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Evolving Paradigms Evolving Paradigms forfor Optimizing Management Optimizing Management
ofof Metastatic Breast CancerMetastatic Breast Cancer
Investigations • Innovation • Clinical ApplicationInvestigations • Innovation • Clinical Application
Focus on Novel Mechanisms of Action and Focus on Novel Mechanisms of Action and Evidence-Based Therapies for Survival Prolongation Evidence-Based Therapies for Survival Prolongation
in Heavily Treated Patients with MBCin Heavily Treated Patients with MBC
Program ChairProgram Chair Debu Tripathy, MDDebu Tripathy, MDProfessor of MedicineProfessor of Medicine
USC/Norris Comprehensive Cancer CenterUSC/Norris Comprehensive Cancer CenterUniversity of Southern CaliforniaUniversity of Southern California
Los Angeles, CALos Angeles, CA
CME-certified symposium CME-certified symposium jointly jointly sponsored by the Postgraduate sponsored by the Postgraduate Institute for Medicine and Institute for Medicine and CMEducation Resources, LLCCMEducation Resources, LLC
Commercial Support: Commercial Support: Sponsored Sponsored by an independent educational by an independent educational grant from Eisai, Inc.grant from Eisai, Inc.
Faculty disclosures: Faculty disclosures: Listed in Listed in program syllabusprogram syllabus
This CME activity may include This CME activity may include discussions of discussions of off-label or off-label or unapproved uses unapproved uses of specific of specific agents agents
Welcome and Program Overview Welcome and Program Overview
Program FacultyProgram Faculty
Program ChairProgram Chair Debu Tripathy, M.D.Debu Tripathy, M.D.Professor of MedicineProfessor of MedicineUSC/Norris Comprehensive USC/Norris Comprehensive Cancer Cancer CenterCenterUniversity of Southern CaliforniaUniversity of Southern CaliforniaLos Angeles, CALos Angeles, CA
Sara Hurvitz, MDSara Hurvitz, MDAssistant Clinical Professor of Assistant Clinical Professor of MedicineMedicineDirector, Breast Oncology Director, Breast Oncology ProgramProgramDavid Geffen School of Medicine David Geffen School of Medicine University of California, Los University of California, Los AngelesAngelesLos Angeles, CALos Angeles, CA
Paraskevi Giannakakou, PhDParaskevi Giannakakou, PhDAssociate Professor of Associate Professor of Pharmacology Pharmacology in Medicinein MedicineWeill Cornell Medical CollegeWeill Cornell Medical CollegeNew York, NYNew York, NY
CME Program AgendaCME Program Agenda
8:30 AM — 8:45 AM8:30 AM — 8:45 AM
Chairman’s Introduction Chairman’s Introduction An Overview of Current Issues and Controversies An Overview of Current Issues and Controversies Surrounding Management of Advanced and Surrounding Management of Advanced and Metastatic Breast Cancer Metastatic Breast Cancer
DEBU TRIPATHY, MD —DEBU TRIPATHY, MD —Program ChairProgram Chair Professor of Medicine │ USC/Norris Comprehensive Cancer Professor of Medicine │ USC/Norris Comprehensive Cancer Center │ University of Southern California │ Los Angeles, CACenter │ University of Southern California │ Los Angeles, CA
8:45 AM — 9:15 AM8:45 AM — 9:15 AM
A Landscape Update on Metastatic Breast Cancer A Landscape Update on Metastatic Breast Cancer (MBC)— What Works? What Doesn’t? Strategies for (MBC)— What Works? What Doesn’t? Strategies for Optimizing Survival: An Evidence-to-Practice Optimizing Survival: An Evidence-to-Practice Roadmap for MBC Roadmap for MBC
DEBU TRIPATHY, MD —DEBU TRIPATHY, MD —Program ChairProgram Chair Professor of Medicine │ USC/Norris Comprehensive Cancer Center Professor of Medicine │ USC/Norris Comprehensive Cancer Center │ University of Southern California │ Los Angeles, CA│ University of Southern California │ Los Angeles, CA
9:15 AM — 9:25 AM9:15 AM — 9:25 AM
Question and Answer SessionQuestion and Answer Session
CME Program AgendaCME Program Agenda
9:25 AM — 9:50 AM9:25 AM — 9:50 AMMicrotubules as a Target for Anticancer Drugs —Multi-Microtubules as a Target for Anticancer Drugs —Multi-Mechanistic Approaches to Mitigating Metastatic Mechanistic Approaches to Mitigating Metastatic Breast Disease Breast Disease
Paraskevi Giannakakou, PhDParaskevi Giannakakou, PhDAssociate Professor of Pharmacology in Medicine Associate Professor of Pharmacology in Medicine ││Weill Cornell Weill Cornell Medical CollegeMedical College │ │New York, NYNew York, NY
9:50 AM — 10:00 AM9:50 AM — 10:00 AMQuestion and Answer SessionQuestion and Answer Session 10:00 AM — 10:30 AM10:00 AM — 10:30 AMImproving Overall Survival Prolongation in MBC: The Improving Overall Survival Prolongation in MBC: The Role of Nontaxane Microtubule Dynamics inhibitors—Role of Nontaxane Microtubule Dynamics inhibitors—Evidence and Implications of Recent Clinical Studies Evidence and Implications of Recent Clinical Studies
Sara Hurvitz, MDSara Hurvitz, MDAssistant Clinical Professor of MedicineAssistant Clinical Professor of Medicine │ │Director, Breast Oncology Director, Breast Oncology Program Program │ │ David Geffen School of Medicine David Geffen School of Medicine ││University of California, University of California, Los AngelesLos Angeles
CME Program AgendaCME Program Agenda
10:30 AM — 10:40 AM10:30 AM — 10:40 AMQuestion and Answer SessionQuestion and Answer Session
10:40 AM — 11:05 AM10:40 AM — 11:05 AMCase Studies in Metastatic Breast CancerCase Studies in Metastatic Breast Cancer
DEBU TRIPATHY, MD —DEBU TRIPATHY, MD —Program ChairProgram Chair Professor of Medicine │ USC/Norris Comprehensive Cancer Professor of Medicine │ USC/Norris Comprehensive Cancer Center │ University of Southern California │ Los Angeles, CACenter │ University of Southern California │ Los Angeles, CA
11:05 AM — 11:15 AM11:05 AM — 11:15 AMQuestion and Answer SessionQuestion and Answer Session
An Overview of Current Issues An Overview of Current Issues and Controversies Surrounding and Controversies Surrounding Management of Advanced and Management of Advanced and
Metastatic Breast CancerMetastatic Breast Cancer
Evolving Paradigms and Optimizing Management Evolving Paradigms and Optimizing Management ofof
Metastatic Breast CancerMetastatic Breast Cancer
Program ChairProgram Chair Debu Tripathy, MDDebu Tripathy, MDProfessor of MedicineProfessor of Medicine
USC/Norris Comprehensive Cancer CenterUSC/Norris Comprehensive Cancer CenterUniversity of Southern CaliforniaUniversity of Southern California
Los Angeles, CALos Angeles, CA
Learning ObjectivesLearning Objectives
► Understand the treatment options for Understand the treatment options for metastatic breast cancer as first-line therapy metastatic breast cancer as first-line therapy and beyondand beyond
► Understand how breast cancer subtype Understand how breast cancer subtype influences treatment options and selection influences treatment options and selection
► Understand the side effect profile associated Understand the side effect profile associated with different agents with different agents
What are the Therapeutic Goals?What are the Therapeutic Goals?
► Survival prolongationSurvival prolongation► Symptom palliation, delay, or preemptionSymptom palliation, delay, or preemption
● Response (surrogate for symptom relief) Response (surrogate for symptom relief) ● PFS, TTP, TTF (surrogates for symptom delay)PFS, TTP, TTF (surrogates for symptom delay)● Quality of life (QOL) instrumentsQuality of life (QOL) instruments
► Achieve favorable tradeoff profile (ie, efficacy Achieve favorable tradeoff profile (ie, efficacy vs. toxicity) vs. toxicity) ● No consistent relationship between RR/PFS and QOLNo consistent relationship between RR/PFS and QOL● No clinically useful tool to measure QOL or tradeoffsNo clinically useful tool to measure QOL or tradeoffs● Subjective assessment often made by clinicians Subjective assessment often made by clinicians
based uponbased upon• objective data from trials (RR, PFS, OS, toxicity)objective data from trials (RR, PFS, OS, toxicity)• subjective data for individual patient (performance status)subjective data for individual patient (performance status)
Therapeutic GoalsTherapeutic Goals
► Live longerLive longer• Prolong survival Prolong survival
► Live better Live better ● Symptom palliation or delaySymptom palliation or delay● Favorable tradeoff profileFavorable tradeoff profile
• ToxicityToxicity• ConvenienceConvenience• CostCost
Complex
Subjective
Simple
Objective
Survival and FDA Approval of Survival and FDA Approval of Oncology Drugs for Metastatic Breast Oncology Drugs for Metastatic Breast
Cancer Cancer ► 2003 (Johnson, Williams, Pazdur. 2003 (Johnson, Williams, Pazdur. J Clin Oncol 2003)J Clin Oncol 2003)
● ““There is a common There is a common misperceptionmisperception that … FDA … requires a that … FDA … requires a survival improvementsurvival improvement for approval of oncology drug marketing for approval of oncology drug marketing applications.””applications.””
● ““Regular …approval …requires substantialRegular …approval …requires substantial evidence of evidence of efficacy…efficacy…””
● “…“…prolongationprolongation of life, a better life, or an established surrogate of life, a better life, or an established surrogate for at leastfor at least one of these.”one of these.”
► 2008 (Cortesar. 2008 (Cortesar. Proc ASCO 2008Proc ASCO 2008))● “…“…survival is both a safety and efficacy parameter…survival is both a safety and efficacy parameter…● ““PFS may be an acceptable endpoint if measured properly and PFS may be an acceptable endpoint if measured properly and
is of sufficient magnitude. “is of sufficient magnitude. “● ““Survival also should be measured to ensure that any new Survival also should be measured to ensure that any new
therapy does not lead to a decrement.”therapy does not lead to a decrement.”
What are the Therapeutic Options?What are the Therapeutic Options?
ModalityModality Selection Selection Improvement inImprovement in
RRRR PFSPFS OSOS
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 What are the Toxicities Associated with Therapeutic Options?with Therapeutic Options?
AgentAgent Non-hematologic toxicitiesNon-hematologic toxicities
Endocrine therapy Hot flushes, gynecologic symptomsHot flushes, gynecologic symptoms
Bevacizumab Hypertension, thromboembolic diseaseHypertension, thromboembolic disease
Trastuzumab Cardiac dysfunctionCardiac dysfunction
Lapatinib DiarrheaDiarrhea
Cytotoxic agents•Anthracycllnes•Paclitaxel•Docetaxel•Ixabepilone•Eribulin•Vinorelbine•Capecitabine•Gemicitabine
•CardiomyopathyCardiomyopathy•NeuropathyNeuropathy•Fluid retentionFluid retention•NeuropathyNeuropathy•NeuropathyNeuropathy•Obstipation, nueropathyObstipation, nueropathy•Hand-foot syndromeHand-foot syndrome•Fever, dyspneaFever, dyspnea
Does Cytotoxic Chemotherapy Does Cytotoxic Chemotherapy Improve Survival? Improve Survival?
