B Analog Reported by Patients versus Clinicians at Successive Office Visits.

  • 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 Reported by Patients versus Clinicians at Successive Office Visits.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.


Capecitabine +/- ixabepilone after anthracyclines and taxanes

.

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

©2007 by American Society of Clinical Oncology


Time to resolution of neuropathy taxanes

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

©2007 by American Society of Clinical Oncology


. taxanes

Ixabepilone After Anthracyclines, Taxanes and Capecitabine

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

©2007 by American Society of Clinical Oncology


Ixabepilone After Anthracyclines, Taxanes and Capecitabine taxanes

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 taxanesTriple Negative MBC

37

Pooled triple negative subgroup (n = 443)

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



Eribulin mesylate e7389
Eribulin mesylate (E7389) taxanes

  • 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


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

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


EMBRACE study taxanes 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 taxanes

OS PFS

RR: Eribulin 12%, TPC 5%

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



Progression-free Survival Overall Survival taxanes

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


E2100 bevacizumab and triple negative breast cancer
E2100: Bevacizumab and taxanesTriple Negative Breast Cancer

KD Miller, et al. NEJM 2007


Ribbon 2 trial design
RIBBON-2 trial design taxanes

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 taxanes(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 taxanes

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 taxanes

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: ORR taxanesa

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 TargetsBreast 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%


Cetuximab in triple negative mbc clinical efficacy
Cetuximab in Triple Negative MBC: TargetsClinical Efficacy

Carey. SABCS. 2007 (abstr 307).



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

TBCRC01: Carey LA, et al. ASCO 2008

BALI-1: Baselga et al. SABCS 2010



ad