Strategic use of available agents through multiple lines of therapy for advanced ER/PR-negative...

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, PhDDana-Farber Cancer Institute

Harvard Medical SchoolBoston, MA

1. Most women are candidates for multiple lines of therapy

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)?

0%

5%

28%

37%

21%

2%

7%

0%

0%

6%

19%

29%

31%

10%

3%

1%

0%

1%

0% 5% 10% 15% 20% 25% 30% 35% 40%

2

3

4

5

6

7

8

9

10

CI PON Love, Research to Practice, 2008

Line of Therapy

Ave

rage

Wee

ks o

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reat

men

t

0

5

10

15

20

25

30

35

40

45

1st 2nd 3rd 4th 5th 6th 7th

Overall

ER+

HER2+

TN

Duration of Chemotherapy for Advanced Breast Cancer

Burstein, Litsas 2010Unpublished data

Line of Therapy

Ave

rage

Wee

ks o

n T

reat

men

t

0

5

10

15

20

25

30

35

40

45


Overall

ER+

HER2+

TN



Median # of regimens: 4

2. Tumor biology / tumor subset governs outcomes –

Triple negative tumors stand out as having a different trajectory

Line of Therapy

Ave

rage

Wee

ks o

n T

reat

men

t

0

5

10

15

20

25

30

35

40

45


Overall

ER+

HER2+

TN



Median # of regimens: 4

Line of Therapy

Ave

rage

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men

t

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5

10

15

20

25

30

35

40

45


Overall

ER+

HER2+

TN



Chemotherapy Outcomes in Non-TN vs TN Metastatic Breast Cancer

RESPONSE

RATES

Study Agents Non-TN TN

CALGB 9342 Paclitaxel 23% 26%

E2100 Paclitaxel 23% 22%

Pac + Bev 54% 43%

BMS Ixabepilone 19% 17%

BMS Capecitabine 16% 9%

Cape + Ixa 37% 27%

TIME TOPROGRESSION

CALGB 9342 Paclitaxel 4.5 m 2.8 m

E2100 Paclitaxel 9 m 5 m

Pac + Bev 13 m 9 m

BMS Ixabepilone 3.6 m 2.7 m

BMS Capecitabine 5.0 m 2.1 m

Cape + Ixa 7.1 m 4.1 m

RIBBON2 Chemo 6.0 m 2.8 m

Chemo + Bev 7.4 m 6.5 m

3. Where are we with PARP inhibitors?

Gem/Carbo +/- BSI-201 in Triple Negative Metastatic Breast Cancer

MBCTriple Negative

Prior ChemoN=120

Gemcitabine 1000 mg/m2 d 1,8Carbo AUC 2 d 1,8

Gemcitabine 1000 mg/m2 d 1,8Carbo AUC 2 d 1,8 BSI-201 5.6 mg/kg d 1,4,8, 11

CYCLES EVERY 21 DAYS

RESTAGE EVERY 2 CYCLESO’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 DataOral Presentation vs Publication Results

Endpoint Venue GC alone GC + BSI201

Response rate ASCO ’09 16% 48%

NEJM ‘11 32% 52%

PFS ASCO ’09 3.3 m 6.9 m

NEJM ‘11 3.6 m 5.9 m

OS ASCO ’09 5.7 m 9.2 m

NEJM ’11 7.7 m 12.3 m

Gem/Carbo (GC)(N= 258)

Gemcitabine 1000 mg/m2 IV d 1, 8Carboplatin AUC2 IV d 1, 8

21-day cycles

Gem/Carbo + Iniparib (GCI)(N= 261)

Gemcitabine - 1000 mg/m2 IV d 1, 8Carboplatin - AUC2 IV d 1, 8

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

21-day cycles

R

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)

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

Schema

Crossover allowed to GCI following

Disease Progression* (central review)

