Investigations • Innovation • Clinical Application
Evolving Paradigms for Optimizing Management of
Metastatic Breast Cancer
Focus on Novel Mechanisms of Action and
Evidence-Based Therapies for Survival Prolongation
in Heavily Treated Patients with MBC
Program Chair
Debu Tripathy, MD
Professor of Medicine
USC/Norris Comprehensive Cancer Center
University of Southern California
Los Angeles, CA
Welcome and Program Overview
CME-certified symposium jointly
sponsored by the Postgraduate
Institute for Medicine and
CMEducation Resources, LLC
Commercial Support: Sponsored by
an independent educational grant
from Eisai, Inc.
Faculty disclosures: Listed in
program syllabus
This CME activity may include
discussions of off-label or
unapproved uses of specific agents
Program Faculty
Program Chair
Debu Tripathy, M.D.
Professor of Medicine
USC/Norris Comprehensive Cancer
Center
University of Southern California
Los Angeles, CA
Sara Hurvitz, MD
Assistant Clinical Professor of
Medicine
Director, Breast Oncology Program
David Geffen School of Medicine
University of California, Los Angeles
Los Angeles, CA
Paraskevi Giannakakou, PhD
Associate Professor of Pharmacology
in Medicine
Weill Cornell Medical College
New York, NY
CME Program Agenda
8:30 AM — 8:45 AM
Chairman’s Introduction
An Overview of Current Issues and Controversies
Surrounding Management of Advanced and Metastatic
Breast Cancer
DEBU TRIPATHY, MD —Program Chair
Professor of Medicine │ USC/Norris Comprehensive Cancer
Center │ University of Southern California │ Los Angeles, CA
8:45 AM — 9:15 AM
A Landscape Update on Metastatic Breast Cancer (MBC)—
What Works? What Doesn’t? Strategies for Optimizing
Survival: An Evidence-to-Practice Roadmap for MBC
DEBU TRIPATHY, MD —Program Chair
Professor of Medicine │ USC/Norris Comprehensive Cancer Center │
University of Southern California │ Los Angeles, CA
9:15 AM — 9:25 AM
Question and Answer Session
CME Program Agenda
9:25 AM — 9:50 AM
Microtubules as a Target for Anticancer Drugs —MultiMechanistic Approaches to Mitigating Metastatic Breast
Disease
Paraskevi Giannakakou, PhD
Associate Professor of Pharmacology in Medicine │Weill Cornell
Medical College │New York, NY
9:50 AM — 10:00 AM
Question and Answer Session
10:00 AM — 10:30 AM
Improving Overall Survival Prolongation in MBC: The Role of
Nontaxane Microtubule Dynamics inhibitors—Evidence and
Implications of Recent Clinical Studies
Sara Hurvitz, MD
Assistant Clinical Professor of Medicine │Director, Breast Oncology
Program │ David Geffen School of Medicine │University of California,
Los Angeles
CME Program Agenda
10:30 AM — 10:40 AM
Question and Answer Session
10:40 AM — 11:05 AM
Case Studies in Metastatic Breast Cancer
DEBU TRIPATHY, MD —Program Chair
Professor of Medicine │ USC/Norris Comprehensive Cancer
Center │ University of Southern California │ Los Angeles, CA
11:05 AM — 11:15 AM
Question and Answer Session
Evolving Paradigms and Optimizing Management of
Metastatic Breast Cancer
An Overview of Current Issues and
Controversies Surrounding
Management of Advanced and
Metastatic Breast Cancer
Program Chair
Debu Tripathy, MD
Professor of Medicine
USC/Norris Comprehensive Cancer Center
University of Southern California
Los Angeles, CA
Learning Objectives
►
Understand the treatment options for metastatic
breast cancer as first-line therapy and beyond
►
Understand how breast cancer subtype influences
treatment options and selection
►
Understand the side effect profile associated with
different agents
What are the Therapeutic Goals?
►
Survival prolongation
►
Symptom palliation, delay, or preemption
●
●
●
►
Response (surrogate for symptom relief)
PFS, TTP, TTF (surrogates for symptom delay)
Quality of life (QOL) instruments
Achieve favorable tradeoff profile (ie, efficacy vs.
toxicity)
●
●
●
No consistent relationship between RR/PFS and QOL
No clinically useful tool to measure QOL or tradeoffs
Subjective assessment often made by clinicians based upon
• objective data from trials (RR, PFS, OS, toxicity)
• subjective data for individual patient (performance status)
Therapeutic Goals
►
Live longer
• Prolong survival
Simple
Objective
►
Live better
●
●
Symptom palliation or delay
Favorable tradeoff profile
• Toxicity
• Convenience
• Cost
Complex
Subjective
Survival and FDA Approval of Oncology
Drugs for Metastatic Breast Cancer
►
2003 (Johnson, Williams, Pazdur. J Clin Oncol 2003)
●
●
●
►
“There is a common misperception that … FDA … requires a survival
improvement for approval of oncology drug marketing applications.””
“Regular …approval …requires substantial evidence of efficacy…”
“…prolongation of life, a better life, or an established surrogate for at
least one of these.”
2008 (Cortesar. Proc ASCO 2008)
●
●
●
“…survival is both a safety and efficacy parameter…
“PFS may be an acceptable endpoint if measured properly and is of
sufficient magnitude. “
“Survival also should be measured to ensure that any new therapy does
not lead to a decrement.”
What are the Therapeutic Options?
Modality
Selection
Improvement in
RR
PFS
OS
Chemotherapy1,2
ER/PR-negative, visceral mets,
failed endocrine therapy



Endocrine1,2
ER and/or PR-positive



Trastuzumab,
lapatinib1,2
Her2/neu-positive



Bevacizumab3,4,5
Her2/neu-negative, first-line therapy



RANKL inibitors,
bisphosphonates1,2
Osteolytic bone mets



1. National Cancer Institute. Breast Cancer Treatment (PDQ®). http://www.cancer.gov/. 2. NCCN
Clinical Practice guidelines in Oncology. Breast Cancer V.2.2010. 3. Miller et al. N Engl J Med.
2007;357:2666-2676. 4. Miles et al. Presented at the San Antonio Breast Cancer Symposium. 2009.
Abstract 41. 5. Robert N, et al. J Clin Oncol. 2009;27(15S). Abstract 1005.
What are the Toxicities Associated
with Therapeutic Options?
Agent
Non-hematologic toxicities
Endocrine therapy
Hot flushes, gynecologic symptoms
Bevacizumab
Hypertension, thromboembolic disease
Trastuzumab
Cardiac dysfunction
Lapatinib
Diarrhea
Cytotoxic agents
•Anthracycllnes
•Paclitaxel
•Docetaxel
•Ixabepilone
•Eribulin
•Vinorelbine
•Capecitabine
•Gemicitabine
•Cardiomyopathy
•Neuropathy
•Fluid retention
•Neuropathy
•Neuropathy
•Obstipation, nueropathy
•Hand-foot syndrome
•Fever, dyspnea
Does Cytotoxic Chemotherapy
Improve Survival?
• Clinical trials
– Hundreds of trials, few show OS benefit
– Few that show benefit - play of chance?
– More positive trials in second or greater line
setting
1.0
• Population-based studies
Overall Survival
0.8
– Suggests that addition of modestly effective
cytotoxic agents have produced incremental
improvements in OS
1999-2001
0.6
1994-1995
0.4
1997-1998
0.2
1991-1992
0.0
0
1
Chia et al. Cancer 2007; 110: 973-979
2
3
Years
4
5
Probability of OS Statistical Significance (%)
Probability of Detecting Significant Difference in OS
as a Function of Median OS Post-Progression (SPP)
100
80% power for PFS
85% power for PFS
90% power for PFS
80
60
40
20
0 0
4
8
12
16
Median SPP (months)
Broglio, K. R. et al. J. Natl. Cancer Inst. 2009
20
24
Does Chemotherapy Palliate Symptoms ?
90
Complete/partial response
Stable disease
Progressive disease
80
70
60
50
40
30
20
10
0
Pain
CRF
Pain
QoL
Shortness Shortness
of breath of breath
CRF
QoL
Geels P, et al. J Clin Oncol 2000;18:2395-2405.
Mood
CRF
Worry
QoL
Depression
QoL
Is Chemotherapy more Effective than
Endocrine Therapy in ER-Positive Disease?