Chia et al. Cancer 2007; 110: 973-979Chia et al. Cancer 2007; 110: 973-979
Overa
ll S
urv
ival
Overa
ll S
urv
ival
YearsYears
1999-20011999-2001
1997-19981997-1998
1994-19951994-1995
1991-19921991-1992
00 1 2 3 4 5 1 2 3 4 5
1.01.0
0.80.8
0.60.6
0.40.4
0.20.2
0.00.0
• Clinical trials Clinical trials – Hundreds of trials, few show OS benefitHundreds of trials, few show OS benefit– Few that show benefit - play of chance?Few that show benefit - play of chance?– More positive trials in second or greater More positive trials in second or greater
line settingline setting• Population-based studiesPopulation-based studies
– Suggests that addition of modestly Suggests that addition of modestly effective cytotoxic agents have produced effective cytotoxic agents have produced incremental improvements in OSincremental improvements in OS
Broglio, K. R. et al. J. Natl. Cancer Inst. 2009
Probability of Detecting Significant Difference in Probability of Detecting Significant Difference in OS as a Function of Median OS Post-Progression OS as a Function of Median OS Post-Progression
(SPP)(SPP)
Median SPP (months)Median SPP (months)
Pro
babili
ty o
f O
S S
tati
stic
al Sig
nifi
cance
(%
)Pro
babili
ty o
f O
S S
tati
stic
al Sig
nifi
cance
(%
)
80% power for PFS80% power for PFS85% power for PFS85% power for PFS90% power for PFS90% power for PFS
0 4 8 12 16 20 240 4 8 12 16 20 24
100100
8080
6060
4040
2020
00
90
80
70
60
50
40
30
20
10
00
Complete/partial responseStable diseaseProgressive disease
PainPainCRFCRF
PainPainQoLQoL
Shortness Shortness of breath of breath
CRFCRF
Shortness Shortness of breath of breath
QoLQoL
Mood Mood
CRFCRF
WorrWorry y
QoLQoL
DepressioDepression QoLn QoL
Does Chemotherapy Palliate Does Chemotherapy Palliate Symptoms ?Symptoms ?
Geels P, et al. Geels P, et al. J Clin OncolJ Clin Oncol 2000;18:2395-2405. 2000;18:2395-2405.
Is Chemotherapy more Effective than Is Chemotherapy more Effective than Endocrine Therapy in ER-Positive Disease?Endocrine Therapy in ER-Positive Disease?
► MethodsMethods● Meta-analysisMeta-analysis● Randomized trials comparing chemotherapy alone with endocrine therapy alone Randomized trials comparing chemotherapy alone with endocrine therapy alone
in metastatic breast cancerin metastatic breast cancer
► Results (8 trials, N=817)Results (8 trials, N=817)● No difference in OS: HR 0.94 (95%CI 0.79-1.12,P=0.5) (heterogeneity P = 0.1)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)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 directionsTwo largest trials showed trends in opposite directions
► ToxicityToxicity● Increased toxicity with chemotherapy (nausea, vomiting and alopecia)Increased toxicity with chemotherapy (nausea, vomiting and alopecia)● 3 of 7 mentioned aspects of QOL, with differing results - only one trial formally 3 of 7 mentioned aspects of QOL, with differing results - only one trial formally
measured QOL, concluding that it was better with chemotherapymeasured QOL, concluding that it was better with chemotherapy
• Authors' conclusionsAuthors' conclusions● ““In women with metastatic breast cancer and where hormone receptors are In women with metastatic breast cancer and where hormone receptors are
present, a policy of treating first with endocrine therapy rather than present, a policy of treating first with endocrine therapy rather than chemotherapy is recommended except in the presence of rapidly progressive chemotherapy is recommended except in the presence of rapidly progressive disease.”disease.”
et al. The Cochrane Database of Syst Rev 2003;(2):CD002747.
What is the role for What is the role for targeted agent as first line targeted agent as first line
therapy or beyond?therapy or beyond?
Evolving Paradigms and Optimizing Management Evolving Paradigms and Optimizing Management ofof
Metastatic Breast CancerMetastatic Breast Cancer
Treatment Effect of Trastuzumab asTreatment Effect of Trastuzumab asFirst Line Therapy in HER2-Positive MBCFirst Line Therapy in HER2-Positive MBC
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< .001P = .0002
P< .001
P< .0001
Chemotherapy alone Chemotherapy plus trastuzumab
Treatment Effect of Trastuzumab asTreatment Effect of Trastuzumab as First-Line Therapy in HER2-Positive MBC First-Line Therapy in HER2-Positive MBC
P = .046
P = .0325
Chemotherapy alone Chemotherapy plus trastuzumab
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 Treatment Effect of Bevacizumab as First-line Therapy for MBC (Mainly HER2-Negative)Therapy for MBC (Mainly HER2-Negative)
P< .0001P = .0097
P = .0054P< .0001
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.
*
†
†
†
* Chemotherapy alone vs chemotherapy plus 10 mg/kg bevacizumab† Chemotherapy plus placebo vs chemotherapy plus 15 mg/kg bevacizumab
E21001 AVADO2 RIBBON-13
Chemotherapy alone/plus placebo Chemotherapy plus bevacizumab
Response Rate
Treatment Effect of Bevacizumab as First-line Treatment Effect of Bevacizumab as First-line Therapy for MBC (Mainly HER2-Negative) Therapy for MBC (Mainly HER2-Negative)
P< .001P = .0002 P = .0001P = .006
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.
*† † †
E21001 AVADO2 RIBBON-13
Chemotherapy alone/plus placebo Chemotherapy plus bevacizumab
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
Progression Free Survival
Bevacizumab: Meta-analysisBevacizumab: Meta-analysis
No No bevacizumabbevacizumab BevacizumabBevacizumab
No. 1008 1439
ORR 32% 49% P<0.05
Median PFS 6.7 mo 9.2 mo. HR 0.64, p<0.000
1
Median OS 26.4 mo 26.7 mo. P=0.56
1-year survival
77% 82% P<0.003
O’Shaughnessy et al. JCO 2010; 28; 152, abst 1005
Second or Greater Line Biologic Second or Greater Line Biologic Agents Agents
Author & Author & PopulationPopulation
ExperimentaExperimental vs. l vs.
StandardStandardNo.No.
Median Median TTP/PFSTTP/PFS
(mo.)(mo.)ORRORR OSOS
(mo.)(mo.)
Geyer et al. NEJM 2006 & Cameron
ASCO 2007HER2+, Trast.
Resistant
Lapatinib + Lapatinib + Cap vs.Cap vs.
Cap aloneCap alone324324
HR 0.57HR 0.576.2 vs. 6.2 vs.
4.34.3
22% 22% vs. vs.
14%*14%*
HR 0.78HR 0.7815.6 vs. 15.6 vs.
15.315.3
Brufsky et al.SABCS, 2009
HER2-, Prior chemo
Bev vs. Bev vs. placeboplacebo
PlusPlusChemotherapChemotherap
yy
684684HR 0.78HR 0.787.2 vs. 7.2 vs.
5.15.1
40%40% vs. vs. 30%30%
HR 0.90HR 0.9018.0 vs. 18.0 vs.
16.116.1
O’Shaughnessy et alASCO 2009 & SABSC 2010
Triple Negative
Carbo/gem Carbo/gem +/- BSI-201+/- BSI-201 123123
HR 0.34HR 0.346.9 vs. 6.9 vs.
3.33.3
48%48% vs. vs. 16%16%
HR 0.50HR 0.5012.2 vs. 12.2 vs.
7.77.7* Statistically significant difference
Is combination cytotoxic Is combination cytotoxic therapy more effective than therapy more effective than
single agent therapy as single agent therapy as first-line therapy or first-line therapy or
beyond? beyond?
Evolving Paradigms and Optimizing Management Evolving Paradigms and Optimizing Management ofof
Metastatic Breast CancerMetastatic Breast Cancer
Single Agent vs Combination Single Agent vs Combination Chemotherapy for Metastatic Breast Chemotherapy for Metastatic Breast
CancerCancer► MethodsMethods
● Randomized trials single agent vs. combination chemotherapyRandomized trials single agent vs. combination chemotherapy
• Results - 43 eligible trials (N=9742 randomized)Results - 43 eligible trials (N=9742 randomized)● Overall survival Overall survival
• HR 0.88 (95% CI=0.83-0.94, P <0.0001) & no heterogeneityHR 0.88 (95% CI=0.83-0.94, P <0.0001) & no heterogeneity• Results are similar if analysis is limited to first-line chemotherapyResults are similar if analysis is limited to first-line chemotherapy
● Time to disease progression Time to disease progression • HR 0.78 (95% CI=0.74-0.82, P <0.00001) (heterogeneity (P = HR 0.78 (95% CI=0.74-0.82, P <0.00001) (heterogeneity (P =
0.002)0.002)● Response rate Response rate
• Odds ratio 1.29 (95% CI=1.14-1.45, P <0.0001) (heterogeneity P Odds ratio 1.29 (95% CI=1.14-1.45, P <0.0001) (heterogeneity P <0.00001) – due to varying efficacy of the comparators <0.00001) – due to varying efficacy of the comparators
● ToxicityToxicity• More neutropenia, alopecia, nausea/vomiting with combinationsMore neutropenia, alopecia, nausea/vomiting with combinations
Carrick S, et al. The Cochrane Database of Syst Rev 2009;(2):CD003372.
The survival benefit seen in older studies not evident in more contemporary studies with
availability of numerous agents and targeted therapies
First Line Cytotoxic Therapy for Metastatic First Line Cytotoxic Therapy for Metastatic Disease: Prior Adjuvant AnthracyclineDisease: Prior Adjuvant Anthracycline
AuthorAuthorCombination Combination
vs. vs.
ComparatorComparator
Median Median TTP/PFSTTP/PFS
(months)(months)ORRORR
OSOS
(months)(months)
Albain et alJCO 2008
Gem + PaclitaxelGem + Paclitaxel
vs. Paclitaxelvs. Paclitaxel
HR 0.70HR 0.70
6.1 vs. 4.2*6.1 vs. 4.2*
(TTP)(TTP)
41% 41%
vs. 26%*vs. 26%*
HR 0.78HR 0.78
18.6 vs. 18.6 vs. 15.8*15.8*
Sparano et alJCO 2009
PLD + DocetaxelPLD + Docetaxel
vs. Docetaxelvs. DocetaxelHR 0.65HR 0.65
9.8 vs. 7.0*9.8 vs. 7.0*
(TTP)(TTP)
35% 35%
vs. 26%*vs. 26%*
HR 1.01HR 1.01
20.5 vs. 20.5 vs. 20.620.6
• * Statistically significant difference* Statistically significant difference
•PLD – pegylated liposomal doxorubicin PLD – pegylated liposomal doxorubicin
Selected TrialsSelected Trials
Second or Greater Line Cytotoxic Therapy:Second or Greater Line Cytotoxic Therapy:Prior Anthracycline/Taxane ExposurePrior Anthracycline/Taxane Exposure
AuthorAuthor Experimental Experimental vs. Standard vs. Standard No.No.
Median Median TTP/PFSTTP/PFS
(mo.)(mo.)ORRORR
OSOS
(mo.)(mo.)
O’Shaughnessy et alJCO 2002
Cap+ Docetaxel Cap+ Docetaxel
vs. Docetaxelvs. Docetaxel511511
HR 0.65HR 0.65
6.1 vs. 6.1 vs. 4.2*4.2*
(TTP)(TTP)
42%42%
vs. vs. 30%*30%*
0.780.78
14.5 vs. 14.5 vs. 11.5*11.5*
Thomas et alJCO 2007
Ixabepilone+Cap Ixabepilone+Cap
vs. Capecitabinevs. Capecitabine 752752
HR 0.75HR 0.75
5.8 vs. 5.8 vs. 4.2*4.2*
(PFS)(PFS)
35%35%
vs. vs. 14%*14%*
12.9 vs. 12.9 vs. 11.111.1
Sparano et alJCO 2010
Ixabepilone+Cap Ixabepilone+Cap
vs. Capecitabinevs. Capecitabine 12211221
HR 0.79HR 0.79
6.2 vs. 6.2 vs. 4.2*4.2*
(PFS)(PFS)
43%43%
vs. vs. 29%*29%*
HR 0.9HR 0.9
16.4 vs. 16.4 vs. 15.615.6
Twelves et alACO 2010
Eribulin vs. Eribulin vs.