N = 519

*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

0 2 4 6 8 10 12 14 16

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Months Since Study Entry

Pro

babi

lity

of P

rogr

essi

on F

ree

Sur

viva

l

No. at risk

GC 258 171 116 63 38 18 6 1 0

GCI 261 187 138 83 53 11 2 0 0

No. at risk

GC 258 239 214 181 151 99 38 11 0

GCI 261 248 230 204 169 111 52 15 0

Efficacy Endpoints – ITT population

0 2 4 6 8 10 12 14 16

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Pro

babi

lity

of S

urvi

val

Months

Pre-specified alpha = 0.04

PFSGC

(N=258)

GCI

(N=261)Median PFS, mos (95% CI)

4.1

(3.1, 4.6)

5.1

(4.2, 5.8)HR (95% CI) 0.79 (0.65, 0.98)p-value 0.027

Pre-specified alpha = 0.01

OSGC

(N=258)

GCI

(N=261)Median OS, mos (95% CI)

11.1

(9.2, 12.1)

11.8

(10.6, 12.9)HR (95% CI) 0.88 (0.69, 1.12)

p-value 0.28

Overall Response Rate* – ITT Population

Response, n (%) GCN = 258

GCIN = 261

Complete response 4 (1.6) 5 (1.9)

Partial response 74(29) 83 (32)

Stable disease 89 (35) 99 (38)

Progressive disease 62 (24) 62 (24)

Inevaluable 29 (11) 12 (4.6)

SD > 6 months 14 (5.4) 19 (7.3)

ORR, n (%)

(95% CI)

78 (30)

(25‒36%)

88 (34)

(28‒40%)

Clinical Benefit Rate, n (%)

[CR +PR +SD(> 6 mos)]92 (36) 107 (41)

17

* Independent central review, RECIST 1.1 + confirmation of response

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 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

4. What are the real goals of treatment for refractory disease?

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?

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.

Basch E. N Engl J Med2010;362:865-869.

Clinical teams under-reportsymptoms relative to patients

Survey of consecutive officevisits among 467 cancer patientsat MSKCC

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

5. There are a lot of choices once you get beyond 1st or 2nd line,

but there really aren’t much data

Author Agent Prior Therapy RR TTP

A T C

Blum

JCO 1999

Capecitabine ✓ ✓ 20% 3m

Miller

JCO 2005

Capecitabine ✓ ✓ 19% 4m

Thomas

JCO 2007

Capecitabine ± Ixabepilone

✓ ✓ 14%

35%

4.2m

5.8m

Geyer

NEJM 2006

Capecitabine ±

Lapatinib

✓ ✓ 14%

22%

4.3m

5.9 m

Perez

JCO 2007

Ixabepilone ✓ ✓ ✓ 11% 3m

O’Shaughnessy

CBC 2005Pemetrexed ✓ ✓ ✓ 8% 2.9m

Krop

SABCS 09

T-DM1

*HER2+ only

✓ ✓ ✓ 32% 7.3m

Chemotherapy Outcomes in Refractory Breast Cancer

Typical Clinical Outcomeswith Single-agent Chemotherapy for

Advanced Breast Cancer

Response rate Time to Progression

1st line 25 to 45% 5 to 8 m

2nd line 15 to 30% 2 to 5 m

3rd line 0 to 20% 1 to 4 m

4th line Few data

5th line Fewer data

6th line etc No data

6. Newer options: ixabepilone

Overview: Mechanism of action of microtubule-targeting drugs

Destabilizers Stabilizers

Polymerization Polymerization

Vinca alkaloids / eribulin Taxanes / epothilones

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

1. 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.

7783

5753

4257

22 12

35

26

3541

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20

30

40

50

60

70

80

90

100

After Adjuvant Anthracycline1 (40 mg/m2 q3w)

Taxane Naïve MBC2

(6 mg/m2 daily X 5)

Taxane Pretreated MBC3

(6 mg/m2 daily X 5)Taxane Resistant MBC4

(40 mg/m2 q3w)

Per

cen

tag

e (%

)

SD

RR

N=65 N=23 N=37 N=49

.

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

©2007 by American Society of Clinical Oncology

Capecitabine +/- ixabepilone after anthracyclines and taxanes

Time to resolution of neuropathy

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


.

