Transcript 10 Things to Know About Metastatic Breast Cancer Beyond

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
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)?
2
0%
6%
5%
3
19%
28%
29%
4
5
6
2%
3%
8
10
21%
10%
7
9
37%
31%
7%
1%
0%
0%
0%
1%
0%
5%
10%
15%
N Love, Research to Practice, 2008
20%
CI
25%
PO
30%
35%
40%
Duration of Chemotherapy for Advanced Breast Cancer
45
Overall
Average Weeks on Treatment
40
ER+
HER2+
35
TN
30
25
20
15
10
5
0
1st
2nd
3rd
4th
5th
Line of Therapy
6th
7th
Burstein, Litsas 2010
Unpublished data
Duration of Chemotherapy for Advanced Breast Cancer
45
Overall
Average Weeks on Treatment
40
ER+
HER2+
35
TN
30
25
Median # of regimens: 4
20
15
10
5
0
1st
2nd
3rd
4th
5th
Line of Therapy
6th
7th
Burstein, Litsas 2010
Unpublished data
2. Tumor biology / tumor subset
governs outcomes –
Triple negative tumors stand out
as having a different trajectory
Duration of Chemotherapy for Advanced Breast Cancer
45
Overall
Average Weeks on Treatment
40
ER+
HER2+
35
TN
30
25
Median # of regimens: 4
20
15
10
5
0
1st
2nd
3rd
4th
5th
Line of Therapy
6th
7th
Burstein, Litsas 2010
Unpublished data
Duration of Chemotherapy for Advanced Breast Cancer
45
Overall
Average Weeks on Treatment
40
ER+
HER2+
35
TN
30
25
20
15
10
5
0
1st
2nd
3rd
4th
5th
Line of Therapy
6th
7th
Burstein, Litsas 2010
Unpublished data
Chemotherapy Outcomes in Non-TN vs TN Metastatic Breast Cancer
RESPONSE
RATES
TIME TO
PROGRESSION
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%
CALGB 9342
Paclitaxel
4.5 m
2.8 m
E2100
Paclitaxel
9m
5m
Pac + Bev
13 m
9m
BMS
Ixabepilone
3.6 m
2.7 m
BMS
Capecitabine
5.0 m
2.1 m
Cape + Ixa
7.1 m
4.1 m
Chemo
6.0 m
2.8 m
Chemo + Bev
7.4 m
6.5 m
RIBBON2
3. Where are we with PARP
inhibitors?
Gem/Carbo +/- BSI-201 in Triple Negative
Metastatic Breast Cancer
MBC
Triple Negative
Prior Chemo
N=120
Gemcitabine 1000 mg/m2 d 1,8
Carbo AUC 2 d 1,8
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
Endpoint
GC alone
GC + BSI201
Response rate ASCO ’09
16%
48%
NEJM ‘11
32%
52%
ASCO ’09
3.3 m
6.9 m
NEJM ‘11
3.6 m
5.9 m
ASCO ’09
5.7 m
9.2 m
NEJM ’11
7.7 m
12.3 m
PFS
OS
Venue
Schema
Study Design: Multi-center, randomized open-label Phase III Trial
N = 519
Gem/Carbo (GC)
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)
(N= 258)
Gemcitabine 1000 mg/m2 IV d 1, 8
Carboplatin AUC2 IV d 1, 8
Crossover allowed
to GCI following
Disease Progression*
(central review)
21-day cycles
R
Gem/Carbo + Iniparib (GCI)
(N= 261)
Gemcitabine - 1000 mg/m2 IV d 1, 8
Carboplatin - AUC2 IV d 1, 8
Iniparib - 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
GC
(N=258)
PFS
Median PFS, mos
(95% CI)
HR (95% CI)
p-value
1.0
4.1
5.1
(3.1, 4.6)
(4.2, 5.8)
0.79 (0.65, 0.98)
0.027
0.9
0.8
0.8
0.7
0.7
0.5
0.4
11.1
11.8
Median OS, mos
(95% CI)
(9.2, 12.1) (10.6, 12.9)
0.88 (0.69, 1.12)
HR (95% CI)
0.28
p-value
1.0
Pre-specified alpha = 0.01
0.6
GC
GCI
(N=258) (N=261)
OS
Probability of Survival
Probability of Progression Free Survival
0.9
GCI
(N=261)
0.6
0.5
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0
Pre-specified alpha = 0.04
0
0
2
4
6
8
10
12
14
16
0
2
4
6
Months Since Study Entry
No. at risk
GC
258
GCI
261
8
10
12
14
99
111
38
52
11
15
16
Months
No. at risk
171
187
116
138
63
83
38
53
18
11
6
2
1
0
0
0
GC
GCI
258
261
239
248
214
230
181
204
151
169
0
0
Overall Response Rate* – ITT Population
GC
GCI
N = 258
N = 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)
78 (30)
(25‒36%)
88 (34)
(28‒40%)
92 (36)
107 (41)
Response, n (%)
ORR, n (%)
(95% CI)
Clinical Benefit Rate, n (%)
[CR +PR +SD(> 6 mos)]
* Independent central review, RECIST 1.1 + confirmation of response
17
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.