►
Methods
●
●
►
●
No difference in OS: HR 0.94 (95%CI 0.79-1.12,P=0.5) (heterogeneity P = 0.1)
Higher RR for chemo OR 1.25 (1.01-1.54, P = 0.04) ((heterogeneity P=0.0.018)
• Two largest trials showed trends in opposite directions
Toxicity
●
●
•
Randomized trials comparing chemotherapy alone with endocrine therapy alone in
metastatic breast cancer
Results (8 trials, N=817)
●
►
Meta-analysis
Increased toxicity with chemotherapy (nausea, vomiting and alopecia)
3 of 7 mentioned aspects of QOL, with differing results - only one trial formally measured
QOL, concluding that it was better with chemotherapy
Authors' conclusions
●
“In women with metastatic breast cancer and where hormone receptors are present, a
policy of treating first with endocrine therapy rather than chemotherapy is recommended
except in the presence of rapidly progressive disease.”
et al. The Cochrane Database of Syst Rev 2003;(2):CD002747.
Evolving Paradigms and Optimizing Management of
Metastatic Breast Cancer
What is the role for targeted
agent as first line therapy or
beyond?
Treatment Effect of Trastuzumab as
First Line Therapy in HER2-Positive MBC
Chemotherapy alone
Chemotherapy plus trastuzumab
P< .0001
P< .001
P = .0002
1. Slamon et al. N Engl J Med. 2001;344(11):783-792.
2. Marty et al. J Clin Oncol. 2005;23(19):4265-4274.
P< .001
Treatment Effect of Trastuzumab as
First-Line Therapy in HER2-Positive MBC
Chemotherapy alone
Chemotherapy plus trastuzumab
P = .0325
P = .046
1. Slamon et al. N Engl J Med. 2001;344(11):783-792.
2. Marty et al. J Clin Oncol. 2005;23(19):4265-4274.
Treatment Effect of Bevacizumab as First-line
Therapy for MBC (Mainly HER2-Negative)
Chemotherapy alone/plus placebo
Chemotherapy plus bevacizumab
Response Rate
P< .0001
†
P< .0001
*
E21001
P = .0054
†
P = .0097
†
AVADO2
RIBBON-13
* Chemotherapy alone vs chemotherapy plus 10 mg/kg bevacizumab
† Chemotherapy plus placebo vs chemotherapy plus 15 mg/kg
bevacizumab
1. Miller et al. N Engl J Med. 2001;357(26):2666-2676. 2. Miles et al. J Clin Oncol. 2010
May 24 [Epub ahead of Print]. 3. Robert et al. J Clin Oncol. 2009;27(15S). Abstract
Treatment Effect of Bevacizumab as First-line
Therapy for MBC (Mainly HER2-Negative)
Chemotherapy alone/plus placebo
P< .001
*
Progression Free Survival
P = .006
†
E21001
Chemotherapy plus bevacizumab
AVADO2
P = .0002
†
P = .0001
†
RIBBON-13
No significant difference in median OS
* Chemotherapy alone vs chemotherapy plus 10 mg/kg bevacizumab
† Chemotherapy plus placebo vs chemotherapy plus 15 mg/kg bevacizumab
1. Miller et al. N Engl J Med. 2001;357(26):2666-2676. 2. Miles et al. J Clin Oncol. 2010 May 24
[Epub ahead of Print]. 3. Robert et al. J Clin Oncol. 2009;27(15S). Abstract 1005.
Bevacizumab: Meta-analysis
No
bevacizumab
Bevacizumab
No.
1008
1439
ORR
32%
49%
P<0.05
Median PFS
6.7 mo
9.2 mo.
HR 0.64,
p<0.0001
Median OS
26.4 mo
26.7 mo.
P=0.56
77%
82%
P<0.003
1-year survival
O’Shaughnessy et al. JCO 2010; 28; 152, abst 1005
Second or Greater Line Biologic Agents
Author &
Population
Experimental
vs. Standard
Geyer et al. NEJM 2006
Lapatinib + Cap
& Cameron ASCO 2007
vs.
HER2+, Trast.
Cap alone
Resistant
Brufsky et al.
SABCS, 2009
HER2-, Prior chemo
Bev vs. placebo
Plus
Chemotherapy
O’Shaughnessy et al
ASCO 2009 &
SABSC 2010
Triple Negative
Carbo/gem +/BSI-201
No.
Median
TTP/PFS
(mo.)
ORR
OS
(mo.)
324
HR 0.57
6.2 vs.
4.3
22%
vs.
14%*
HR 0.78
15.6 vs.
15.3
684
HR 0.78
7.2 vs.
5.1
40%
vs.
30%
HR 0.90
18.0 vs. 16.1
123
HR 0.34
6.9 vs.
3.3
48%
vs.
16%
HR 0.50
12.2 vs. 7.7
* Statistically significant difference
Evolving Paradigms and Optimizing Management of
Metastatic Breast Cancer
Is combination cytotoxic
therapy more effective than
single agent therapy as firstline therapy or beyond?
Single Agent vs Combination Chemotherapy
for Metastatic Breast Cancer
►
Methods
●
Randomized trials single agent vs. combination chemotherapy
•
Results - 43 eligible trials (N=9742 randomized)
●
●
●
●
Overall survival
• HR 0.88 (95% CI=0.83-0.94, P <0.0001) & no heterogeneity
• Results are similar if analysis is limited to first-line chemotherapy
Time to disease progression
• HR 0.78 (95% CI=0.74-0.82, P <0.00001) (heterogeneity (P = 0.002)
Response rate
• Odds ratio 1.29 (95% CI=1.14-1.45, P <0.0001) (heterogeneity P
The survival benefit seen in older
studies not evident in more
<0.00001) – due to varying efficacy of the comparators
contemporary studies with
Toxicity
• More neutropenia, alopecia,
with combinations
availability
of nausea/vomiting
numerous
agents
and targeted therapies
Carrick S, et al. The Cochrane Database of Syst Rev 2009;(2):CD003372.
First Line Cytotoxic Therapy for Metastatic
Disease: Prior Adjuvant Anthracycline
Selected Trials
Author
Combination vs.
Comparator
Median
TTP/PFS
(months)
ORR
OS
(months)
Albain et al
JCO 2008
Gem + Paclitaxel
vs. Paclitaxel
HR 0.70
6.1 vs. 4.2*
(TTP)
41%
vs. 26%*
HR 0.78
18.6 vs.
15.8*
HR 0.65
9.8 vs. 7.0*
(TTP)
35%
vs. 26%*
HR 1.01
20.5 vs. 20.6
Sparano et al
JCO 2009
PLD + Docetaxel
vs. Docetaxel
• * Statistically significant difference
•PLD – pegylated liposomal doxorubicin
Second or Greater Line Cytotoxic Therapy:
Prior Anthracycline/Taxane Exposure
Selected Trials
Author
O’Shaughnessy et al
JCO 2002
Thomas et al
JCO 2007
Sparano et al
JCO 2010
Experimental
vs. Standard
Cap+ Docetaxel
vs. Docetaxel
Ixabepilone+Cap
vs. Capecitabine
Ixabepilone+Cap
vs. Capecitabine
No.
Median
TTP/PFS
(mo.)
ORR
OS
(mo.)
511
HR 0.65
6.1 vs.
4.2*
(TTP)
42%
vs.
30%*
0.78
14.5 vs.
11.5*
752
HR 0.75
5.8 vs.
4.2*
(PFS)
35%
vs.
14%*
12.9 vs.
11.1
1221
HR 0.79
6.2 vs.
4.2*
(PFS)
43%
vs.
29%*
HR 0.9
16.4 vs.
15.6
HR 0.87
3.7 vs. 2.2
(PFS)
12%
vs.7%*
0.81
13.1 vs.
10.7*
Twelves et al
Eribulin vs.
762
2010
Physician’sdifference
Choice
*ACO
Statistically
significant
Combination Chemotherapy Versus
Sequential Single-agent Chemotherapy
►
Both combinations of cytotoxic chemotherapy and singleagent chemotherapy are reasonable options as first-line
systemic therapy
►
NCCN guidelines & ESO-mBC task force, sequential singleagent chemotherapy should be the preferred choice
●
●
●
►
In absence of rapid clinical progression
Life-threatening visceral metastases or
Need for rapid symptom and/or disease control
Guidelines did not address use of biologics in
combinations
Cardoso et al. J Natl Cancer Inst. 2009;101(17):1174-1181.