Physician’s Physician’s ChoiceChoice
762762HR 0.87HR 0.87
3.7 vs. 2.23.7 vs. 2.2
(PFS)(PFS)
12% 12% vs.7%*vs.7%*
0.810.81
13.1 vs. 13.1 vs. 10.7*10.7*
* Statistically significant difference
Selected TrialsSelected Trials
Combination Chemotherapy Versus Combination Chemotherapy Versus Sequential Single-agent ChemotherapySequential Single-agent Chemotherapy
► Both combinations of cytotoxic chemotherapy and Both combinations of cytotoxic chemotherapy and single-agent chemotherapy are reasonable options single-agent chemotherapy are reasonable options as first-line systemic therapyas first-line systemic therapy
► NCCN guidelines & ESO-mBC task force, sequential NCCN guidelines & ESO-mBC task force, sequential single-agent chemotherapy should be the single-agent chemotherapy should be the preferred choicepreferred choice● In absence of rapid clinical progressionIn absence of rapid clinical progression● Life-threatening visceral metastases or Life-threatening visceral metastases or ● Need for rapid symptom and/or disease controlNeed for rapid symptom and/or disease control
► Guidelines did not address use of biologics in Guidelines did not address use of biologics in combinationscombinations
Cardoso et al. J Natl Cancer Inst. 2009;101(17):1174-1181.
Conclusions:Conclusions:Systemic Therapy for MBCSystemic Therapy for MBC
► Treatment regimen should be individualizedTreatment regimen should be individualized● Identify and prioritize therapeutic goals Identify and prioritize therapeutic goals ● Select least toxic option required to achieve therapeutic Select least toxic option required to achieve therapeutic
goalsgoals
► Decision based upon multiple factors includingDecision based upon multiple factors including
● Disease-specific factors (Her2/neu, ER/PR status)Disease-specific factors (Her2/neu, ER/PR status)• ER/PR-positive: endocrine therapy ER/PR-positive: endocrine therapy • Her2/neu-positive: anti-HER2 therapy Her2/neu-positive: anti-HER2 therapy
● Patient-specific factorsPatient-specific factors• Prior treatment history Prior treatment history • Performance statusPerformance status• AgeAge• Co-morbidities (eg, cardiac disease)Co-morbidities (eg, cardiac disease)• Patient preference (eg, avoid alopecia)Patient preference (eg, avoid alopecia)
Conclusions: Conclusions: General Principles in Selecting General Principles in Selecting
TherapyTherapy► Cytotoxic therapyCytotoxic therapy
● Usually reserved for ER-negative disease, or ER-positive disease Usually reserved for ER-negative disease, or ER-positive disease resistant to endocrine therapy or associated with substantial symptom resistant to endocrine therapy or associated with substantial symptom burdenburden
● Use single agents rather than combinations whenever feasibleUse single agents rather than combinations whenever feasible● Combination cytotoxic therapy may be indicated in selected Combination cytotoxic therapy may be indicated in selected
circumstancescircumstances
► Breast cancer subtypesBreast cancer subtypes● ER-Positive DiseaseER-Positive Disease
• Use endocrine therapy (ET) as first line therapy whenever feasibleUse endocrine therapy (ET) as first line therapy whenever feasible• Switch to alternative ET if prolonged benefit from first or Switch to alternative ET if prolonged benefit from first or
second/greater lines of ET second/greater lines of ET ● HER2-Positive DiseaseHER2-Positive Disease
• When chemotherapy indicated, always used in combination with When chemotherapy indicated, always used in combination with anti-HER2 directed therapy anti-HER2 directed therapy
● Triple-negative disease or resistant to endocrine therapy Triple-negative disease or resistant to endocrine therapy • Cytototoxic therapyCytototoxic therapy
A Landscape Update on Metastatic A Landscape Update on Metastatic Breast Cancer (MBC):— What Works? Breast Cancer (MBC):— What Works?
What Doesn’t? What Doesn’t?
Strategies for Optimizing Survival: Strategies for Optimizing Survival: An Evidence-to-Practice Roadmap for MBC An Evidence-to-Practice Roadmap for MBC
Evolving Paradigms and Optimizing Management Evolving Paradigms and Optimizing Management ofof
Metastatic Breast CancerMetastatic Breast Cancer
Program ChairProgram Chair Debu Tripathy, M.D.Debu Tripathy, M.D.Professor of MedicineProfessor of Medicine
USC/Norris Comprehensive Cancer CenterUSC/Norris Comprehensive Cancer CenterUniversity of Southern CaliforniaUniversity of Southern California
Los Angeles, CALos Angeles, CA
Principles of Systemic Therapy forPrinciples of Systemic Therapy forAdvanced Metastatic Breast CancerAdvanced Metastatic Breast Cancer
► Evaluation includes careful history and examination Evaluation includes careful history and examination with staging scans, biopsy and biomarkers (if with staging scans, biopsy and biomarkers (if possible)possible)
► For ER or PR+, trial of salvage hormonal therapyFor ER or PR+, trial of salvage hormonal therapy► Chemotherapy for hormone-insensitive or aggressive Chemotherapy for hormone-insensitive or aggressive
presentationspresentations► Doublets of chemotherapy – higher response and Doublets of chemotherapy – higher response and
time to progression , marginal effects on survival, ↑ time to progression , marginal effects on survival, ↑ toxicitiestoxicities
► Addition of HER2 blockade to hormonal or Addition of HER2 blockade to hormonal or chemotherapy (trastuzumab, lapatinib) for HER2+ chemotherapy (trastuzumab, lapatinib) for HER2+ diseasedisease
► Addition of anti-angiogenic therapy improves time to Addition of anti-angiogenic therapy improves time to progression, but not survivalprogression, but not survival
► Newer targeted therapies in appropriate subgroups Newer targeted therapies in appropriate subgroups and combinations being actively studiedand combinations being actively studied
Key Issues Surrounding Key Issues Surrounding ChemotherapyChemotherapy
for Advanced Breast Cancerfor Advanced Breast Cancer► Are there specific chemotherapy agents that are Are there specific chemotherapy agents that are
superior in first or subsequent lines of therapy?superior in first or subsequent lines of therapy?► Should chemotherapy breaks be given in patients Should chemotherapy breaks be given in patients
with stable or responsive disease?with stable or responsive disease?► Should chemotherapy combinations be given Should chemotherapy combinations be given
instead of single agents?instead of single agents?► If so when should combinations be used?If so when should combinations be used?► What is the role of schedule and dose?What is the role of schedule and dose?► Can drug delivery be improved (eg. nanoparticle, Can drug delivery be improved (eg. nanoparticle,
liposomes, immunotoxins)?liposomes, immunotoxins)?► Can one predict toxicities of single or combination Can one predict toxicities of single or combination
therapy?therapy?► What is the basis for individualizing treatment What is the basis for individualizing treatment
choices?choices?
Cell Cycle-Specific Activity of Cytotoxics•Antimicrotubule agents
PaclitaxelDocetaxelEpothilonesEribulin
•Antimetabolites5-FU, fluoropyrimidinesGemcitabineMethotrexate
Cell CycleNon-Specific Agents
•Alkylating AgentsPlatinumCyclophos-
phamideThiotepaNitrosoureas
•AntibioticsAnthracycines
o Doxorubicino Epirubicino Mitoxantron
e
•PodopyllotoxinsEtoposide
•Camptothecins Irinotecan
•Vinca AlkaloidsVinorelbineVinblastine
Response Rates with Single-AgentResponse Rates with Single-AgentChemotherapy in Advanced Breast CancerChemotherapy in Advanced Breast Cancer
First-Line Second-LineFirst-Line Second-Line
DoxorubicinDoxorubicin 40 - 50% 40 - 50% 32 - 36% 32 - 36%
EpirubicinEpirubicin 52 - 68% 52 - 68% ~28% ~28%
PaclitaxelPaclitaxel 29 - 63% 29 - 63% 19 - 57% 19 - 57%
Docetaxel Docetaxel 47 - 65% 47 - 65% 39 - 58% 39 - 58%
Capecitabine ~25%Capecitabine ~25% 20 - 27% 20 - 27%
GemcitabineGemcitabine 23 - 37% 23 - 37% 13 - 41% 13 - 41%
Vinorelbine Vinorelbine 40 - 44% 40 - 44% 17 - 36% 17 - 36%
Pre – Year 2000Pre – Year 2000
0
0.2
0.4
0.6
0.8
1
0 20 40 60 80 100
Survival (Months)
Pro
port
ion A
live
Censored
Paclitaxel 175 mg/m2
Docetaxel 100 mg/m2
Docetaxel vs. PaclitaxelDocetaxel vs. PaclitaxelOverall SurvivalOverall Survival
P=0.03
Jones SE, et al. J Clin Oncol 2005
Intention-to-Treat PopulationIntention-to-Treat Population
Docetaxel N= 222
Paclitaxel N= 222
Overall Gr 3/4 Overall Gr 3/4
Neutropenia* 96% 93% 83% 55%
Febrile Neutropenia* 15% 2%
Anemia 77% 10% 61% 7%
Thrombocytopenia 52% 5% 32% 3%
Hematologic ToxicityHematologic Toxicity
*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 Maintenance Therapy for Advanced Hormonally Sensitive Breast CancerHormonally Sensitive Breast Cancer
• Prior response/stability to hormonal therapy
• Low disease burden, minimal visceral involvement
• Low level of symptoms
• Hormonal therapy• For HER2+, hormonal
therapy plus HER2-directed therapy
• Significant visceral involvement
• Significant symptoms• Likely clinical sequelae
with small degree of progression
• Chemotherapy• For HER2+,
Chemotherapy + HER2-directed therapy
Maintenance Therapy
“Induction”
Study Treatment Schedules NMed TTP (mo)
pMed OS
(mo)p
Coates A et al NEJM 1987
AC/CMF until PD305
60.02
10.70.19AC x 3 cycles 4 9.4
Harris AL et alLancet 1990
Mitoxantrone until PD43
5.5NS
11NS
Mitoxantrone x 4 6.5 12
Muss H et alNEJM 1991
FAC x 6 → CMF x 12 145
9.4<0.001
21.10.67FAC x 6 3.2 19.6
Ejlertsen BEur J Ca 1993
FEC + TAM x 18254
14< .003
230.03FEC + TAM x 6 10 18
Gregory R et alEur J Ca 1997
VAC/VEC x 6 → MMM x 6 100
100.01
13.00.3VAC/VEC/MMM x 6 7 10.5
Falkson G et alJCO 1998
A x 6 → CMFPTH x 8
195
18.7<0.000
1
32.2
0.74A x 6 7.8 28.7
Nooij M et alEur J Ca 2003
CMF until PD196
5.20.01
14.00.77CMF x 6 3.5 14.4
Trials Examining Continuous vs. Trials Examining Continuous vs. Interrupted/Fixed TherapyInterrupted/Fixed Therapy
StudyStudy Treatment Treatment SchedulesSchedules NN
Med Med TTP TTP (mo)(mo)
ppMed Med OS OS
(mo)(mo)pp
Gennari Aet alJCO 2006
E/A + P x 6-8 → P x E/A + P x 6-8 → P x 88
215215
8.0*8.0*0.8170.817
26.026.0
0.5470.547E/A + P x 6-8E/A + P x 6-8 9.0*9.0* 29.029.0
Alba Eet alASCO 2007
A →T x 6 → PLDA →T x 6 → PLD
155155
13.213.28.4*8.4* 0.0060.006
**0.0050.005A →T x 6 A →T x 6 10.210.2
5.1*5.1*
Trials Examining Continuous vs. Trials Examining Continuous vs. Interrupted/Fixed Therapy Interrupted/Fixed Therapy
* From time of randomization to maintenance armE = epirubicin; A = doxorubicin; P = paclitaxel; T = docetaxel; PLD = pegylated liposomal doxorubicin
Contemporary RegimensContemporary Regimens
Doxorubicin + PaclitaxelDoxorubicin + Paclitaxel
36% 34% 47% 36% 34% 47%
QOLQOL
Median TTFMedian TTF
ResponseResponse
PaclitaxelPaclitaxelDoxorubicinDoxorubicin
6 mos. 6 mos. 8 mos. 6 mos. 6 mos. 8 mos.