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
• 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
Chemotherapy Outcomes in Refractory Breast Cancer
Author
Agent
Prior Therapy
A
T
RR
TTP
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
Pemetrexed
✓
✓
✓
8%
2.9m
T-DM1
*HER2+ only
✓
✓
✓
32%
7.3m
CBC 2005
Krop
SABCS 09
Typical Clinical Outcomes
with 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
Vinca alkaloids / eribulin
Taxanes / epothilones
Destabilizers
Stabilizers
 Polymerization
 Polymerization
Ixabepilone: Epothilone B Analog
S.cellulosum
Epothilone B
Ixabepilone
• 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 tubulinbinding mode distinct from other agents
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
100
90
Percentage (%)
80
83
77
70
60
26
57
35
53
SD
RR
50
40
35
30
20
42
22
10
0
41
57
N=65
After Adjuvant
Anthracycline1
(40 mg/m2 q3w)
N=23
N=37
12
N=49
3
4
Taxane Naïve MBC2 Taxane Pretreated MBC Taxane Resistant MBC
2
2
(6 mg/m daily X 5)
(40 mg/m q3w)
(6 mg/m2 daily X 5)
1. Roche H et al. J Clin Oncol. 2007;23:3415-3420.
2. Denduluri N et al. J Clin Oncol. 2007;23:3421-3427.
3. Low et al. J Clin Oncol 2005;23:2726–2734.
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
Thomas E S et al. JCO 2007;25:5210-5217
©2007 by American Society of Clinical Oncology
.
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
Perez E A et al. JCO 2007;25:3407-3414
©2007 by American Society of Clinical Oncology
37
Capecitabine ± Ixabepilone in
Triple Negative MBC
Pooled triple negative subgroup (n = 443)
Efficacy
ORR
CR
PR
Median PFS
Ixa + Cape (n
= 191)
Cape
(n =
208)
31%
15%
3%
1%
28%
14%
4.2 mo
1.7 mo
HR
0.63
P value
Median OS
< 0.0001
10.3 mos
(n = 213)
9.0 mos
(n = 230)
HR
0.87
P value
0.18
Rugo H, et al. SABCS 2008. Abstract 3057.
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%
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
MCF7
Jordan M A et al. Mol Cancer Ther 2005;4:1086-1095
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
EMBRACE study design
 Global, randomized, open-label Phase III trial (Study 305)
Patients (N=762)
• Locally recurrent or MBC
• 2-5 prior chemotherapies
− ≥2 for advanced disease
− Prior anthracycline and
taxane
• Progression ≤6 months
of last chemotherapy
• Neuropathy ≤grade 2
• ECOG ≤2
Eribulin mesylate
mg/m2,
1.4
2-5 min IV
Day 1, 8 q21 days
Primary
endpoint
• Overall
survival
Randomization 2:1
Treatment of Physician’s
Choice (TPC)
Any monotherapy (chemotherapy,
hormonal, biological)* or
supportive care only†
 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
Secondary
endpoints
• PFS
• ORR
• Safety
EMBRACE Trial
OS
PFS
RR: Eribulin 12%, TPC 5%
Cortest, et al. 2011:377; 914-923
7. Angiogenesis inhibition in
TN BC
Progression-free Survival
Response
Rates
Overall Survival
Paclitaxel
Paclitaxel +
Bevacizumab
P
Value
All patients
14.2%
28.2%
<0.0001
Measurable
disease
9.1%
10.97%
<0.0001
Miller K et al. N Engl J Med 2007;357:2666-2676
E2100: Bevacizumab and
Triple Negative Breast Cancer
Tumor
No.