Conclusions:
Systemic Therapy for MBC
►
Treatment regimen should be individualized
●
●
►
Identify and prioritize therapeutic goals
Select least toxic option required to achieve therapeutic goals
Decision based upon multiple factors including
●
Disease-specific factors (Her2/neu, ER/PR status)
●
Patient-specific factors
• ER/PR-positive: endocrine therapy
• Her2/neu-positive: anti-HER2 therapy
•
•
•
•
•
Prior treatment history
Performance status
Age
Co-morbidities (eg, cardiac disease)
Patient preference (eg, avoid alopecia)
Conclusions:
General Principles in Selecting Therapy
►
Cytotoxic therapy
●
●
●
►
Usually reserved for ER-negative disease, or ER-positive disease resistant to
endocrine therapy or associated with substantial symptom burden
Use single agents rather than combinations whenever feasible
Combination cytotoxic therapy may be indicated in selected circumstances
Breast cancer subtypes
●
●
●
ER-Positive Disease
• Use endocrine therapy (ET) as first line therapy whenever feasible
• Switch to alternative ET if prolonged benefit from first or second/greater
lines of ET
HER2-Positive Disease
• When chemotherapy indicated, always used in combination with anti-HER2
directed therapy
Triple-negative disease or resistant to endocrine therapy
• Cytototoxic therapy
Evolving Paradigms and Optimizing Management of
Metastatic Breast Cancer
A Landscape Update on Metastatic Breast
Cancer (MBC):— What Works? What Doesn’t?
Strategies for Optimizing Survival:
An Evidence-to-Practice Roadmap for MBC
Program Chair
Debu Tripathy, M.D.
Professor of Medicine
USC/Norris Comprehensive Cancer Center
University of Southern California
Los Angeles, CA
Principles of Systemic Therapy for
Advanced Metastatic Breast Cancer
►
Evaluation includes careful history and examination with
staging scans, biopsy and biomarkers (if possible)
►
For ER or PR+, trial of salvage hormonal therapy
►
Chemotherapy for hormone-insensitive or aggressive
presentations
►
Doublets of chemotherapy – higher response and time to
progression , marginal effects on survival, ↑ toxicities
►
Addition of HER2 blockade to hormonal or chemotherapy
(trastuzumab, lapatinib) for HER2+ disease
►
Addition of anti-angiogenic therapy improves time to
progression, but not survival
►
Newer targeted therapies in appropriate subgroups and
combinations being actively studied
Key Issues Surrounding Chemotherapy
for Advanced Breast Cancer
►
►
►
►
►
►
►
►
Are there specific chemotherapy agents that are superior in
first or subsequent lines of therapy?
Should chemotherapy breaks be given in patients with
stable or responsive disease?
Should chemotherapy combinations be given instead of
single agents?
If so when should combinations be used?
What is the role of schedule and dose?
Can drug delivery be improved (eg. nanoparticle,
liposomes, immunotoxins)?
Can one predict toxicities of single or combination therapy?
What is the basis for individualizing treatment choices?
Cell Cycle-Specific Activity of Cytotoxics
•Vinca Alkaloids
 Vinorelbine
 Vinblastine
•Podopyllotoxins
 Etoposide
•Camptothecins
 Irinotecan
•Antimetabolites
 5-FU, fluoropyrimidines
 Gemcitabine
 Methotrexate
•Antimicrotubule agents
 Paclitaxel
 Docetaxel
 Epothilones
 Eribulin
Cell CycleNonSpecific Agents
• Alkylating Agents
 Platinum
 Cyclophosphamide
 Thiotepa
 Nitrosoureas
• Antibiotics
 Anthracycines
o Doxorubicin
o Epirubicin
o Mitoxantrone
Response Rates with Single-Agent
Chemotherapy in Advanced Breast Cancer
Pre – Year 2000
First-Line
Second-Line
Doxorubicin
40 - 50%
32 - 36%
Epirubicin
52 - 68%
Paclitaxel
29 - 63%
19 - 57%
Docetaxel
47 - 65%
39 - 58%
Capecitabine
~25%
20 - 27%
Gemcitabine
23 - 37%
13 - 41%
Vinorelbine
40 - 44%
17 - 36%
~28%
Docetaxel vs. Paclitaxel
Overall Survival
Intention-to-Treat Population
Proportion Alive
1
Censored
0.8
Paclitaxel 175 mg/m2
Docetaxel 100 mg/m2
0.6
0.4
P=0.03
0.2
0
0
20
Jones SE, et al. J Clin Oncol 2005
40
60
Survival (Months)
80
100
Hematologic Toxicity
Docetaxel
N= 222
Paclitaxel
N= 222
Overall Gr 3/4 Overall Gr 3/4
Neutropenia*
Febrile Neutropenia*
96%
93%
83%
15%
55%
2%
Anemia
77%
10%
61%
7%
Thrombocytopenia
52%
5%
32%
3%
*For difference in grade 3 / 4 toxicities, p < 0.05
3 treatment related deaths in the docetaxel arm (due to
infection) and 1 non-treatment related death (GI bleed); no
treatment related deaths with paclitaxel
Jones SE, et al. J Clin Oncol 2005
Maintenance Therapy for Advanced
Hormonally Sensitive Breast Cancer
“Induction”
• Significant visceral
involvement
• Significant symptoms
• Likely clinical sequelae with
small degree of progression
• Chemotherapy
• For HER2+,
Chemotherapy + HER2directed therapy
Maintenance
Therapy
• Prior response/stability to
hormonal therapy
• Low disease burden, minimal
visceral involvement
• Low level of symptoms
• Hormonal therapy
• For HER2+, hormonal
therapy plus HER2directed therapy
Trials Examining Continuous vs.
Interrupted/Fixed Therapy
Study
Treatment Schedules
Coates A et al
NEJM 1987
AC/CMF until PD
Harris AL et al
Lancet 1990
Mitoxantrone until PD
Muss H et al
NEJM 1991
FAC x 6 → CMF x 12
Ejlertsen B
Eur J Ca 1993
FEC + TAM x 18
Gregory R et al
Eur J Ca 1997
VAC/VEC x 6 → MMM x 6
Falkson G et al
JCO 1998
A x 6 → CMFPTH x 8
Nooij M et al
Eur J Ca 2003
CMF until PD
AC x 3 cycles
Mitoxantrone x 4
FAC x 6
FEC + TAM x 6
VAC/VEC/MMM x 6
Ax6
CMF x 6
N
Med TTP
(mo)
p
6
305
43
4
5.5
6.5
3.2
0.02
NS
10
<0.001
7
< .003
7.8
0.01
3.5
NS
19.6
0.67
18
0.03
10.5
0.3
32.2
<0.0001
5.2
196
12
13.0
18.7
195
11
0.19
23
10
100
9.4
21.1
14
254
p
10.7
9.4
145
Med OS
(mo)
28.7
0.74
14.0
0.01
14.4
0.77
Trials Examining Continuous vs.
Interrupted/Fixed Therapy
Contemporary Regimens
Study
Treatment Schedules
Gennari A
et al
JCO 2006
E/A + P x 6-8 → P x 8
Alba E
et al
ASCO 2007
A →T x 6 → PLD
E/A + P x 6-8
A →T x 6
N
Med
TTP
(mo)
p
8.0*
215
9.0*
10.2
5.1*
p
26.0
0.817
13.2
8.4*
155
Med
OS
(mo)
29.0
0.006*
0.005
* From time of randomization to maintenance arm
E = epirubicin; A = doxorubicin; P = paclitaxel; T = docetaxel;
PLD = pegylated liposomal doxorubicin
0.547
Single vs. Combination vs.
Sequential Chemotherapy
Paclitaxel
Doxorubicin
+ Paclitaxel
36%
34%
47%
Median TTF
6 mos.
6 mos.
8 mos.
Median Survival
19 mos.
22 mos.
22 mos.