= = = = = =
19 mos. 22 mos. 22 mos. 19 mos. 22 mos. 22 mos.
Median SurvivalMedian Survival
Single vs. Combination vs.Single vs. Combination vs.Sequential ChemotherapySequential Chemotherapy
Crossover Responses:
Crossover Responses:
AA
TT AA
TT = 22%
= 22%
= 20%
= 20%
NSNS
Sledge G et al. J Clin Oncol 2003Sledge G et al. J Clin Oncol 2003
Finnish Randomized Comparison of Single AgentsFinnish Randomized Comparison of Single Agentsvs Combinations As First- and Second-Linevs Combinations As First- and Second-Line
Chemotherapy for Metastatic Breast CancerChemotherapy for Metastatic Breast Cancer
MCMCMCMC
MCMCMCMC
MCMCMCMCMCMCMCMC
MCMCMCMC MCMCMCMC MCMCMCMC
MCMCMCMC
VVVV VVVV VVVV VVVV
1 5 9 131 5 9 131 5 9 131 5 9 13
1 4 7 10 13 1 4 7 10 13 1 4 7 10 13 1 4 7 10 13
WeeksWeeksWeeksWeeks
WeeksWeeksWeeksWeeks
First -LineFirst -LineFirst -LineFirst -Line
Second-LineSecond-LineSecond-LineSecond-Line
EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE
EEEE EEEE EEEE EEEE EEEE
FFFF FFFF FFFF FFFF FFFF
CCCC CCCC CCCC CC CCCC
500 mg/m500 mg/m22500 mg/m500 mg/m22
500 mg/m500 mg/m22500 mg/m500 mg/m22
60 mg/m60 mg/m22 60 mg/m60 mg/m22
8 mg/m8 mg/m228 mg/m8 mg/m22
6 mg/m6 mg/m226 mg/m6 mg/m22
8 mg/m8 mg/m228 mg/m8 mg/m22
20 mg/m20 mg/m2220 mg/m20 mg/m22weeklyweeklyweeklyweekly
Joensuu H et al. J Clin Oncol 1998Joensuu H et al. J Clin Oncol 1998
Single Agents vs Combinations asSingle Agents vs Combinations as1st- and 2nd-Line Chemotherapy for MBC1st- and 2nd-Line Chemotherapy for MBC
► No significant difference in overall TTP for E M vs CEF MV (No significant difference in overall TTP for E M vs CEF MV (P P = = 0.28)0.28)
► No difference in overall survival for E M vs CEF MV (No difference in overall survival for E M vs CEF MV (P P = 0.96) or = 0.96) or survival calculated from second-line Rx (survival calculated from second-line Rx (P P = 0.56)= 0.56)
► Less toxicity and better QOL with single agentsLess toxicity and better QOL with single agents
Regimen RR Response DurationRegimen RR Response Duration
CEF 55% 12 mosCEF 55% 12 mosE 48% 10.5 mosE 48% 10.5 mos
MV 16% -MV 16% -
M 7% -M 7% -
Joensuu H et al. J Clin Oncol 1998Joensuu H et al. J Clin Oncol 1998
Finnish Breast Cancer Group StudyFinnish Breast Cancer Group Study
Combination vs. Monotherapy for Combination vs. Monotherapy for MBC: MBC:
No Survival Benefit (n=2,490) No Survival Benefit (n=2,490) ► Dox + Paclitaxel = Single Agents SequentiallyDox + Paclitaxel = Single Agents Sequentially (Sledge, J Clin Oncol 2003)(Sledge, J Clin Oncol 2003)
► FEC then MV = Epirubicin then Mitomycin CFEC then MV = Epirubicin then Mitomycin C
(Joensuu, J Clin Oncol 1998)(Joensuu, J Clin Oncol 1998)
► Taxotere > Mitomycin C + VinblastineTaxotere > Mitomycin C + Vinblastine
(Nabholtz, J Clin Oncol 1999)(Nabholtz, J Clin Oncol 1999)
► Taxol > CMFPTaxol > CMFP (Bishop, J Clin Oncol 1998)(Bishop, J Clin Oncol 1998)
► FEC = MitoxantroneFEC = Mitoxantrone (Heidemann, Ann Oncol 2002)(Heidemann, Ann Oncol 2002)
► Dox + Vinorelbine = DoxorubicinDox + Vinorelbine = Doxorubicin
(Norris, J Clin Oncol 2000)(Norris, J Clin Oncol 2000)
► Epirubicin + Vinorelbine = EpirubicinEpirubicin + Vinorelbine = Epirubicin
Ejlertsen, J Clin Oncol 2004
Single vs Combination Chemotherapy:Single vs Combination Chemotherapy:Recent Positive Trials in MBC - Overall SurvivalRecent Positive Trials in MBC - Overall Survival
O'Shaughnessy J et al J Clin Oncol 2002Albain K et al J Clin Oncol 2009
11.5 14.5
Hazard ratio = 0.775
Log-rankp=0.0126
Capecitabine/docetaxelDocetaxel
15.818.5
0 10 20
Survival
Gemcitabine + Paclitaxel (n=267)
Paclitaxel(n=262)
12 mo 70.7% 60.9%
18 mo 50.7% 41.9%
Log rank P=0.018HR 0.78 (0.63-0.96)
0 12 24
Months
Months
100%
100%
72% 14.5 (12.3–16.3) 79% 11.5 (9.8–12.7)
Events Median (CI)
Capecitabine plus Docetaxel: Most Common Capecitabine plus Docetaxel: Most Common (>5%) Grade 3/4 Treatment-Related Toxicities(>5%) Grade 3/4 Treatment-Related Toxicities
30
25
20
15
10
5
0
Pati
ents
(%
)
Capecitabine/docetaxel (n=251)
Diarrh
ea
Stom
atiti
s
Hand-
foot
synd
rom eN
ause
a
Fatig
ue/
asth
enia
Neutro
peni
c fe
ver
Docetaxel (n=255)
Grade 3Grade 4
Grade 3Grade 4
O'Shaughnessy J, et al J Clin Onocol 2002
Combination vs. Single-Agent Therapy for Combination vs. Single-Agent Therapy for MBC: Meta-Analysis of Randomized TrialsMBC: Meta-Analysis of Randomized Trials
0 0.5 1.0 1.5 2.0Combination better Single agent better
Efficacy: 2 17.5 (p=0.00002)
0.87 (0.78–0.97)
0.70 (0.59–0.84)
0.82 (0.75–0.90)
Hazard ratio of death(combination:single agent)
Regimens
Single agentCombination
Subtotal (deaths/patients)
Subtotal (deaths/patients)
Total (deaths/patients)
AVA + DBDA + MMCVACCF + P ± VCF + P ± VA + ETOAV + MMCE + VDSFEC 75
CMF + VBLCMFCMFV + PCF + P ± VCF + P ± V
FEC 50
619/738
206/252
825/990
AAAAAAAAEE
CPAMFCCNUI
E
649/747
225/249
874/996
Fossati R et al. J Clin Oncol 1998Fossati R et al. J Clin Oncol 1998
= paclitaxel 80 mg/m2* qw vs 175 mg/m2 q 3w
= trastuzumab 4mg/kg load, 2 mg/kg/w
Paclitaxel: Dose/Schedule ComparisonPaclitaxel: Dose/Schedule ComparisonCALGB 9840 CALGB 9840
q3w P
q1w P
1998-2000(n=171; HER2 unknown)
q3wP+T
q1wP+T
2000-2003(n=406; HER2 known)
H E R 2(+)
H E R 2(-)*first 116 pts at 100 mg/m2/wk x 6,
then all pts 80 mg/m2 q wk
Seidman A, et al. J Clin Oncol 2008
Paclitaxel: Dose/Schedule ComparisonPaclitaxel: Dose/Schedule ComparisonCALGB 9840 CALGB 9840
Seidman A, et al. J Clin Oncol 2008
Pegylated Liposomal Doxorubicin (PLD)Pegylated Liposomal Doxorubicin (PLD)
► Prolonged half life (>55 hours)Prolonged half life (>55 hours)
- Pegylation reduced uptake by reticuloendothelial Pegylation reduced uptake by reticuloendothelial systemsystem
► Preferential tumor penetrationPreferential tumor penetration
- Compromised vasculature in tumor tissueCompromised vasculature in tumor tissue► Reduced volume of distributionReduced volume of distribution
- Limited exposure to normal tissue, e.g. heart.Limited exposure to normal tissue, e.g. heart.
Doxorubicin Liposomal doxorubicin
Pegylated liposomal doxorubicin
Gabizon A et al. Clin Pharmacokinet 2003
Phase III trial: Pegylated liposomal doxorubicin Phase III trial: Pegylated liposomal doxorubicin (PLD) plus Docetaxel vs. Docetaxel(PLD) plus Docetaxel vs. Docetaxel
Phase III trial: Pegylated liposomal doxorubicin Phase III trial: Pegylated liposomal doxorubicin (PLD) plus Docetaxel vs. Docetaxel(PLD) plus Docetaxel vs. Docetaxel
Randomize
PLD (30 mg/m2) + Docetaxel (60 mg/m2) day
1 every 21 days
Docetaxel (75 mg/m2) day 1 every 21 days
N=751
Eligibility:
- Advanced breast cancer- Relapsed ≥1 year following neo/adjuvant anthracyclines (≥180 and ≤360 mg/m2)
Primary endpoint: TTPSecondary endpoints: OS, ORR, overall safety, cardiac safety
N=378
N=373
Sparano J et al. JCO 2009
Alone in Advanced Breast CancerAlone in Advanced Breast Cancer
DocetaxelPLD +
DocetaxelHR 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
PLD plus Docetaxel vs. Docetaxel PLD plus Docetaxel vs. Docetaxel Alone in Advanced Breast CancerAlone in Advanced Breast CancerPLD plus Docetaxel vs. Docetaxel PLD plus Docetaxel vs. Docetaxel Alone in Advanced Breast CancerAlone in Advanced Breast Cancer
Sparano J et al. JCO 2009
Select Grade 3/4 Adverse EventsDocetaxel (N=373)
PLD + Docetaxel (N=377)
Neutropenia 59% 57%
Febrile Neutropenia 6% 7%
Hand-Foot syndrome 0 24%*
Stomatitis 1% 11%
* 20% patients discontinued due to HFS generally managed by dose modification
Grade ≥2 cardiac AEs: similar for Doc vs. Doc + PLD (4% vs. 5%)
Randomized Randomized nabnab-Paclitaxel-PaclitaxelTrial Design: CA012 Trial Design: CA012
Albumin-bound paclitaxel 260 mg/m2
iv over 30 min q3w No standard premedication
Paclitaxel 175 mg/m2 iv over 3 hrs q3w
Standard premedication with dexamethasone and antihistamines
MBC with prior anthracycline and no prior taxane for MBCRandomisation (1:1)
n = 460
Gradishar et al. J Clin Oncol 2005
Randomized Randomized nabnab-Paclitaxel Trial-Paclitaxel TrialResponse RatesResponse Rates
0
10
20
30
40
50
60
All patients First-linetherapy
≥ Second-linetherapy
Anthracyclineexposed
Visceraldisease
Albumin-bound paclitaxel
Paclitaxel
229
225
n
OR
R (
± 9
5%
CI)
97
89
132
136
176
175
176
182
33.2%
42.3%
18.7%
27.0%
26.5%
13.2%
34.1%
18.3%
33.5%
18.7%
P = 0.001 P = 0.029 P = 0.006 P = 0.002 P = 0.002
Gradishar et al. J Clin Oncol 2005
Nab-Paclitaxel:Nab-Paclitaxel:Different Dose/Schedules vs. DocetaxelDifferent Dose/Schedules vs. Docetaxel
Gradishar W et al. JCO 2009
0
10
20
30
40
50
60
70
80
90
100 Response Rates
100 mg/m2
q3wn = 74
300 mg/m2
q3wn = 76
100 mg/m2
qw 3/4n = 76
150 mg/m2
qw 3/4n = 74
DocetaxelNab-Paclitaxel
Capecitabine Capecitabine ± Ixabepilone in± Ixabepilone inTaxane and Anthracyline-Resistant MBCTaxane and Anthracyline-Resistant MBC
% Response% Response
InvestigatorInvestigator Independent Independent Radiology ReviewRadiology Review
Ixabepilone + Ixabepilone + CapecitabineCapecitabine
(N=375)(N=375)
CapecitabinCapecitabinee
(N=377)(N=377)
Ixabepilone Ixabepilone + +
CapecitabineCapecitabine
(N=375)(N=375)
CapecitabineCapecitabine
(N=377)(N=377)
ORR (CR + PR) 42 23 35 14
P < 0.0001 P <0.0001
Stable Disease 36 38 41 46
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
Median 95% CI
Ixabepilone + Capecitabine
5.8 mo (5.5–7.0)
Capecitabine 4.2 mo (3.8–4.5)
Progression-free Survival Progression-free Survival by Independent Radiologic Reviewby Independent Radiologic Review
P=0.0003
HR: 0.75 (0.64–0.88)
Pro
port
ion
Pro
gre
ssio
n F
ree
1.0
0.8
0.6
0.4
0.2
00 4 8 12 16 20 24 28 32 36
MonthsVahdat L et al. JCO 2007
Basal subtype1. 10-15% of tumors2. ER/PR/HER2-negative3. very proliferative4. EGFR, c-kit, c-myc +5. includes BRCA1 mutations
HER2+ subtype1. 15-20% of tumors2. prognostic/predictive2. proliferation3. two types (ER -/+)
Luminal A and B (ER+)1. continuum 2. prognostic/predictive3. ER-GATA3-HNF3a-XBP14. proliferation (mutant
p53)5. cyclin D1 and BCL2 +
Ki-67, STK6, Survivin, Cyclin B1 and MYBL2
Gene Expression Profiling Reveals Distinct ClustersGene Expression Profiling Reveals Distinct Clusters
Sorlie T et al. PNAS 2003
p <0.0001
p <0.001
Sorlie T et al.