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


Ixabepilone After Anthracyclines, Taxanes and Capecitabine

Ixabepilone After Anthracyclines, Taxanes and Capecitabine

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


Capecitabine ± Ixabepilone in Triple Negative MBC

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

Pooled triple negative subgroup (n = 443)Pooled triple negative subgroup (n = 443)

Efficacy Ixa + Cape (n = 191)

Cape (n = 208)

ORR 31% 15%

CR 3% 1%

PR 28% 14%

Median PFS 4.2 mo 1.7 mo

HR 0.63

P value < 0.0001

Median OS 10.3 mos(n = 213)

9.0 mos(n = 230)

HR 0.87

P value 0.18

Selected Grade 3/4 AEs

Ixa + Cape (n = 209)

Cape (n = 226)

Neutropenia 70% 8%

Febrile neutropenia

4% < 1%

Leukopenia 63% 5%

Peripheral neuropathy

23% < 1%

Hand-foot syndrome

14% 16%

Fatigue 11% 3%

37

7. New options: eribulin

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

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

MCF7

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

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

Dosing1.4 mg/m2 days 1, 8, 15 q28dor 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%

• Locally recurrent or MBC• 2-5 prior chemotherapies

• Progression ≤6 months of last chemotherapy

• Neuropathy ≤grade 2• ECOG ≤2

Eribulin mesylate1.4 mg/m2, 2-5 min IV

Day 1, 8 q21 days

Treatment of Physician’s Choice (TPC)Any monotherapy

(chemotherapy, hormonal, biological)* or supportive care

only†

Randomization 2:1

• PFS• ORR• Safety

• Overall survival

Primary endpoint

Secondary endpoints

EMBRACE study design

Stratification:– Geographical region, prior capecitabine, HER2/neu status

Global, randomized, open-label Phase III trial (Study 305)

Patients (N=762)

− ≥2 for advanced disease− Prior anthracycline and

taxane

* Approved for treatment of cancer†Or palliative treatment or radiotherapy administered according to local practice, if applicableECOG, Eastern Cooperative Oncology Group; IV, intravenous; PFS, progression-free survival;HER2/neu, human epidermal growth factor receptor 2

EMBRACE TrialOS PFS

RR: Eribulin 12%, TPC 5% Cortest, et al. 2011:377; 914-923

7. Angiogenesis inhibition in TN BC

Progression-free Survival Overall Survival

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

Response Rates

PaclitaxelPaclitaxel +

BevacizumabP

Value

All patients 14.2% 28.2% <0.0001

Measurable disease

9.1% 10.97% <0.0001

E2100: Bevacizumab andTriple Negative Breast Cancer

Tumor No. PFS

(median; months)

Response Rate

(%)

Pac Pac + Bev

HR Pac Pac + Bev

ER-

PR-

223 4.8 8.8 0.53 22% 43%

ER+

PR-

109 9.3 12.6 0.88

23% 54%

ER+

PR+

289 8.0 14.4 0.54

KD Miller, et al. NEJM 2007

RIBBON-2 trial design

• 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

Investigator’s choice of

chemotherapy

Taxane or gemcitabine or capecitabine

or vinorelbine

Treat to disease

progression; crossover

after progression

permitted

BEV + CT

PLA + CT

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

(n=684)

R

2:1

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

Summary of efficacy in RIBBON-2 (all patients)

Brufsky et al. SABCS 2009

Endpoint BEV + CT (n=459)

PLA + CT (n=225)

Median PFS, months 7.2 5.1

PFS hazard ratio (95% CI)a

Log-rank test

0.78 (0.64–0.93)

p=0.0072

Median overall survival (OS), months 18.0 16.4

OS hazard ratio (95% CI), preliminary analysisa

0.90 (0.71–1.14)

Log-rank testa p=0.3741

1-year OS rate, % 69.5 66.2

ORR, % 40 30

Mantel–Haenszel testa,b p=0.0193aStratified analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression, ER/PgR receptor status)bNot significant at prespecified α=0.01

Baseline characteristics

Characteristic

TNBC population All patientsBEV + CT (n=112)

PLA + CT (n=47)

BEV + CT (n=459)

PLA + CT (n=225)