Doxorubicin
Response
QOL
=
=
Crossover Responses:
=
A
T
Sledge G et al. J Clin Oncol 2003
T = 22%
A = 20%
NS
Finnish Randomized Comparison of Single Agents
vs Combinations As First- and Second-Line
Chemotherapy for Metastatic Breast Cancer
First -Line
20 mg/m2 weekly
E
E
E
E
E
E
E
E
E
E
E
E
C 500 mg/m2 C
C
C
C
E 60 mg/m2 E
E
E
E
F 500 mg/m2 F
F
F
F
1
Second-Line
E
4
7
10
Weeks
13
MC 8 mg/m2
MC
MC
MC
MC 8 mg/m2
MC
MC
MC
V 6 mg/m2
V
V
V
1
Joensuu H et al. J Clin Oncol 1998
5
Weeks
9
13
Single Agents vs Combinations as
1st- and 2nd-Line Chemotherapy for MBC
Finnish Breast Cancer Group Study
Regimen
CEF
E
MV
M
RR
Response Duration
55%
48%
16%
12 mos
10.5 mos
-
7%
-
►
No significant difference in overall TTP for E
►
No difference in overall survival for E M vs CEF
calculated from second-line Rx (P = 0.56)
►
Less toxicity and better QOL with single agents
Joensuu H et al. J Clin Oncol 1998
M vs CEF
MV (P = 0.28)
MV (P = 0.96) or survival
Combination vs. Monotherapy for MBC:
No Survival Benefit (n=2,490)
►
Dox + Paclitaxel = Single Agents Sequentially
(Sledge, J Clin Oncol 2003)
►
FEC then MV = Epirubicin then Mitomycin C
(Joensuu, J Clin Oncol 1998)
►
Taxotere > Mitomycin C + Vinblastine
(Nabholtz, J Clin Oncol 1999)
►
Taxol > CMFP
(Bishop, J Clin Oncol 1998)
►
FEC = Mitoxantrone
(Heidemann, Ann Oncol 2002)
►
Dox + Vinorelbine = Doxorubicin
(Norris, J Clin Oncol 2000)
►
Epirubicin + Vinorelbine = Epirubicin
Ejlertsen, J Clin Oncol 2004
Single vs Combination Chemotherapy:
Recent Positive Trials in MBC - Overall Survival
Capecitabine/docetaxel
Docetaxel
100%
Events
72%
79%
Median (CI)
14.5 (12.3–16.3)
11.5 (9.8–12.7)
Survival
12 mo
18 mo
Hazard ratio = 0.775
Log-rank
p=0.0126
Gemcitabine +
Paclitaxel (n=267)
70.7%
50.7%
Paclitaxel
(n=262)
60.9%
41.9%
100%
11.5
0
Log rank P=0.018
HR 0.78 (0.63-0.96)
14.5
10
20
Months
15.8
O'Shaughnessy J et al J Clin Oncol 2002
Albain K et al J Clin Oncol 2009
0
12
18.5
24
Months
Patients (%)
Capecitabine plus Docetaxel: Most Common
(>5%) Grade 3/4 Treatment-Related Toxicities
30
Capecitabine/docetaxel
(n=251)
Grade 3
Grade 4
25
Docetaxel
(n=255)
Grade 3
Grade 4
20
15
10
5
0
O'Shaughnessy J, et al J Clin Onocol 2002
Combination vs. Single-Agent Therapy for
MBC: Meta-Analysis of Randomized Trials
Regimens
Combination
Single agent
AV
A + DBD
A + MMC
VAC
CF + P ± V
A + ETO
AV + MMC
E + VDS
FEC 75
FEC 50
Hazard ratio of death
(combination:single agent)
A
A
A
A
A
A
A
E
E
E
Subtotal (deaths/patients) 619/738
649/747
0.87 (0.78–0.97)
CMF + VBL
CMF
CMFV + P
CF + P ± V
CF + P ± V
Subtotal (deaths/patients) 206/252
C
PAM
F
CCNU
I
225/249
0.70 (0.59–0.84)
874/996
0.82 (0.75–0.90)
Total (deaths/patients)
825/990
0
0.5
1.0
1.5
2.0
Combination better
Single agent better
Efficacy: c 17.5 (p=0.00002)
2
Fossati R et al. J Clin Oncol 1998
Paclitaxel: Dose/Schedule Comparison
CALGB 9840
1998-2000
(n=171; HER2 unknown)
2000-2003
(n=406; HER2 known)
q3w P
q1w P
H
E
R
2
(+)
*first 116 pts at 100 mg/m2/wk x 6, q3wP+T
then all pts 80 mg/m2 q wk
q1wP+T
H
E
R
2
(-)
= paclitaxel 80 mg/m2* qw vs 175 mg/m2 q 3w
= trastuzumab 4mg/kg load, 2 mg/kg/w
Seidman A, et al. J Clin Oncol 2008
Paclitaxel: Dose/Schedule Comparison
CALGB 9840
Seidman A, et al. J Clin Oncol 2008
Pegylated Liposomal Doxorubicin (PLD)
Doxorubicin
Liposomal
doxorubicin
Pegylated liposomal
doxorubicin
► Prolonged half life (>55 hours)
- Pegylation reduced uptake by reticuloendothelial system
► Preferential tumor penetration
- Compromised vasculature in tumor tissue
► Reduced volume of distribution
- Limited exposure to normal tissue, e.g. heart.
Gabizon A et al. Clin Pharmacokinet 2003
Phase III trial: Pegylated liposomal doxorubicin
(PLD) plus Docetaxel vs. Docetaxel
Alone in Advanced Breast Cancer
Eligibility:
R
a
n
d
o
m
i
z
e
- Advanced breast
cancer
- Relapsed ≥1 year
following
neo/adjuvant
anthracyclines (≥180
and ≤360 mg/m2)
N=751
PLD (30 mg/m2) +
Docetaxel (60 mg/m2)
day 1 every 21 days
N=378
Docetaxel (75 mg/m2)
day 1 every 21 days
N=373
Primary endpoint: TTP
Secondary endpoints: OS, ORR, overall safety, cardiac safety
Sparano J et al. JCO 2009
PLD plus Docetaxel vs. Docetaxel
Alone in Advanced Breast Cancer
Docetaxel
PLD +
Docetaxel
HR
P-Value
Median TTP
7.0 months
9.8 months
0.65
.000001
ORR
26%
35%
-
.0085
Median OS*
20.7 months
20.6 months
1.03
.75
Docetaxel
(N=373)
PLD + Docetaxel
(N=377)
Neutropenia
59%
57%
Febrile Neutropenia
6%
7%
0
24%*
1%
11%
Select Grade 3/4 Adverse Events
Hand-Foot syndrome
Stomatitis
* 20% patients discontinued due to HFS generally managed by dose
modification
Grade ≥2 cardiac AEs: similar for Doc vs. Doc + PLD (4% vs. 5%)
Sparano J et al. JCO 2009
Randomized nab-Paclitaxel
Trial Design: CA012
Albumin-bound paclitaxel 260 mg/m2
iv over 30 min q3w
No standard premedication
MBC with prior
anthracycline and no prior
taxane for MBC
Randomisation (1:1)
n = 460
Paclitaxel 175 mg/m2
iv over 3 hrs q3w
Standard premedication with
dexamethasone and antihistamines
Gradishar et al. J Clin Oncol 2005
Randomized nab-Paclitaxel Trial
Response Rates
ORR (± 95% CI)
60
P = 0.001
P = 0.029
P = 0.006
P = 0.002
P = 0.002
50
42.3%
40
34.1%
33.2%
27.0%
30
26.5%
18.7%
20
33.5%
18.3%
18.7%
13.2%
10
0
All patients
First-line
therapy
≥ Second-line Anthracycline
therapy
exposed
Visceral
disease
Albumin-bound n
229
paclitaxel
97
132
176
176
225
89
136
175
182
Paclitaxel
Gradishar et al. J Clin Oncol 2005
Nab-Paclitaxel:
Different Dose/Schedules vs. Docetaxel
100
Response Rates
90
80
70
60
50
40
30
20
10
0
300
mg/m2
q3w
n = 76
100
mg/m2
qw 3/4
n = 76
150
mg/m2
qw 3/4
n = 74
Nab-Paclitaxel
100
mg/m2
q3w
n = 74
Docetaxel
Gradishar W et al. JCO 2009
Capecitabine ± Ixabepilone in
Taxane and Anthracyline-Resistant MBC
Investigator
% Response
ORR (CR + PR)
Ixabepilone +
Capecitabine
(N=375)
Capecitabine
(N=377)
Ixabepilone +
Capecitabine
(N=375)
Capecitabine
(N=377)
42
23
35
14
P < 0.0001
Stable Disease
Independent
Radiology Review
36
38
P <0.0001
41
Median Progression-Free Survival: by IRR (95% CI)
Ixabepilone + capecitabine: 5.8 months (5.5-7.0)
Capecitabine: 4.2 months (3.8-4.5)
Hazard ratio: 0.75 (0.64-0.88); P=0.0003
Vahdat L et al. JCO 2007
46
Progression-free Survival
by Independent Radiologic Review
Proportion Progression Free
1.0
0.8
Median
95% CI
Ixabepilone +
Capecitabine
5.8 mo
(5.5–7.0)
Capecitabine
4.2 mo
(3.8–4.5)
0.6
HR: 0.75 (0.64–0.88)
P=0.0003
0.4
0.2
0 0
4
8
12
16
20
Months
Vahdat L et al. JCO 2007
24
28
32
36
Gene Expression Profiling Reveals Distinct Clusters
HER2+ subtype
1. 15-20% of tumors
2. prognostic/predictive
2. proliferation
3. two types (ER -/+)
Basal subtype
1. 10-15% of tumors
2. ER/PR/HER2-negative
3. very proliferative
4. EGFR, c-kit, c-myc +
5. includes BRCA1
mutations
Luminal A and B (ER+)
1. continuum
2. prognostic/predictive
3. ER-GATA3-HNF3a-XBP1
4. proliferation (mutant
p53)
5. cyclin D1 and BCL2 +
Ki-67, STK6,
Survivin, Cyclin B1
and MYBL2
Sorlie T et al. PNAS 20
p <0.0001
p <0.001
Sorlie T et
al.