PNAS 2003
Where are We Today with ChemotherpyWhere are We Today with Chemotherpyfor Advanced Breast Cancer ?for Advanced Breast Cancer ?
► No clear single agent stands out as superior, but No clear single agent stands out as superior, but certain comparisons have been notedcertain comparisons have been noted• First line (eg. docetaxel > paclitaxel)First line (eg. docetaxel > paclitaxel)• Late line (eg. eribulin > several single agents after 2 or Late line (eg. eribulin > several single agents after 2 or
more chemotherapy regimens for MBC)more chemotherapy regimens for MBC)► Combinations are superior for response and TTP, so Combinations are superior for response and TTP, so
may be indicated for symptoms or high visceral may be indicated for symptoms or high visceral burdenburden
► Dose and schedule matter, particularly for taxanesDose and schedule matter, particularly for taxanes► Certain combinations may be synergistic in Certain combinations may be synergistic in
preclinical models, but difficult to prove in the clinicpreclinical models, but difficult to prove in the clinic► Molecular diagnostics and pharmacogenomics may Molecular diagnostics and pharmacogenomics may
point the way to individualizing chemotherapy for point the way to individualizing chemotherapy for efficacy and toxicityefficacy and toxicity
Microtubules as a Target for Microtubules as a Target for Anticancer Drugs —Multi-Anticancer Drugs —Multi-
Mechanistic Approaches to Mechanistic Approaches to Mitigating Metastatic Breast Disease Mitigating Metastatic Breast Disease
The Role of Nontaxane Microtubule Dynamics The Role of Nontaxane Microtubule Dynamics Inhibitors – Evidence and Implications of Recent Inhibitors – Evidence and Implications of Recent
Clinical StudiesClinical Studies
Evolving Paradigms and Optimizing Management Evolving Paradigms and Optimizing Management ofof
Metastatic Breast CancerMetastatic Breast Cancer
Paraskevi Giannakakou, PhDParaskevi Giannakakou, PhDAssociate Professor of Pharmacology in Medicine │Weill Associate Professor of Pharmacology in Medicine │Weill
Cornell Cornell Medical College │New York, NYMedical College │New York, NY
Improving Overall Survival in Improving Overall Survival in Metastatic Breast CancerMetastatic Breast Cancer
The Role of Nontaxane Microtubule Dynamics The Role of Nontaxane Microtubule Dynamics Inhibitors – Evidence and Implications of Recent Inhibitors – Evidence and Implications of Recent
Clinical StudiesClinical Studies
Evolving Paradigms and Optimizing Management Evolving Paradigms and Optimizing Management ofof
Metastatic Breast CancerMetastatic Breast Cancer
Sara Hurvitz, MDSara Hurvitz, MDAssistant Clinical Professor of MedicineAssistant Clinical Professor of Medicine
Director, Breast Oncology Program Director, Breast Oncology Program David Geffen School of Medicine David Geffen School of Medicine
University of California, Los AngelesUniversity of California, Los AngelesLos Angeles, CALos Angeles, CA
Microtubule Targeting AgentsMicrotubule Targeting Agents
► TaxanesTaxanes● Docetaxel, paclitaxel, nab-paclitaxelDocetaxel, paclitaxel, nab-paclitaxel
► Vinca alkaloidsVinca alkaloids● Vinorelbine, vinflunineVinorelbine, vinflunine
► EpothilonesEpothilones● Ixabepilone, KOS 862 (EPO D), ZK-EPO, patupiloneIxabepilone, KOS 862 (EPO D), ZK-EPO, patupilone
► Halichondrin B analogueHalichondrin B analogue● Eribulin (E7389)Eribulin (E7389)
► 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
Microtubules
Destabilizers Stabilizers
Polymerization
Polymerization
Vinca alkaloids
Taxanes/Epothilones
Mitotic spindleformation blocked
MT BundlingMultipolar spindles
Graphic courtesy of Harold J. Burstein, MD, PhD.
Mechanisms of action of microtubule-targeted agents
Mechanisms of action of microtubule-targeted agents
Sorangium cellulosumSorangium cellulosum
► MyxobacteriaMyxobacteria● Secondary metabolites Secondary metabolites
(epothilones/fungicides)(epothilones/fungicides)
Zambezi river
Ixabepilone (BMS-247550)Ixabepilone (BMS-247550)
Epothilone BEpothilone BIxabepiloneIxabepilone
► Semisynthetic analog of epothilone B Semisynthetic analog of epothilone B (aza-epothilone B)(aza-epothilone B)
► Molecular difference between Molecular difference between ixabepilone and epothilone because of ixabepilone and epothilone because of amine vs ester moietyamine vs ester moiety
Conclusions: Preclinical Conclusions: Preclinical
► IxabepiloneIxabepilone● Semisynthetic analog of epothilone BSemisynthetic analog of epothilone B● Bind specifically and uniquely to beta-tubulin Bind specifically and uniquely to beta-tubulin ● Tubulin polymerizing activity 2-10 x greater than Tubulin polymerizing activity 2-10 x greater than
paclitaxelpaclitaxel● Have activity in tumors that use MDR as a Have activity in tumors that use MDR as a
resistance mechanismresistance mechanism● Active in multiple in vivo tumor modelsActive in multiple in vivo tumor models● Similar mechanism of action (G2/M arrest, Bax Similar mechanism of action (G2/M arrest, Bax
conformational change)conformational change)● Linear pharmacologyLinear pharmacology
► Ixabepilone + other agentsIxabepilone + other agents● Synergy with capecitabine, cetuximab, trastuzumabSynergy with capecitabine, cetuximab, trastuzumab● Greater in vivo synergy with bevacizumab than Greater in vivo synergy with bevacizumab than
paclitaxelpaclitaxel
Ixabepilone: Preclinical ActivityIxabepilone: Preclinical Activity
(P=0.0001)
Days post-tumor implant
Me
dia
n tu
mo
r w
eig
ht
(mg
)
Control IxabepiloneCapecitabine Combination
0
500
1000
1500
2000
2500
10 30 50
250 mg/kg (MTD)
10 mg/kg (MTD)
Capecitabine SynergyCapecitabine Synergy
Days Post-Tumor ImplantPat-21 Xenograft
Ixabepilone
Paclitaxel
Control
1000
40 70 100 130 160
Me
dia
n T
um
or W
eig
ht
(mg
)
Paclitaxel Rx (36 mg/kg/inj)
Ixabepilone Rx (10 mg/kg/inj)
100
10
N = 8Activity in Paclitaxel ResistanceActivity in Paclitaxel Resistance
Bevacizumab IP 4 mg/kgIxabepilone IV
1000
750
500
250
0
15 35 55 75
Control
Bevacizumab
Ixabepilone
Combined
Me
dia
n T
um
or W
eig
ht
(mg
)
Days Post-Tumor ImplantL2987 Human Lung Carcinoma
Bevacizumab SynergyBevacizumab Synergy
Rx
20 40 601
10
100
1000
10000
Me
dia
n tu
mo
r w
eig
ht
(mg
)Control
Trastuzumab
Ixabepilone
Combined
Trastuzumab SynergyTrastuzumab Synergy
Days Post-Tumor ImplantHER2 receptor positive KPL4
Human breast Carcinoma XenograftsData on file. Bristol Myers Squibb Company; Princeton, NJ
Ixabepilone in Metastatic Breast Cancer: Ixabepilone in Metastatic Breast Cancer: Summary of Single-Agent Phase II TrialsSummary 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.
PD or unacceptable toxicity
Max 18 cycles
Phase II Study 081: Ixabepilone in Phase II Study 081: Ixabepilone in Triple Refractory MBCTriple Refractory MBC
Primary end point: ORRPrimary end point: ORR
Prior therapy with Prior therapy with anthracycline, taxane, anthracycline, taxane,
and capecitabineand capecitabine(N=126)(N=126)
Ixabepilone 40 mg/m2 IV q3w1
Resistance CriteriaResistance Criteria• Neoadjuvant or Adjuvant: ≤ 6 months of last doseNeoadjuvant or Adjuvant: ≤ 6 months of last dose• Metastatic: Metastatic: ≤ 8 weeks of last dose≤ 8 weeks of last dose • Progression during or after discontinuation of trastuzumab in HER2+ Progression during or after discontinuation of trastuzumab in HER2+
patientspatients
Perez E, et al. J Clin Oncol. 2007;23: 3407-3414.
Phase II Study 081: Ixabepilone in Phase II Study 081: Ixabepilone in Triple Refractory MBCTriple Refractory MBC
CharacteristicCharacteristic Patients, no. (%)Patients, no. (%)(N=126)(N=126)
Median age (min-max) in years 51 (30–78)51 (30–78)
Visceral disease (liver and/or lung) 108 (86)108 (86)
No. of disease sites: 3–4 ≥5
62 (49)62 (49) 19 (15)19 (15)
ER-, PR-, HER2- 42 (33)42 (33)
Prior neoadjuvant/adjuvant chemotherapy 95 (75) 95 (75)
No. of prior chemotherapy regimens for metastatic disease 1 2 3
15 (12)15 (12)51 (40)51 (40)60 (48)60 (48)
No. of prior taxane-containing regimen Any ≥2 ≥3
126 (100)126 (100)38 (30)38 (30)7 (6)7 (6)
Perez E, et al. J Clin Oncol. 2007;23: 3407-3414.