Median age, years (range) 55 (28–86) 49 (33–79) 55 (25–86) 55 (23–90) Age <40 years, % 9 13 9 9Measurable disease, % 89 83 79 80Metastatic sites, % ≥3 48 32 44 47 Visceral 74 62 74 71Interval from LR/MBC diagnosis to 1st progression <6 months, %

33 38 27 29

CT partner, % Taxane 42 43 44 46 Gemcitabine 23 28 24 23 Capecitabine 16 21 21 21 Vinorelbine 19 9 12 10

No. at risk:BEV + CT 112 65 26 8 4Placebo + CT 47 11 4 2

No. at risk:BEV + CT 112 65 26 8 4Placebo + CT 47 11 4 2

TNBC population: PFS

PFSBEV + CT(n=112)

PLA + CT(n=47)

Events, n (%) 94 (84) 42 (89)

Median, months 6.0 2.7

HRa (95% CI)Log-rank test

0.494 (0.33–0.74) p=0.0006

1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 250 5 10 15 20 25

Time (months)Time (months)

2.7 6.0

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

Estimated probabilityEstimated probability

No. at risk:BEV + CT 112 92 73 27 14 5Placebo + CT 47 38 25 14 4 2 1

No. at risk:BEV + CT 112 92 73 27 14 5Placebo + CT 47 38 25 14 4 2 1

TNBC population: Interim OSOS

BEV + CT(n=112)

PLA + CT(n=47)

Events, n (%) 52 (46) 29 (62)

Median, months 17.9 12.6

HRa (95% CI)Log-rank test

0.624 (0.39–1.007) p=0.0534

1.0

0.8

0.6

0.4

0.2

0

1.0

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0.4

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0

Estimated probabilityEstimated probability

0 5 10 15 20 25 300 5 10 15 20 25 30

12.6 17.9


Time (months)Time (months)

TNBC population: ORRa

Patients (%)Patients (%)

BEV + CT (n=112)

PLA + CT (n=47)

41 (95% CI 31–51)

18 (95% CI 8–34)

Difference: 23% (95% CI 7–39%)

p=0.0078


8. Other targets for TN BC

Triple-Negative Breast Cancers: Potential Therapeutic Targets

Cell Cycle

Transcriptional Control

MAP Kinase Pathway Akt Pathway

EGFR Tyrosine

Kinase

C-KIT tyrosine kinase

Cell DeathAfter Cleator S et al. Lancet

Oncol. 2006:8:235-244

DNA Repair pathways

Anti-Angiogenesis

Cetuximab Dasatinib Sunitinib

PARP inhibitors;

Trabectedin

Bevacizumab

MAPK inhibitors; NOTCH inhibitors

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%

Cetuximab in Triple Negative MBC: Clinical Efficacy

Carey. SABCS. 2007 (abstr 307).

Best

Response

Cetuximab Alone

(n=31)

CR 0

PR 2 (6%)

SD 5 (16%)

Clinical Benefit 3 (105)

Cisplatin For Advanced Breast Cancer

Author Sledge, et al.

JCO 1988;6:1811

Kolaric, et al.

Can Chem Pharm

1983;11:108

Martino, et al.

J Can Res Clin Onc 1984;108:354

Forastriere, et al.

Am J Clin Onc 1982:5:243

No. Patients 20 38 36 37

Line of therapy 1st 1st refractory refractory

Dose / schedule

and

Responses

30 mg/m2 d1-4 30 mg/m2 d1-4 15 mg/m2 d 1-5

0 of 15

60 mg/m2 q3

0 of 1847% 54%

ER+ 1 of 7

ER - 5 of 8

100-120 mg/m2

2 of 13

120 mg/m2 q3

4 of 19

Platinum & EGFR Inhibition in Triple-negative Breast Cancer

0%

5%

10%

15%

20%

25%

CDDP Cetux CDDP+Cetux

Carbo +Cetux

Re

sp

on

se

Ra

te

TBCRC01: Carey LA, et al. ASCO 2008BALI-1: Baselga et al. SABCS 2010

9. Caring for patients with refractory MBC is where you practice the art of medicine

Strategic use of available agents through multiple lines of therapy for advanced ER/PR-negative...

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