Where are We Today with Chemotherpy
for Advanced Breast Cancer ?
►
No clear single agent stands out as superior, but certain
comparisons have been noted
•
•
►
►
►
►
First line (eg. docetaxel > paclitaxel)
Late line (eg. eribulin > several single agents after 2 or more
chemotherapy regimens for MBC)
Combinations are superior for response and TTP, so may be
indicated for symptoms or high visceral burden
Dose and schedule matter, particularly for taxanes
Certain combinations may be synergistic in preclinical
models, but difficult to prove in the clinic
Molecular diagnostics and pharmacogenomics may point
the way to individualizing chemotherapy for efficacy and
toxicity
Evolving Paradigms and Optimizing Management of
Metastatic Breast Cancer
Microtubules as a Target for Anticancer
Drugs —Multi-Mechanistic Approaches to
Mitigating Metastatic Breast Disease
The Role of Nontaxane Microtubule Dynamics Inhibitors –
Evidence and Implications of Recent Clinical Studies
Paraskevi Giannakakou, PhD
Associate Professor of Pharmacology in Medicine │Weill Cornell
Medical College │New York, NY
Evolving Paradigms and Optimizing Management of
Metastatic Breast Cancer
Improving Overall Survival in
Metastatic Breast Cancer
The Role of Nontaxane Microtubule Dynamics Inhibitors –
Evidence and Implications of Recent Clinical Studies
Sara Hurvitz, MD
Assistant Clinical Professor of Medicine
Director, Breast Oncology Program
David Geffen School of Medicine
University of California, Los Angeles
Los Angeles, CA
Microtubule Targeting Agents
►
Taxanes
●
►
Vinca alkaloids
●
►
Vinorelbine, vinflunine
Epothilones
●
►
Docetaxel, paclitaxel, nab-paclitaxel
Ixabepilone, KOS 862 (EPO D), ZK-EPO, patupilone
Halichondrin B analogue
●
Eribulin (E7389)
Microtubules
►
Key component of cell cytoskeleton made of
dynamic filamentous protein polymers
arranged in specific formation essential to cell
division
►
Mitosis (mitotic spindle)
►
Chemotaxis/locomotion
►
Intracellular transport
►
Secretory processes
►
Receptor anchorage
►
Receptor signaling
Mechanisms of action
of microtubule-targeted agents
Vinca
alkaloids
Taxanes/Epothilones
Destabilizers
Stabilizers
 Polymerization
 Polymerization
Mitotic spindle
formation blocked
MT Bundling
Multipolar spindles
Graphic courtesy of Harold J. Burstein, MD, PhD.
Sorangium cellulosum
►
Myxobacteria
● Secondary metabolites
(epothilones/fungicides)
Zambezi river
Ixabepilone (BMS-247550)
►
Semisynthetic analog of epothilone B (azaepothilone B)
►
Molecular difference between ixabepilone and
epothilone because of amine vs ester moiety
Ixabepilone
Epothilone B
Conclusions: Preclinical
►
Ixabepilone
●
●
●
●
●
●
●
►
Semisynthetic analog of epothilone B
Bind specifically and uniquely to beta-tubulin
Tubulin polymerizing activity 2-10 x greater than paclitaxel
Have activity in tumors that use MDR as a resistance
mechanism
Active in multiple in vivo tumor models
Similar mechanism of action (G2/M arrest, Bax
conformational change)
Linear pharmacology
Ixabepilone + other agents
●
●
Synergy with capecitabine, cetuximab, trastuzumab
Greater in vivo synergy with bevacizumab than paclitaxel
Ixabepilone: Preclinical Activity
Capecitabine Synergy
Activity in Paclitaxel Resistance
N=8
Control
Capecitabine
2500
Ixabepilone
100
Paclitaxel
Control
Paclitaxel Rx (36 mg/kg/inj)
Ixabepilone Rx (10 mg/kg/inj)
10
Median tumor weight (mg)
Median Tumor Weight (mg)
1000
Ixabepilone
Combination
250 mg/kg (MTD)
2000
10 mg/kg (MTD)
1500
1000
500
(P=0.0001)
0
40
70
100
130
160
10
750
Control
Bevacizumab
Ixabepilone
Combined
0
Bevacizumab IP 4 mg/kg
Ixabepilone IV
15
35
55
75
Days Post-Tumor Implant
L2987 Human Lung Carcinoma
Data on file. Bristol Myers Squibb Company; Princeton, NJ
Median tumor weight (mg)
Median Tumor Weight (mg)
10000
1000
250
50
Trastuzumab Synergy
Bevacizumab Synergy
500
30
Days post-tumor implant
Days Post-Tumor Implant
Pat-21 Xenograft
1000
Control
Trastuzumab
Ixabepilone
100
Combined
Rx
10
1
20
40
60
Days Post-Tumor Implant
HER2 receptor positive KPL4
Human breast Carcinoma Xenografts
Ixabepilone in Metastatic Breast Cancer:
Summary of Single-Agent Phase II Trials
Roche H et al. J Clin Oncol. 2007;23:3415-3420; Denduluri N et al. J Clin Oncol. 2007;23:3421-3427;
Low et al. J Clin Oncol 2005;23:2726–2734; Thomas E et al. J Clin Oncol. 2007;23:3399-3406.
Phase II Study 081: Ixabepilone in
Triple Refractory MBC
Prior therapy with
anthracycline, taxane,
and capecitabine
(N=126)
Ixabepilone
40 mg/m2 IV q3w1
PD or unacceptable
toxicity
Max 18 cycles
Primary end point: ORR
Resistance Criteria
• Neoadjuvant or Adjuvant: ≤ 6 months of last dose
• Metastatic: ≤ 8 weeks of last dose
• Progression during or after discontinuation of trastuzumab in HER2+
patients
Perez E, et al. J Clin Oncol. 2007;23: 3407-3414.
Phase II Study 081: Ixabepilone in
Triple Refractory MBC
Characteristic
Median age (min-max) in years
Visceral disease (liver and/or lung)
No. of disease sites: 3–4
≥5
ER-, PR-, HER2-
Patients, no. (%)
(N=126)
51 (30–78)
108 (86)
62 (49)
19 (15)
42 (33)
Prior neoadjuvant/adjuvant chemotherapy
95 (75)
No. of prior chemotherapy regimens for
metastatic disease
1
2
3
15 (12)
51 (40)
60 (48)
No. of prior taxane-containing regimen
Any
≥2
≥3
126 (100)
38 (30)
7 (6)
Perez E, et al. J Clin Oncol. 2007;23: 3407-3414.
Phase II Study 081: Efficacy
Outcome
Response-Evaluable
(n=113)
Tumor response rate, % (95% CI)
IRR assessment
12.4 (6.9-19.9)
Investigator assessment
18.6 (11.9-27.0)
Median response duration, mo (95% CI)
Stable disease rate, %
Median duration of stable disease,
mo (95% CI)
6.0 (5.0-7.6)
49.6
4.5 (3.7–6.0)
Treated Patients (n=126)
Median PFS, mo (95% CI)
3.2 (2.8-4.3)
Median survival, mo (95% CI)
9.0 (7.3-11.2)
IRR = independent radiology review.
Perez E, et al. J Clin Oncol. 2007;23: 3407-3414.
Phase II Study 081: Safety
Grade 3/4 Toxicity
Hematologic
Neutropenia
Febrile neutropenia
Leukopenia
% of Patients
(n=126)
54
2
49
Anemia
8
Thrombocytopenia
7
Nonhematologic
Peripheral sensory neuropathy
14
Fatigue
13
Myalgia/arthralgia
8
Stomatitis
6
Perez E, et al. J Clin Oncol. 2007;23: 3407-3414.
Conclusions
►
►
This is the first large prospective trial in triple therapy
refractory metastatic breast cancer
Ixabepilone demonstrates efficacy in patients with
anthracycline-taxane and capecitabine refractory MBC
● Overall population
• Median PFS 3.2 months
• Median overall survival 9 months
• Response rate 18% (investigator assessment)
►
►
Safety profile is acceptable
In summary, ixabepilone represent a new choice in patients
with patients with triple-therapy refractory MBC
Capecitabine  Ixabepilone Study 046:
Clinical Eligibility Criteria for Resistance
Strict definition: patients whose tumors rapidly progressed in the adjuvant
or metastatic setting after receiving both anthracyclines and taxanes
Setting
Metastatic
Neo/adjuvant
Any
Anthracycline
Taxane
≤3 months of last dose
≤4 months of last dose
≤6 months of last dose
≤12 months of last
dose
Minimum cumulative
dose
Doxorubicin: 240 mg/m2
Epirubicin: 360 mg/m2
Perez E, et al. J Clin Oncol. 2007;23: 3407-3414.