Phase II Study 081: EfficacyPhase II Study 081: Efficacy
OutcomeOutcome Response-Evaluable Response-Evaluable (n=113)(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)
6.0 (5.0-7.6)
Stable disease rate, %Median duration of stable disease, mo (95% CI)
49.6 4.5 (3.7–6.0)
Treated Patients (n=126)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: SafetyPhase II Study 081: Safety
Grade 3/4 ToxicityGrade 3/4 Toxicity % of Patients % of Patients (n=126)(n=126)
Hematologic Neutropenia 54
Febrile neutropenia 2
Leukopenia 49
Anemia 8
Thrombocytopenia 7
NonhematologicPeripheral sensory neuropathy 14
Fatigue 13
Myalgia/arthralgia 8
Stomatitis 6
Perez E, et al. J Clin Oncol. 2007;23: 3407-3414.
ConclusionsConclusions
► This is the first large prospective trial in triple therapy This is the first large prospective trial in triple therapy refractory metastatic breast cancerrefractory metastatic breast cancer
► Ixabepilone demonstrates efficacy in patients with Ixabepilone demonstrates efficacy in patients with anthracycline-taxane and capecitabine refractory MBCanthracycline-taxane and capecitabine refractory MBC● Overall populationOverall population
• Median PFS 3.2 monthsMedian PFS 3.2 months• Median overall survival 9 monthsMedian overall survival 9 months• Response rate 18% (investigator Response rate 18% (investigator
assessment)assessment)► Safety profile is acceptableSafety profile is acceptable► In summary, ixabepilone represent a new choice in In summary, ixabepilone represent a new choice in
patients with patients with triple-therapy refractory patients with patients with triple-therapy refractory MBCMBC
Capecitabine Capecitabine Ixabepilone Study 046: Ixabepilone Study 046: Clinical Eligibility Criteria for ResistanceClinical Eligibility Criteria for Resistance
Strict definition:Strict definition: patients whose tumors rapidly progressed in the patients whose tumors rapidly progressed in the adjuvant or metastatic setting after receiving both anthracyclines adjuvant or metastatic setting after receiving both anthracyclines and taxanesand taxanes
Setting Setting AnthracyclineAnthracycline TaxaneTaxane
Metastatic ≤≤3 months of last 3 months of last dosedose
≤≤4 months of last 4 months of last dosedose
Neo/adjuvant
≤≤6 months of last 6 months of last dosedose
≤≤12 months of last 12 months of last dosedose
Any
Minimum cumulative Minimum cumulative dosedose
Doxorubicin: Doxorubicin: 240 mg/m240 mg/m22
Epirubicin: 360 mg/mEpirubicin: 360 mg/m22
Perez E, et al. J Clin Oncol. 2007;23: 3407-3414.
046/048 Phase III MBC Trials: Ixabepilone 046/048 Phase III MBC Trials: Ixabepilone and Capecitabine Combinationand Capecitabine Combination
► Pivotal trial CA163-046Pivotal trial CA163-046● Patients prospectively defined using Patients prospectively defined using
a strict definition of resistance to a strict definition of resistance to previous anthracycline and taxane previous anthracycline and taxane therapytherapy
► Confirmatory trial CA163-048Confirmatory trial CA163-048● Patients with metastatic disease who Patients with metastatic disease who
were pretreated with or resistant to were pretreated with or resistant to an anthracycline and a taxanean anthracycline and a taxane• 50% met strict resistance criteria 50% met strict resistance criteria
in pivotal trialin pivotal trial
Ixabepilone(40 mg/m2 IV over 3 hr d1 q3wk)
+Capecitabine
(2000 mg/m2/day BID 14 days q3wk)
Capecitabine(2500 mg/m2/day BID 14 days q3wk)
Metastatic / locally Metastatic / locally advanced breast canceradvanced breast cancer
pretreatedpretreated withwith or or resistantresistant to taxanesto taxanes and anthracyclinesand anthracyclines
046/048 Phase III MBC Trials: 046/048 Phase III MBC Trials: Study DesignStudy Design
Hortobagyi GN et al ASCO Breast 2008
046/048 Phase III Trials:046/048 Phase III Trials:Progression Free SurvivalProgression Free Survival
Outcome
Study 046 Study 048
Ixa + Cape
N=375
CapeN=377
Ixa + Cape
N=480
CapeN=480
Median PFS, months
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 log-rank P-value
0.0011 0.0005
Roche et al. BCRT 2010
046/048 Phase III Trials:046/048 Phase III Trials:Objective Response RateObjective Response Rate
OutcomeOutcome
Study 046* Study 048
Ixa + Ixa + CapeCapeN=375N=375
CapeCapeN=377N=377
Ixa + Ixa + CapeCapeN=462N=462
CapeCapeN=462N=462
Objective response rate, %
42.1 22.5 43.3 28.8
95% CI37.1 – 47.3
18.4 – 27.1
38.7 – 47.924.7 – 33.2
Best Response, N (%)
Complete response 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)*ORR in 046 presented by investigator assessment.
Roche et al. BCRT 2010
046/048 Phase III Trials:046/048 Phase III Trials:Overall SurvivalOverall Survival
Outcome
Study 046Study 046 Study 048Study 048
Ixa + Ixa + CapeCapeN=375N=375
CapeCapeN=377N=377
Ixa + Ixa + CapeCapeN=609N=609
CapeCapeN=612N=612
Median overall survival,months
12.9 11.1 16.4 15.6
No. of events 318 321 430 450
Hazard ratio (95.17% CI)
0.90(0.77 – 1.05)
0.90(0.78 – 1.03)
Stratified log-rank P-value
0.1936 0.1162
Roche et al. BCRT 2010
046/048 Planned 046/048 Planned Subset AnalysesSubset Analyses
Evolving Paradigms and Optimizing Management Evolving Paradigms and Optimizing Management ofof
Metastatic Breast CancerMetastatic Breast Cancer
Pooled Subgroup Analyses:Pooled Subgroup Analyses:Objective Response RatesObjective Response Rates
Patients WithPatients With Ixa + Cape, Ixa + Cape, %%
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: Pooled Subgroup Analyses: Median Progression Free SurvivalMedian Progression Free Survival
Patients WithPatients With Ixa + Cape, Ixa + Cape, monthsmonths
Cape, Cape, monthsmonths PP value 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
Roche et al. BCRT 2010
046/048 Phase III Trials: Summary046/048 Phase III Trials: Summary
► Ixabepilone + capecitabine demonstrated clinically Ixabepilone + capecitabine demonstrated clinically meaningful efficacy (increase in PFS and ORR) in a meaningful efficacy (increase in PFS and ORR) in a large heavily pretreated patient population (~2000) large heavily pretreated patient population (~2000) with limited treatment optionswith limited treatment options
► The difference in median overall survival favored the The difference in median overall survival favored the combination: this difference did not reach statistical combination: this difference did not reach statistical significancesignificance
► Ixabepilone plus capecitabine treatment showed Ixabepilone plus capecitabine treatment showed consistent clinical benefit in difficult to treat sub-consistent clinical benefit in difficult to treat sub-populations, including triple receptor MBCpopulations, including triple receptor MBC
► Study 048 reinforced the manageable safety profile Study 048 reinforced the manageable safety profile of ixabepiloneof ixabepilone
● Similar profile as study 046Similar profile as study 046● Low frequency of toxicity related deaths (<1%) in both armsLow frequency of toxicity related deaths (<1%) in both arms
Roche et al. BCRT 2010
Halichondrin B Analogue Halichondrin B Analogue (E7389)(E7389)
after Anthracyclines, Taxanes after Anthracyclines, Taxanes and Capecitabine: and Capecitabine:
Evolving Paradigms and Optimizing Management Evolving Paradigms and Optimizing Management ofof
Metastatic Breast CancerMetastatic Breast Cancer
Microtubule stabilizationMicrotubule stabilization
De-polymerizeDe-polymerize
PolymerizePolymerize
PaclitaxelPaclitaxel EribulinEribulinInhibits Microtubule AssemblyInhibits Microtubule Assembly
Non-productive aggregatesNon-productive aggregates
Microtubule dynamicsMicrotubule dynamics
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
Eribulin (E7389): Mechanism of Action
Eribulin: Tubulin-based Eribulin: Tubulin-based Antimitotic MechanismAntimitotic Mechanism
Inhibition of tubulin polymerization Inhibition of tubulin polymerization in vitroin vitro
U937 cells, 100 nM
G2/M cycle blocksG2/M cycle blocks
DU 145 cells, 3xIC50 @ 20 h
Control Eribulin
Disruption of mitotic spindles (DAPI/β-tubulin)Disruption of mitotic spindles (DAPI/β-tubulin)
Towle et al., Cancer Research, 61:1013-1021, 2001
Eribulin: Preclinical Activity Across a Eribulin: Preclinical Activity Across a Range of ModelsRange of Models
Control
Eribulin
LOX melanomaTowle MJ unpublished results, ERI, 2007
0
400
800
1200
1600
2000
0 7 14 21 28 35 42
ControlER-086526 0.05 mg/kg
ER-086526 0.1 mg/kgER-086526 0.25 mg/kg
ER-086526 0.5 mg/kgPaclitaxel 12.5 mg/kg
Ave
rag
e tu
mor
vol
um
es (
µl)
Day
0
200
400
600
800
0 14 28 42 56 70 84 98
Control
ER-086526 0.25 mg/kgER-086526 0.5 mg/kg
ER-086526 1 mg/kg
Paclitaxel 25 mg/kg
Ave
rag
e tu
mor
vol
um
es (
µl)
Day
MDA-MB-435 Human Breast CancerMWFx4, i.v.
0
500
1000
1500
0 14 28 42 56 70
ControlER-086526 0.125 mg/kgER-086526 0.5 mg/kgPaclitaxel 20 mg/kg
Ave
rage
tum
or v
olum
es (
µl)
Day
COLO 205 Human Colon CancerMWFx4, i.p.
0
500
1000
1500
39 46 53 60 67 74 81 88 95
Control
ER-086526 0.125 mg/kg
ER-086526 0.25 mg/kg
ER-086526 0.5 mg/kg
ER-086526 1 mg/kg
Paclitaxel 20 mg/kg
Ave
rag
e tu
mor
vol
um
es (
µl)
Day
OVCAR-3 Human Ovarian CancerMWFx3, i.v.
LOX Human MelanomaQ1Dx5[x2], i.p.
Human tumor xenografts (0.05-1.0 mg/kgHuman tumor xenografts (0.05-1.0 mg/kg))
Avera
ge t
um
or
volu
me
(mm
3)
Avera
ge t
um
or
volu
me
(mm
3)
Avera
ge t
um
or
volu
me
(mm
3)
Avera
ge t
um
or
volu
me
(mm
3)
Towle et al., Cancer Research, 61:1013-1021, 2001
Summary of Eribulin Phase II Studies Summary of Eribulin Phase II Studies in Breast Cancerin Breast Cancer
211 Study[2]
(N = 299)
Prior anthra, taxane, &
cape Tx*
201 Study[1] (N = 103)
Prior anthra & taxane
Tx*
Eribulin IV 1.4 mg/m2 (n = 70) over 2-5 mins on Days 1, 8, 15 q4w
Assessments
1. Vahdat LT, et al. J Clin Oncol. 2009;27:2954-2956. 2. Vahdat LT, et al. ASCO 2008. Abstract 1084.
*MBC patients with progression of disease ≤ 6 mos of last chemotherapy, if present, preexisting neuropathy ≤ grade 2.