PFS
(median; months)
Response Rate
(%)
Pac
Pac +
Bev
HR
Pac
Pac +
Bev
22%
43%
23%
54%
ERPR-
223
4.8
8.8
0.53
ER+
PR-
109
9.3
12.6
0.88
ER+
PR+
289
KD Miller, et al. NEJM 2007
8.0
14.4
0.54
RIBBON-2 trial design
Investigator’s
choice of
chemotherapy
HER2-negative
LR/mBC, one prior
line of CT, no prior
anti-VEGF therapy
(n=684)
Taxane or
gemcitabine or
capecitabine
or vinorelbine
2:1
BEV + CT
R
PLA + CT
Treat to
disease
progression;
crossover
after
progression
permitted
• 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)
Endpoint
Median PFS, months
BEV + CT
(n=459)
PLA + CT
(n=225)
7.2
5.1
PFS hazard ratio (95% CI)a
0.78 (0.64–0.93)
Log-rank test
Median overall survival (OS), months
p=0.0072
18.0
OS hazard ratio (95% CI), preliminary
analysisa
0.90 (0.71–1.14)
Log-rank testa
1-year OS rate, %
ORR, %
Mantel–Haenszel testa,b
aStratified
16.4
p=0.3741
69.5
66.2
40
30
p=0.0193
analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression,
ER/PgR receptor status)
Brufsky et al. SABCS 2009
bNot significant at prespecified α=0.01
Baseline characteristics
Characteristic
Median age, years (range)
Age <40 years, %
Measurable disease, %
Metastatic sites, %
≥3
Visceral
Interval from LR/MBC diagnosis
to 1st progression <6 months, %
CT partner, %
Taxane
Gemcitabine
Capecitabine
Vinorelbine
TNBC population
All patients
BEV + CT PLA + CT
(n=112)
(n=47)
55 (28–86) 49 (33–79)
9
13
89
83
BEV + CT PLA + CT
(n=459)
(n=225)
55 (25–86) 55 (23–90)
9
9
79
80
48
74
33
32
62
38
44
74
27
47
71
29
42
23
16
19
43
28
21
9
44
24
21
12
46
23
21
10
TNBC population: PFS
Estimated
probability
PFS
1.0
Events, n (%)
BEV + CT
(n=112)
PLA + CT
(n=47)
94 (84)
42 (89)
2.7
0.8
Median, months
6.0
0.6
HRa (95% CI)
Log-rank test
0.494 (0.33–0.74)
p=0.0006
aStratified
analysis (CT regimen, interval from
LR/MBC diagnosis to 1st progression)
0.4
0.2
2.7
0
0
No. at risk:
BEV + CT
112
Placebo + CT 47
6.0
5
10
15
Time (months)
65
11
26
4
8
2
20
4
25
TNBC population: Interim OS
Estimated
probability
BEV + CT
(n=112)
PLA + CT
(n=47)
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
OS
Events, n (%)
1.0
0.8
aStratified
analysis (CT regimen, interval from
LR/MBC diagnosis to 1st progression)
0.6
0.4
0.2
12.6
0
0
No. at risk:
BEV + CT
112
Placebo + CT 47
5
10
92
38
73
25
17.9
15
Time (months)
27
14
20
25
30
14
4
5
2
1
TNBC population: ORRa
Patients (%)
Difference: 23%
(95% CI 7–39%)
p=0.0078
41
(95% CI 31–51)
18
(95% CI 8–34)
BEV + CT
(n=112)
aStratified
PLA + CT
(n=47)
analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression)
8. Other targets for TN BC
Triple-Negative Breast Cancers:
Potential Therapeutic Targets
Cetuximab
EGFR
Tyrosine
Kinase
C-KIT
Dasatinib
tyrosine Sunitinib
kinase
MAP Kinase Pathway
MAPK inhibitors;
NOTCH inhibitors
AntiAngiogenesis
Akt Pathway
Transcriptional
Control
Cell
Cycle
Bevacizumab
Cell Death
PARP inhibitors;
Trabectedin
DNA Repair
pathways
After Cleator S et al. Lancet
Oncol. 2006:8:235-244
EGFR Inhibitors in
Breast Cancer
In unselected metastatic breast cancer, single agent EGFR
inhibitors have not shown great activity:
•
•
•
•
Phase II ZD1839 (Robertson)
Phase II ZD1839 (Baselga)
Phase II OSI-774 (Dickler, Winer)
Phase II ZD1839 (Albain)
2/27 PR
0/31 PR
1/69 PR
1/63 PR
Summary RR: 2%
6/27 SD
12/31 SD
3/69 SD
7/63 SD
Cetuximab in Triple Negative MBC:
Clinical Efficacy
Best
Response
CR
Cetuximab
Alone
(n=31)
0
PR
2 (6%)
SD
5 (16%)
Clinical Benefit
3 (105)
Carey. SABCS. 2007 (abstr 307).
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
30 mg/m2 d1-4
30 mg/m2 d1-4
15 mg/m2 d 1-5
60 mg/m2 q3
0 of 15
0 of 18
and
47%
54%
Responses
ER+
1 of 7
100-120 mg/m2
120 mg/m2 q3
ER -
5 of 8
2 of 13
4 of 19
Platinum & EGFR Inhibition in
Triple-negative Breast Cancer
Response Rate
25%
20%
15%
10%
5%
0%
CDDP
Cetux
CDDP+
Cetux
TBCRC01: Carey LA, et al. ASCO 2008
BALI-1: Baselga et al. SABCS 2010
Carbo +
Cetux
9. Caring for patients with
refractory MBC is where you
practice the art of medicine