046/048 Phase III MBC Trials: Ixabepilone
and Capecitabine Combination
►
Pivotal trial CA163-046
●
►
Patients prospectively defined using a
strict definition of resistance to previous
anthracycline and taxane therapy
Confirmatory trial CA163-048
●
Patients with metastatic disease who were
pretreated with or resistant to an
anthracycline and a taxane
• 50% met strict resistance criteria in
pivotal trial
046/048 Phase III MBC Trials:
Study Design
Ixabepilone
(40 mg/m2 IV over 3 hr d1 q3wk)
Metastatic / locally advanced
breast cancer pretreated with
or resistant to taxanes
and anthracyclines
+
Capecitabine
(2000 mg/m2/day BID 14 days q3wk)
Capecitabine
(2500 mg/m2/day BID 14 days q3wk)
Hortobagyi GN et al ASCO Breast 2008
046/048 Phase III Trials:
Progression Free Survival
Study 046
Outcome
Median PFS,
months
Study 048
Ixa +
Cape
N=375
Cape
N=377
Ixa +
Cape
N=480
Cape
N=480
5.26
3.81
6.24
4.40
Hazard ratio
(95.17% CI)
0.78
(0.67 – 0.91)
0.79
(0.69 – 0.90)
Stratified logrank
P-value
0.0011
0.0005
Roche et al. BCRT 2010
046/048 Phase III Trials:
Objective Response Rate
Study 046*
Outcome
Ixa +
Cape
Study 048
Cape
Ixa + Cape
N=462
N=462
42.1
22.5
43.3
28.8
37.1 – 47.3
18.4 –
27.1
38.7 – 47.9
24.7 – 33.2
12 (3)
3 (1)
16 (3)
11 (2)
Partial response
146 (39)
82 (22)
184 (40)
122 (26)
Stable disease
136 (36)
144 (38)
170 (37)
182 (39)
Progressive disease
51 (14)
109 (29)
57 (12)
111 (24)
Unable to determine
30 (8)
39 (10)
35 (8)
36 (8)
N=375
Objective response
rate, %
95% CI
N=377
Cape
Best Response, N (%)
Complete response
*ORR in 046 presented by investigator assessment.
Roche et al. BCRT 2010
046/048 Phase III Trials:
Overall Survival
Study 046
Outcome
Ixa +
Cape
N=375
Median overall
survival,
months
No. of events
Hazard ratio
(95.17% CI)
Stratified log-rank Pvalue
Roche et al. BCRT 2010
Cape
N=377
Study 048
Ixa +
Cape
N=609
Cape
N=612
12.9
11.1
16.4
15.6
318
321
430
450
0.90
(0.77 – 1.05)
0.90
(0.78 – 1.03)
0.1936
0.1162
Evolving Paradigms and Optimizing Management of
Metastatic Breast Cancer
046/048 Planned
Subset Analyses
Pooled Subgroup Analyses:
Objective Response Rates
Patients With
Ixa + Cape, % Cape, %
Triple negative tumors
31
15
Taxane resistant tumors
39
22
Poor KPS (70-80)
35
19
Roche et al. BCRT 2010
Pooled Subgroup Analyses:
Median Progression Free Survival
Ixa + Cape,
months
Cape,
months
P value
Triple negative tumors
4.2
1.7
.0005
Taxane resistant
tumors
5.1
3.7
.0003
Poor KPS (70-80)
4.6
3.1
.0007
Patients With
Roche et al. BCRT 2010
046/048 Phase III Trials: Summary
► Ixabepilone
+ capecitabine demonstrated clinically
meaningful efficacy (increase in PFS and ORR) in a large
heavily pretreated patient population (~2000) with limited
treatment options
► The
difference in median overall survival favored the
combination: this difference did not reach statistical
significance
► Ixabepilone
plus capecitabine treatment showed consistent
clinical benefit in difficult to treat sub-populations, including
triple receptor MBC
► Study
048 reinforced the manageable safety profile of
ixabepilone
●
●
Similar profile as study 046
Low frequency of toxicity related deaths (<1%) in both arms
Roche et al. BCRT 2010
Evolving Paradigms and Optimizing Management of
Metastatic Breast Cancer
Halichondrin B Analogue (E7389)
after Anthracyclines, Taxanes and
Capecitabine:
Eribulin (E7389): Mechanism of Action
Microtubule dynamics
Polymerize
De-polymerize
E7389-induced formation of tubulin aggregates
No drug
1 µM E7389
3.3 µM E7389
M.A. Jordan et al, Mol Cancer Ther 4:1086, 2005
Paclitaxel
Microtubule stabilization
Eribulin
Inhibits Microtubule Assembly
Non-productive aggregates
Eribulin: Tubulin-based
Antimitotic Mechanism
Inhibition of tubulin polymerization in vitro
Absorbance (340 nm)
G2/M cycle blocks
0.16
E7389
0 μM
1.5 μM
0.12
3 μM
0.08
5 μM
7.5 μM
0.04
15 μM
0
0
10
20
30
40
Minutes
U937 cells, 100 nM
Disruption of mitotic spindles (DAPI/β-tubulin)
Control
DU 145 cells, 3xIC50 @ 20 h
Towle et al., Cancer Research, 61:1013-1021, 2001
Eribulin
50
60
70
Eribulin: Preclinical Activity Across a
Range of Models
Human tumor xenografts (0.05-1.0 mg/kg)
MDA-MB-435 Human Breast Cancer
MWFx4, i.v.
ER-086526 1 mg/kg
Paclitaxel 25 mg/kg
600
400
200
0
0
14
28
42
56
70
84
98
Day
1600
1200
800
400
0
0
ER-086526 1 mg/kg
ER-086526 0.25 mg/kg
Paclitaxel 20 mg/kg
Average tumor volume
tumor volumes (µl)
(mm3Average
)
Average tumor volume
(mm3)
Average tumor volumes (µl)
ER-086526 0.5 mg/kg
14
21
28
35
42
Eribulin
COLO 205 Human Colon Cancer
MWFx4, i.p.
1500
ER-086526 0.125 mg/kg
7
Day
OVCAR-3 Human Ovarian Cancer
MWFx3, i.v.
Control
Control
Control
ER-086526 0.05 mg/kg
ER-086526 0.1 mg/kg
ER-086526 0.25 mg/kg
ER-086526 0.5 mg/kg
Paclitaxel 12.5 mg/kg
2000
Average tumor volume
(mm3)
Average tumor volumes (µl)
Control
ER-086526 0.25 mg/kg
ER-086526 0.5 mg/kg
Average tumor volume
(mm3)
Average tumor volumes (µl)
800
LOX Human Melanoma
Q1Dx5[x2], i.p.
1000
500
0
1500
Control
ER-086526 0.125 mg/kg
ER-086526 0.5 mg/kg
Paclitaxel 20 mg/kg
1000
500
0
39
46
53
60
67
74
81
88
95
Day
Towle et al., Cancer Research, 61:1013-1021, 2001
LOX melanoma
Towle MJ unpublished results, ERI, 2007
0
14
28
42
Day
56
70
Summary of Eribulin Phase II Studies
in Breast Cancer
Study[1]
201
(N = 103)
Eribulin IV 1.4
(n = 70)
over 2-5 mins on Days 1, 8, 15 q4w
Prior anthra &
taxane Tx*
Eribulin IV 1.4 mg/m2 (n = 33)
over 2-5 mins on Days 1, 8 q3w
211 Study[2]
(N = 299)
Prior anthra,
taxane, &
cape Tx*
mg/m2
Assessments
ORR with
independent
review
Response
duration,
PFS, and OS
Eribulin IV 1.4 mg/m2
over 2-5 min on Days 1, 8 q3w
*MBC patients with progression of disease ≤ 6 mos of last chemotherapy, if present,
preexisting neuropathy ≤ grade 2.
1. Vahdat LT, et al. J Clin Oncol. 2009;27:2954-2956. 2. Vahdat LT, et al. ASCO 2008. Abstract 1084.
Adverse
events
ITT Efficacy Summary of Phase II
Eribulin Breast Cancer Studies
201 Trial1
211 Trial2
4
4
Response rate,* %
13.6
9.0
Clinical benefit rate,† %
20.4
17.1
Duration of response, median mos
5.6
4.1
Characteristic/Response
Previous regimens, median n
(N = 103)
(N = 269)
*CR + PR.
†CR+ PR + SD for ≥ 6 mos.