Eribulin IV 1.4 mg/m2 (n = 33) over 2-5 mins on Days 1, 8 q3w
Eribulin IV 1.4 mg/m2 over 2-5 min on Days 1, 8 q3w
ORR with independent review
Response duration, PFS, and OS
Adverse events
ITT Efficacy Summary of Phase II ITT Efficacy Summary of Phase II Eribulin Breast Cancer StudiesEribulin Breast Cancer Studies
Characteristic/ResponseCharacteristic/Response 201 Trial201 Trial11(N = 103)(N = 103)
211 Trial211 Trial22(N = 269)(N = 269)
Previous regimens, median n 4 4
Response rate,* % 13.6 9.0
Clinical benefit rate,† % 20.4 17.1
Duration of response, median mos
5.6 4.1
1. Vahdat LT, et al. J Clin Oncol. 2009;27:2954-2956. 2. Vahdat LT, et al. ASCO 2008. Abstract 1084.
*CR + PR.†CR+ PR + SD for ≥ 6 mos.
Summary of Eribulin Phase II Study Summary of Eribulin Phase II Study Grade 3/4 Adverse EventsGrade 3/4 Adverse Events
Adverse Events, Adverse Events, %%
201 Trial201 Trial[1][1] (N = 103)(N = 103)
211 Trial211 Trial[2][2]
(N = 291)(N = 291)
Neutropenia 6464 5454
Febrile neutropenia 44 66
Thrombocytopenia 22 11
Mucositis 11 11
Peripheral neuropathy 55 66
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 Additional Studies of Eribulin in Metastatic Breast CancerMetastatic Breast Cancer
EMBRACE Study (305)*
Phase III
Eribulin IV on Days 1, 8, q21 Days
Physicians choice (monotherapy)
OSASCO 2010
301 Study†
Phase III
Eribulin
Capecitabine
MBCPhase II
Eribulin IV on Days 1, 8, q21 Days
Ixabepilone 40 mg/m2 IV q3w
Development of
peripheral neuropathy
PFS, OScompleted
Primary endpoints:
*Third-line breast cancer treatment.†Second-line breast cancer treatment.
ClinicalTrials.gov. NCT00388726; NCT00337103; NCT00879086.
A Phase III study (EMBRACE*) of eribulin A Phase III study (EMBRACE*) of eribulin mesylate vs. treatment of physician’s choice mesylate vs. treatment of physician’s choice in patients with locally recurrent or in patients with locally recurrent or metastatic breast cancer previously treated metastatic breast cancer previously treated with an anthracycline and a taxanewith an anthracycline and a taxane
Dr Chris TwelvesDr Chris TwelvesProfessor of Clinical Cancer Pharmacology and OncologyProfessor of Clinical Cancer Pharmacology and Oncology
University of Leeds & St James’s University Hospital, Leeds, UKUniversity of Leeds & St James’s University Hospital, Leeds, UK
On behalf of the abstract co-authors and EMBRACE On behalf of the abstract co-authors and EMBRACE investigatorsinvestigators
*Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus Eribulin (E7389)
EMBRACEEMBRACE
• 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 DesignEMBRACE Study Design
Stratification:Stratification:– Geographical region, prior capecitabine, HER2/neu status
Global, randomized, open-label Phase III trial (Study 305)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 Patient CharacteristicsEMBRACE Patient Characteristics
CharacteristicCharacteristic EribulinEribulin(n=508)(n=508)
TPCTPC(n=254) (n=254)
TOTAL TOTAL (n=762)(n=762)
Median age (range)55
(28-85)56
(27-81)55
(27-85)
ECOG, % 0 1 2 Missing
4348 81.6
4150 9 1
4249 8 1
Geographic region, % I North America, Western Europe,
AustraliaII Eastern Europe, Russia, Turkey
III Latin America, South Africa
642511
642511
642511
Prior capecitabine, %YesNo
7327
7426
7327
Median no. prior chemotherapy regimens (range)
4 (1-7) 4 (2-7) 4 (1-7)ITT population
EMBRACE Disease CharacteristicsEMBRACE Disease Characteristics
CharacteristicCharacteristic Eribulin Eribulin (n=508)(n=508)
TPCTPC(n=254) (n=254)
TOTAL TOTAL (n=762)(n=762)
ER positive, % 66 67 67
PR positive, % 50 48 50
HER2/neu status, %
Positive 16 16 16
Negative 73 76 74
Unknown 10 9 10
Triple (ER/PR/HER2) negative, % 18 21 20
No. organs involved, %
≤2 51 46 49
>2 49 54 51
Sites of disease,* %
Liver 58 63 61
Lung 39 37 38
Bone 60 62 61
ITT population; *Clinically relevant sites of disease; ER, estrogen receptor; PR, progesterone receptor
EMBRACE: Demographic and EMBRACE: Demographic and Baseline CharacteristicsBaseline Characteristics
Cortes J, et al. The Lancet, Early Online Publication, 3 March 2011
Hormone TherapyHormone Therapy Eribulin Eribulin (n=508)(n=508)
TPC TPC (n=254)(n=254)
Overall Overall (n=762)(n=762)
Previous hormone therapy 430 (85%) 210 (83%)640
(84%)
Number of previous hormone regiments
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%)
EMBRACE TPC Treatment ReceivedEMBRACE TPC Treatment Received
ITT population; Taxanes: paclitaxel, docetaxel, abraxane, (ixabepilone)Anthracyclines: doxorubicin, liposomal doxorubicin, mitoxantrone
96% of patients treated with chemotherapy
% of patients
Total patients = 247
n=61
n=46 n=44n=38
n=24 n=25
n=9
No patient received best supportive care or “biological” therapies only
ResponseResponse
Independent Independent reviewreview
Investigator Investigator reviewreview
EribulinEribulin(n=468)(n=468)
TPCTPC(n=214)(n=214)
EribulinEribulin(n=468(n=468
))
TPCTPC(n=214)(n=214)
ORR (CR+PR), % 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
Clinical benefit rate(CR + PR + SD ≥6 months),%
22.6 16.8 27.8 20.1
EMBRACE Best Overall ResponseEMBRACE Best Overall Response
Response evaluable populationCR, complete response; PR, partial response; SD, stable disease;PD, progressive disease; NE, non-evaluable
EMBRACE: ITT Progression-Free EMBRACE: ITT Progression-Free Survival by Independent ReviewSurvival by Independent Review
Cortes J, et al. The Lancet, Early Online Publication, 3 March 2011
PFS 3.7 vs 2.2 mos
p=0.137
PFS 3.7 vs 2.2 mos
p=0.137
EMBRACE: Per-Protocol Population EMBRACE: Per-Protocol Population Progression-Free Survival by Independent Progression-Free Survival by Independent
ReviewReview
Cortes J, et al. The Lancet, Early Online Publication, 3 March 2011
Overall survival (months)
0.0
0.2
0.4
0.6
0.8
1.0
0 282624222018161412108642
Sur
viva
l pro
babi
lity
EMBRACE Overall SurvivalEMBRACE Overall Survival
EribulinMedian 13.12 months
TPCMedian 10.65 months
HR* 0.81 (95% CI 0.66, 0.99)p-value†=0.041
2.47 months
TPC (n=254)
Eribulin (n=508) 53.9%
1 year survival
43.7%
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 EMBRACE: Overall Survival in an Updated AnalysisUpdated Analysis
Cortes J, et al. The Lancet, Early Online Publication, 3 March 2011
EMBRACE: Exploratory Subgroup EMBRACE: Exploratory Subgroup Analysis of Overall SurvivAnalysis of Overall Survivalal
Cortes J, et al. The Lancet, Early Online Publication, 3 March 2011
EMBRACE Overall Incidence of AEsEMBRACE Overall Incidence of AEs
Adverse event (AE), %Adverse event (AE), % EribulinEribulin(n=503)(n=503)
TPCTPC(n=247)(n=247)
All AEs 98.8 93.1
Serious AEs 25.0 25.9
AEs leading to
Interruption 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 EventsAdverse Events
Grade 3Grade 3 Grade 4Grade 4
EribulinEribulin(n=503) (n=503)
TPCTPC(n=247)(n=247)
EribulinEribulin(n=503) (n=503)
TPCTPC(n=247)(n=247)
Hematologic events, %
Neutropenia 21.1 14.2 24.1 6.9
Leukopenia 11.7 4.9 2.2 0.8
Anemia 1.8 3.2 0.2 0.4
Febrile neutropenia 3.0 0.8 1.2 0.4
Non-hematologic events, %
Asthenia / fatigue 8.2 10.1 0.6 0
Peripheral neuropathy† 7.8 2.0 0.4 0
Nausea 1.2 2.4 0 0
Dyspnea 3.6 2.4 0 0.4
Mucosal inflammation 1.4 2.0 0 0
Hand-foot syndrome 0.4 3.6 0 0
EMBRACE Grade 3 and 4 AEs*EMBRACE Grade 3 and 4 AEs*
*>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 Phase 3 Trials in MBC Patients Previously Treated with an Anthracycline and a TaxaneTreated with an Anthracycline and a Taxane
Cortes J, et al. The Lancet, Early Online Publication, 3 March 2011
EMBRACE: ConclusionsEMBRACE: Conclusions
► EMBRACE is the first Phase III single-agent study in EMBRACE is the first Phase III single-agent study in heavily pre-treated MBC to meet its primary endpoint of heavily pre-treated MBC to meet its primary endpoint of prolonged overall survivalprolonged overall survival
► Eribulin demonstrated a statistically significant Eribulin demonstrated a statistically significant improvement in improvement in overall survivaloverall survival
● Improvement of median overall survival was 2.5 months (23%) Improvement of median overall survival was 2.5 months (23%)
● Clinically meaningful in heavily pretreated patientsClinically meaningful in heavily pretreated patients
► Overall response rate and progression-free survival also Overall response rate and progression-free survival also favored eribulinfavored eribulin
► These benefits were achieved with a manageable safety These benefits were achieved with a manageable safety profileprofile
ConclusionsConclusions
► Ixabepilone and eribulin are new therapeutic Ixabepilone and eribulin are new therapeutic options for metastatic breast canceroptions for metastatic breast cancer
► Approved for pretreated breast cancerApproved for pretreated breast cancer
► Neutropenia and neuropathy are most Neutropenia and neuropathy are most common adverse events common adverse events
Case Study 1Case Study 1
► 43-year-old Army wife and mother of 5 43-year-old Army wife and mother of 5 children presents with a 6 cm, 5/12 + children presents with a 6 cm, 5/12 + LN, ER+, PR+, Her2 nonamplified breast LN, ER+, PR+, Her2 nonamplified breast cancer in early 2007.cancer in early 2007.
► No PMH other than postpartum No PMH other than postpartum depressiondepression
► No medicationsNo medications► Staging studies including a bone scan, Staging studies including a bone scan,
CT/PET scan and cardiac echo are within CT/PET scan and cardiac echo are within normal limitsnormal limits
► Patient receives 6 cycles of TAC followed Patient receives 6 cycles of TAC followed by tamoxifen at an outside institution. by tamoxifen at an outside institution. Tolerates well.Tolerates well.
► One year after completing her One year after completing her chemotherapy, patient develops chemotherapy, patient develops midthoracic pain. Bone scan reveals midthoracic pain. Bone scan reveals metastatic disease at T8 and L1. CT metastatic disease at T8 and L1. CT scan reveals no visceral disease.scan reveals no visceral disease.
► Bone biopsy confirms ER+ and HER2- Bone biopsy confirms ER+ and HER2- recurrencerecurrence
Case Study 1Case Study 1
► Patient receives radiation to L1 spine with Patient receives radiation to L1 spine with good pain relief. Undergoes laparascopic good pain relief. Undergoes laparascopic oophorectomy followed by enrollment on a oophorectomy followed by enrollment on a clinical trial of Exemestane and a IGFR mAb. clinical trial of Exemestane and a IGFR mAb. Zoledronic acid is initiated. Zoledronic acid is initiated.