1. Vahdat LT, et al. J Clin Oncol. 2009;27:2954-2956. 2. Vahdat LT, et al. ASCO 2008. Abstract 1084.
Summary of Eribulin Phase II Study
Grade 3/4 Adverse Events
201 Trial[1]
211 Trial[2]
Neutropenia
64
54
Febrile neutropenia
4
6
Thrombocytopenia
2
1
Mucositis
1
1
Peripheral
neuropathy
5
6
Adverse Events, %
(N = 103)
(N = 291)
1.Vahdat l, et al. J Clin Oncol. 2009;27:2954-2956. 2. Vahdat LT, et al. ASCO 2008. Abstract 1084.
Additional Studies of Eribulin in
Metastatic Breast Cancer
EMBRACE
Study (305)*
Phase III
Eribulin IV on Days 1, 8, q21 Days
Physicians choice (monotherapy)
Eribulin
301 Study†
Phase III
MBC
Phase II
Capecitabine
Eribulin IV on Days 1, 8, q21 Days
Ixabepilone 40 mg/m2 IV q3w
*Third-line breast cancer treatment.
†Second-line breast cancer treatment.
ClinicalTrials.gov. NCT00388726; NCT00337103; NCT00879086.
Primary endpoints:
OS
ASCO 2010
PFS, OS
completed
Development
of peripheral
neuropathy
EMBRACE
A Phase III study (EMBRACE*) of eribulin
mesylate vs. treatment of physician’s choice
in patients with locally recurrent or
metastatic breast cancer previously treated
with an anthracycline and a taxane
Dr Chris Twelves
Professor of Clinical Cancer Pharmacology and Oncology
University of Leeds & St James’s University Hospital, Leeds, UK
On behalf of the abstract co-authors and EMBRACE
investigators
*Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus Eribulin (E7389)
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 Patient Characteristics
Characteristic
Eribulin
(n=508)
TPC
(n=254)
TOTAL
(n=762)
Median age (range)
55
(28-85)
56
(27-81)
55
(27-85)
ECOG, %
0
1
2
Missing
43
48
8
1.6
41
50
9
1
42
49
8
1
Geographic region, %
I North America, Western Europe, Australia
II Eastern Europe, Russia, Turkey
III Latin America, South Africa
64
25
11
64
25
11
64
25
11
Prior capecitabine, %
Yes
No
73
27
74
26
73
27
4 (1-7)
4 (2-7)
4 (1-7)
Median no. prior chemotherapy regimens (range)
ITT population
EMBRACE Disease Characteristics
Characteristic
Eribulin
(n=508)
TPC
(n=254)
TOTAL
(n=762)
ER positive, %
66
67
67
PR positive, %
50
48
50
Positive
16
16
16
Negative
73
76
74
Unknown
10
9
10
18
21
20
≤2
51
46
49
>2
49
54
51
Liver
58
63
61
Lung
39
37
38
Bone
60
62
61
HER2/neu status, %
Triple (ER/PR/HER2) negative, %
No. organs involved, %
Sites of disease,* %
ITT population; *Clinically relevant sites of disease; ER, estrogen receptor; PR, progesterone receptor
EMBRACE: Demographic and
Baseline Characteristics
Hormone Therapy
Eribulin
(n=508)
TPC
(n=254)
Overall
(n=762)
Previous hormone therapy
430 (85%)
210 (83%)
640 (84%)
1
220 (43%)
96 (38%)
316 (41%)
2
109 (21%)
65 (26%)
174 (23%)
3
60 (12%)
23 (9%)
83 (11%)
>4
41 (8%)
26 (10%)
67 (9%)
Number of previous hormone
regiments
Cortes J, et al. The Lancet, Early Online Publication, 3 March 2011
EMBRACE TPC Treatment Received
96% of patients treated with chemotherapy
Total patients = 247
% of
patients
n=61
n=46
n=44
n=38
n=24
n=25
n=9
No patient received best supportive care or “biological” therapies only
ITT population; Taxanes: paclitaxel, docetaxel, abraxane, (ixabepilone)
Anthracyclines: doxorubicin, liposomal doxorubicin, mitoxantrone
EMBRACE Best Overall Response
Response
ORR (CR+PR), %
Independent
review
Investigator
review
Eribulin
(n=468)
TPC
(n=214)
Eribulin
(n=468)
TPC
(n=214)
12
5
13
7
p-value
0.002
0.028
SD, %
44.4
44.9
46.8
44.9
PD, %
40.6
49.1
37.6
45.3
NE, %
2.6
1.4
2.4
2.3
22.6
16.8
27.8
20.1
Clinical benefit rate
(CR + PR + SD ≥6 months),%
Response evaluable population
CR, complete response; PR, partial response; SD, stable disease;
PD, progressive disease; NE, non-evaluable
EMBRACE: ITT Progression-Free
Survival by Independent Review
PFS 3.7 vs 2.2 mos
p=0.137
Cortes J, et al. The Lancet, Early Online Publication, 3 March 2011
EMBRACE: Per-Protocol Population ProgressionFree Survival by Independent Review
Cortes J, et al. The Lancet, Early Online Publication, 3 March 2011
EMBRACE Overall Survival
1 year survival
1.0
Eribulin (n=508)
53.9%
TPC (n=254)
43.7%
Survival probability
0.8
Eribulin
Median 13.12 months
0.6
HR* 0.81 (95% CI 0.66, 0.99)
p-value†=0.041
TPC
Median 10.65 months
0.4
0.2
2.47 months
0.0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
Overall survival (months)
ITT population; *HR Cox model including geographic region, HER2/neu status, and prior capecitabine therapy as strata
†p value from stratified log-rank test (pre-defined primary analysis); HR, hazard ratio; CI, confidence intervals
EMBRACE: Overall Survival in an
Updated Analysis
Cortes J, et al. The Lancet, Early Online Publication, 3 March 2011
EMBRACE: Exploratory Subgroup
Analysis of Overall Survival
Cortes J, et al. The Lancet, Early Online Publication, 3 March 2011
EMBRACE Overall Incidence of AEs
Eribulin
(n=503)
TPC
(n=247)
All AEs
98.8
93.1
Serious AEs
25.0
25.9
5.0
10.1
Discontinuation
13.3
15.4
Dose reduction
16.9
15.8
Dose delay
35.2
32.4
Fatal AEs
4.0
7.3
Fatal AEs (treatment-related)
1.0
0.8
Adverse event (AE), %
AEs leading to
Interruption
EMBRACE Grade 3 and 4 AEs*
Grade 3
Adverse Events
Grade 4
Eribulin
(n=503)
TPC
(n=247)
Eribulin
(n=503)
TPC
(n=247)
Hematologic events, %
Neutropenia
Leukopenia
Anemia
Febrile neutropenia
21.1
11.7
1.8
3.0
14.2
4.9
3.2
0.8
24.1
2.2
0.2
1.2
6.9
0.8
0.4
0.4
Non-hematologic events, %
Asthenia / fatigue
Peripheral neuropathy†
Nausea
Dyspnea
Mucosal inflammation
Hand-foot syndrome
8.2
7.8
1.2
3.6
1.4
0.4
10.1
2.0
2.4
2.4
2.0
3.6
0.6
0.4
0
0
0
0
0
0
0
0.4
0
0
*>2% incidence; † Neuropathy peripheral, neuropathy, paresthesia, peripheral motor neuropathy, polyneuropathy, peripheral
sensory neuropathy, peripheral sensorimotor neuropathy, demyelinating polyneuropathy
Phase 3 Trials in MBC Patients Previously
Treated with an Anthracycline and a Taxane
Cortes J, et al. The Lancet, Early Online Publication, 3 March 2011
EMBRACE: Conclusions
►
EMBRACE is the first Phase III single-agent study in heavily pretreated MBC to meet its primary endpoint of prolonged overall
survival
►
Eribulin demonstrated a statistically significant improvement in
overall survival
●
Improvement of median overall survival was 2.5 months (23%)
●
Clinically meaningful in heavily pretreated patients
►
Overall response rate and progression-free survival also favored
eribulin
►
These benefits were achieved with a manageable safety profile
Conclusions
►
Ixabepilone and eribulin are new therapeutic
options for metastatic breast cancer
►
Approved for pretreated breast cancer
►
Neutropenia and neuropathy are most common
adverse events
Case Study 1
►
43-year-old Army wife and mother of 5
children presents with a 6 cm, 5/12 + LN,
ER+, PR+, Her2 nonamplified breast cancer in
early 2007.
►
No PMH other than postpartum depression
►
No medications
►
Staging studies including a bone scan, CT/PET
scan and cardiac echo are within normal limits
Case Study 1
►
Patient receives 6 cycles of TAC followed by
tamoxifen at an outside institution. Tolerates
well.
►
One year after completing her chemotherapy,
patient develops midthoracic pain. Bone scan
reveals metastatic disease at T8 and L1. CT
scan reveals no visceral disease.
►
Bone biopsy confirms ER+ and HER2recurrence
Case Study 1
►
Patient receives radiation to L1 spine with good
pain relief. Undergoes laparascopic oophorectomy
followed by enrollment on a clinical trial of
Exemestane and a IGFR mAb. Zoledronic acid is
initiated.
►
Does well until early 2009 when staging studies
reveal new bony mets. LFTs remain normal. Bone
scan is stable. Patient receives fulvestrant.
Case Study 1
►
Patient does well until late 2009 when staging
studies reveal multiple new liver lesions. LFTs
remain normal. Bone scan is stable.
Case Study 1
►
Capecitabine is initiated at 900
mg/m2, po, bid. Patient requires dose
reduction to 700 mg/m2, po, bid
secondary to diarrhea and hand foot
syndrome after first cycle.
►
Initial scans show a near complete
response in the liver
Case Study 1
►
In the middle of 2010, patient demonstrated
progression within the liver on single agent
Capecitabine after 8 months and Bevacizumab
was added.
►
Restaging after 6 weeks of combination
therapy demonstrated further progression.
LFTs still normal. Patient wants additional
therapy.
Case Study 1
►
Patient was placed on single agent eribulin.
Her scans have shown a near complete
response in the liver after 3 cycles.
►
Last cycle, patient reported an increase in
peripheral neuropathy and she was dose
reduced per package insert.
Case Study 2
►
64-year-old retired bookkeeper
●
●
Stage II ER+, PR-, HER2- breast cancer, dose dense AC-T
Developed cough 5 years later on anastrazole
• Bilateral pulmonary nodules
• CT guided biopsy positive
– ER+, PR-, HER2- disease
• Bone scan positive
– Lytic lesions on CT
– No symptoms
• Other factors
– ECOG PS 1
– Non-insulin dependent diabetes
– Hypertension
What will you recommend?
Your choice for initial systemic therapy is:
1. Chemotherapy
2. Chemotherapy plus bevacizumab
3. Endocrine therapy
What will you recommend?
► Received fulvestrant with SD for 9 months, then
develops increasing cough and bone pain.
What chemotherapy regimen do you recommend?
1. Single agent capecitabine
2. Single agent taxane
3. Paclitaxel or docetaxel + bevacizumab
4. Paclitaxel + gemcitabine
5. Docetaxel + capecitabine
6. Carboplatin + gemcitabine
7. Other
What will you recommend?
Received paclitaxel with bevacizumab with response,
then progression 12 months later.
What chemotherapy regimen do you recommend?
1. Single agent capecitabine
2. Ixabepilone
3. Ixabepilone + capecitabine
4. Eribulin
Case Study 3
► 44-year-old unemployed investment banker with T3N2M0 “triple
negative” invasive breast cancer
– In 2006, received adjuvant docetaxel/doxorubicin/
cyclophosphamide
– Abdominal cramping and distention.
 CT scan: omental “caking”, peritoneal nodularity and a moderate
amount of ascites; the ovaries and adnexae appeared normal. 6
bilateral pulmonary nodules, and a small right pleural effusion was
noted.
 Serum CA-125: normal.
 Serum CA 15-3: elevated at 235.
 Abdominal paracentesis: straw colored fluid
• Cytologic examination: adenocarcinoma cells morphologically
similar to her prior primary invasive breast cancer.
What will you recommend?
1. Single agent capecitabine
2. Single agent taxane
3. Paclitaxel or docetaxel + bevacizumab
4. Paclitaxel + gemcitabine
5. Docetaxel + capecitabine
6. Carboplatin + gemcitabine
7. Other
What will you recommend?
► Received paclitaxel with bevacizumab with response
and then PD at 12 months, then capecitabine with
progression at 6 months.
What chemotherapy regimen do you recommend?
1. Carboplatin + gemcitabine
2. Ixabepilone
3. Ixabepilone + capecitabine
4. Eribulin
5. Other
Case Study 4
► A 62-year-old woman is treated with modified radical
mastectomy 5 years prior, for a T2N0M0 ER/PR/HERnegative infiltrating ductal cancer.
► She is treated with doxorubicin and cyclophosphamide for
four cycles.
► She now is noted on a routine chest x-ray to have 4
pulmonary nodules in the right and left lungs, with CT
and bone scans showing no other disease other than
several rib metastases.
► A CT-directed biopsy of the lung shows infiltrating ductal
cancer, ER/PR/HER-negative, and TTF-1-negative. She
has no symptoms and ECOG performance score of 0.
What will you recommend?
At this point, which strategy would you recommend?
1.Single agent paclitaxel every 3 weeks
2.Single agent paclitaxel weekly
3.Docetaxel plus gemcitabine
4.Ixabepilone
Case Study 5
► This patient is treated with docetaxel plus capecitabine for
3 cycles and exhibits a response, but subsequently
required dose reductions of both drugs do to fatigue,
delayed count recovery and hand-foot syndrome.
► After 6 months, scans show progression in the lung and
three new liver metastases, 1-2 cm in size
► Apart from fatigue, she has no symptoms, but has
reduced her work to part time. Blood work and serum
chemistries are normal except for a mild anemia. ECOG
performance score is 1
What will you recommend?
At this point, which strategy would you recommend?
1.Paclitaxel plus gemcitabine
2.Albumin-bound paclitaxel plus gemcitabine
3.Albumin-bound paclitaxel alone
4.Ixabepilone
Case Study 6
Patient M.C., 61 years old, female
► No Family Hx for cancer
► No hormone replacing therapy
► Annual screening mammography, always negative
► 2004: during self palpation, she notices a non-tender
mass in her left breast
► No skin changes, no palpable adenopathies in the
omolateral axilla
► Mammography: presence of a 2,3 cm density, with
irregular edges
Courtesy of Giuseppe Galletti, MD Weill Cornell Medical College
Case Study 6
FNA of the lesion: Invasive Ductal Carcinoma
► No evidence of metastatic disease at PET/CT scan
► April 2004: lumpectomy and SLN (positive) followed by
omolateral axillary lymph node dissection
► Pathology results: Invasive Ductal Carcinoma
► pT2 (2,7 cm) pN1a (3/18 positive nodes) M0 Stage IIB
Courtesy of Giuseppe Galletti, MD Weill Cornell Medical College
Case Study 6
► May-June 2004: adjuvant chemotherapy
Doxorubicin 60 mg/m2 + Cyclophosphamide 600
mg/m2 x 4 → Docetaxel 75 mg/m2 x 4 →
Trastuzumab for 1 year
► Left breast irradiation (50 Gy + 10 Gy boost)
NCCN Guideline Version 2.2011 Clinical
Case Study 6
► June 2009: increase of Ca 15-3 levels; a CT scan revealed
the presence of liver and bone metastases
► 1st line metastatic chemotherapy: weekly paclitaxel 80
mg/m² + Zoledronic Acid 4 mg every 28 days
► Side effects: two episodes G2 neutropenia
► After 8 weeks of treatment, Partial Response at CT scan
► She continued paclitaxel for further 16 weeks and
experienced G2-3 peripheral neuropathy (paresthesia) as
main side effect.
► December 2009: stable disease at CT scan; she stopped
chemo and started Examestane as hormonal therapy
Courtesy of Giuseppe Galletti, MD Weill Cornell Medical College
Case Study 6
► July 2010: onset of dispnea and
headaches; evidence of right pleural
effusion, increase in size of liver mets
and presence of brain lesions at CT
scan
► July-August 2010: stereotactic
radiation therapy on brain mets
followed by complete regression of the
two lesions on subsequent MRI
► August 2010: patient started
Ixabepilone 40 mg
Thomas E et al. JCO 2007; 25(33): 5210-17
Case Study 6
► After the 2nd cycle, a Total Body CT scan showed stable
disease
► Chemotherapy continued for further 4 cycles
► At the end of the 3rd administration, patient referred G3
peripheral neuropathy (paresthesia and sensory loss tp
lower limbs), partially recovered
► December 2010: A total body CT scan confirmed the
stable disease
► Currently relapse free and under 3rd line
Courtesy of Giuseppe Galletti, MD Weill Cornell Medical College
Case Study 6
► Microtubule targeting agents as backbone of breast
cancer chemotherapy in the adjuvant and metastatic
setting
► Taxanes fundamental to improve disease free survival
and overall survival in the adjuvant strategies
► Ixabepilone still active against a very taxane-resistant
disease
► Neurological toxicitiy as main side effects of almost all
microtubule targeting agents (eribulin seems to better
tolerated)
Courtesy of Giuseppe Galletti, MD Weill Cornell Medical College