► Does well until early 2009 when staging Does well until early 2009 when staging studies reveal new bony mets. LFTs remain studies reveal new bony mets. LFTs remain normal. Bone scan is stable. Patient receives normal. Bone scan is stable. Patient receives fulvestrant.fulvestrant.
Case Study 1Case Study 1
► Patient does well until late 2009 when Patient does well until late 2009 when staging studies reveal multiple new liver staging studies reveal multiple new liver lesions. LFTs remain normal. Bone scan lesions. LFTs remain normal. Bone scan is stable.is stable.
Case Study 1Case Study 1
► Capecitabine is initiated at 900 Capecitabine is initiated at 900 mg/m2, po, bid. Patient requires mg/m2, po, bid. Patient requires dose reduction to 700 mg/m2, dose reduction to 700 mg/m2, po, bid secondary to diarrhea and po, bid secondary to diarrhea and hand foot syndrome after first hand foot syndrome after first cycle.cycle.
► Initial scans show a near Initial scans show a near complete response in the livercomplete response in the liver
Case Study 1Case Study 1
► In the middle of 2010, patient In the middle of 2010, patient demonstrated progression within the demonstrated progression within the liver on single agent Capecitabine after liver on single agent Capecitabine after 8 months and Bevacizumab was added.8 months and Bevacizumab was added.
► Restaging after 6 weeks of combination Restaging after 6 weeks of combination therapy demonstrated further therapy demonstrated further progression. LFTs still normal. Patient progression. LFTs still normal. Patient wants additional therapy.wants additional therapy.
Case Study 1Case Study 1
► Patient was placed on single agent Patient was placed on single agent eribulin. Her scans have shown a near eribulin. Her scans have shown a near complete response in the liver after 3 complete response in the liver after 3 cycles.cycles.
► Last cycle, patient reported an increase Last cycle, patient reported an increase in peripheral neuropathy and she was in peripheral neuropathy and she was dose reduced per package insert.dose reduced per package insert.
Case Study 1Case Study 1
Case Study 2Case Study 2
► 64-year-old retired bookkeeper64-year-old retired bookkeeper● Stage II ER+, PR-, HER2- breast cancer, dose dense Stage II ER+, PR-, HER2- breast cancer, dose dense
AC-T AC-T ● Developed cough 5 years later on anastrazoleDeveloped cough 5 years later on anastrazole
• Bilateral pulmonary nodulesBilateral pulmonary nodules• CT guided biopsy positiveCT guided biopsy positive
– ER+, PR-, HER2- diseaseER+, PR-, HER2- disease
• Bone scan positiveBone scan positive– Lytic lesions on CTLytic lesions on CT– No symptomsNo symptoms
• Other factorsOther factors– ECOG PS 1ECOG PS 1– Non-insulin dependent diabetes Non-insulin dependent diabetes – HypertensionHypertension
Your choice for initial systemic therapy Your choice for initial systemic therapy is:is:
1.1. ChemotherapyChemotherapy
2.2. Chemotherapy plus bevacizumabChemotherapy plus bevacizumab
3.3. Endocrine therapyEndocrine therapy
What will you recommend?What will you recommend?
► Received fulvestrant with SD for 9 months, Received fulvestrant with SD for 9 months, then develops increasing cough and bone then develops increasing cough and bone pain. pain.
What chemotherapy regimen do you What chemotherapy regimen do you recommend?recommend?1.1. Single agent capecitabineSingle agent capecitabine
2.2. Single agent taxaneSingle agent taxane
3.3. Paclitaxel or docetaxel + bevacizumabPaclitaxel or docetaxel + bevacizumab
4.4. Paclitaxel + gemcitabinePaclitaxel + gemcitabine
5.5. Docetaxel + capecitabineDocetaxel + capecitabine
6.6. Carboplatin + gemcitabine Carboplatin + gemcitabine
7.7. Other Other
What will you recommend?What will you recommend?
Received paclitaxel with bevacizumab with Received paclitaxel with bevacizumab with response, then progression 12 months later. response, then progression 12 months later.
What chemotherapy regimen do you What chemotherapy regimen do you recommend?recommend?
1.1. Single agent capecitabineSingle agent capecitabine
2.2. IxabepiloneIxabepilone
3.3. Ixabepilone + capecitabineIxabepilone + capecitabine
4.4. EribulinEribulin
What will you recommend?What will you recommend?
Case Study 3Case Study 3
► 44-year-old unemployed investment banker with 44-year-old unemployed investment banker with T3N2M0 “triple negative” invasive breast cancer T3N2M0 “triple negative” invasive breast cancer
– In 2006, received adjuvant docetaxel/doxorubicin/ In 2006, received adjuvant docetaxel/doxorubicin/ cyclophosphamide cyclophosphamide
– Abdominal cramping and distention. Abdominal cramping and distention. CT scan: omental “caking”, peritoneal nodularity and a CT scan: omental “caking”, peritoneal nodularity and a
moderate amount of ascites; the ovaries and adnexae moderate amount of ascites; the ovaries and adnexae appeared normal. 6 bilateral pulmonary nodules, and a small appeared normal. 6 bilateral pulmonary nodules, and a small right pleural effusion was noted. right pleural effusion was noted.
Serum CA-125: normal.Serum CA-125: normal. Serum CA 15-3: elevated at 235. Serum CA 15-3: elevated at 235. Abdominal paracentesis: straw colored fluidAbdominal paracentesis: straw colored fluid
• Cytologic examination: adenocarcinoma cells Cytologic examination: adenocarcinoma cells morphologically similar to her prior primary invasive morphologically similar to her prior primary invasive breast cancer.breast cancer.
1.1. Single agent capecitabineSingle agent capecitabine
2.2. Single agent taxaneSingle agent taxane
3.3. Paclitaxel or docetaxel + bevacizumabPaclitaxel or docetaxel + bevacizumab
4.4. Paclitaxel + gemcitabinePaclitaxel + gemcitabine
5.5. Docetaxel + capecitabine Docetaxel + capecitabine
6.6. Carboplatin + gemcitabineCarboplatin + gemcitabine
7.7. OtherOther
What will you recommend?What will you recommend?
► Received paclitaxel with bevacizumab with Received paclitaxel with bevacizumab with response and then PD at 12 months, then response and then PD at 12 months, then capecitabine with progression at 6 months.capecitabine with progression at 6 months.
What chemotherapy regimen do you What chemotherapy regimen do you recommend?recommend?
1.1. Carboplatin + gemcitabine Carboplatin + gemcitabine
2.2. IxabepiloneIxabepilone
3.3. Ixabepilone + capecitabineIxabepilone + capecitabine
4.4. EribulinEribulin
5.5. OtherOther
What will you recommend?What will you recommend?
Case Study 4Case Study 4
► A 62-year-old woman is treated with modified A 62-year-old woman is treated with modified radical mastectomy 5 years prior, for a T2N0M0 radical mastectomy 5 years prior, for a T2N0M0 ER/PR/HER-negative infiltrating ductal cancer. ER/PR/HER-negative infiltrating ductal cancer.
► She is treated with doxorubicin and She is treated with doxorubicin and cyclophosphamide for four cycles.cyclophosphamide for four cycles.
► She now is noted on a routine chest x-ray to have She now is noted on a routine chest x-ray to have 4 pulmonary nodules in the right and left lungs, 4 pulmonary nodules in the right and left lungs, with CT and bone scans showing no other disease with CT and bone scans showing no other disease other than several rib metastases. other than several rib metastases.
► A CT-directed biopsy of the lung shows infiltrating A CT-directed biopsy of the lung shows infiltrating ductal cancer, ER/PR/HER-negative, and TTF-1-ductal cancer, ER/PR/HER-negative, and TTF-1-negative. She has no symptoms and ECOG negative. She has no symptoms and ECOG performance score of 0.performance score of 0.
At this point, which strategy would you At this point, which strategy would you recommend?recommend?
1.1.Single agent paclitaxel every 3 weeksSingle agent paclitaxel every 3 weeks
2.2.Single agent paclitaxel weeklySingle agent paclitaxel weekly
3.3.Docetaxel plus gemcitabineDocetaxel plus gemcitabine
4.4.IxabepiloneIxabepilone
What will you recommend?What will you recommend?
Case Study 5Case Study 5
► This patient is treated with docetaxel plus This patient is treated with docetaxel plus capecitabine for 3 cycles and exhibits a response, capecitabine for 3 cycles and exhibits a response, but subsequently required dose reductions of both but subsequently required dose reductions of both drugs do to fatigue, delayed count recovery and drugs do to fatigue, delayed count recovery and hand-foot syndrome. hand-foot syndrome.
► After 6 months, scans show progression in the After 6 months, scans show progression in the lung and three new liver metastases, 1-2 cm in lung and three new liver metastases, 1-2 cm in sizesize
► Apart from fatigue, she has no symptoms, but has Apart from fatigue, she has no symptoms, but has reduced her work to part time. Blood work and reduced her work to part time. Blood work and serum chemistries are normal except for a mild serum chemistries are normal except for a mild anemia. ECOG performance score is 1anemia. ECOG performance score is 1
At this point, which strategy would you At this point, which strategy would you recommend?recommend?
1.1.Paclitaxel plus gemcitabinePaclitaxel plus gemcitabine
2.2.Albumin-bound paclitaxel plus gemcitabineAlbumin-bound paclitaxel plus gemcitabine
3.3.Albumin-bound paclitaxel aloneAlbumin-bound paclitaxel alone
4.4.IxabepiloneIxabepilone
What will you recommend?What will you recommend?
Patient M.C., 61 years old, femalePatient M.C., 61 years old, female►No Family Hx for cancerNo Family Hx for cancer
►No hormone replacing therapyNo hormone replacing therapy
►Annual screening mammography, always negativeAnnual screening mammography, always negative
►2004: during self palpation, she notices a non-2004: during self palpation, she notices a non-tender mass in her left breasttender mass in her left breast
►No skin changes, no palpable adenopathies in the No skin changes, no palpable adenopathies in the omolateral axillaomolateral axilla
►Mammography: presence of a 2,3 cm density, with Mammography: presence of a 2,3 cm density, with irregular edgesirregular edges
Case Study 6Case Study 6
Courtesy of Giuseppe Galletti, MD Weill Cornell Medical College
FNA of the lesion: Invasive Ductal CarcinomaFNA of the lesion: Invasive Ductal Carcinoma
► No evidence of metastatic disease at PET/CT scanNo evidence of metastatic disease at PET/CT scan
► April 2004: lumpectomy and SLN (positive) April 2004: lumpectomy and SLN (positive) followed by omolateral axillary lymph node followed by omolateral axillary lymph node dissectiondissection
► Pathology results: Invasive Ductal CarcinomaPathology results: Invasive Ductal Carcinoma
► pT2 (2,7 cm) pN1a (3/18 positive nodes) M0 pT2 (2,7 cm) pN1a (3/18 positive nodes) M0 Stage Stage IIBIIB
Case Study 6Case Study 6
Courtesy of Giuseppe Galletti, MD Weill Cornell Medical College
► May-June 2004: adjuvant chemotherapy May-June 2004: adjuvant chemotherapy Doxorubicin 60 mg/m2 + Doxorubicin 60 mg/m2 + Cyclophosphamide 600 mg/m2 x 4 → Cyclophosphamide 600 mg/m2 x 4 → Docetaxel 75 mg/m2 x 4 → Trastuzumab for Docetaxel 75 mg/m2 x 4 → Trastuzumab for 1 year1 year
► Left breast irradiation (50 Gy + 10 Gy Left breast irradiation (50 Gy + 10 Gy boost)boost)
Case Study 6Case Study 6
NCCN Guideline Version 2.2011 Clinical
► June 2009: increase of Ca 15-3 levels; a CT scan June 2009: increase of Ca 15-3 levels; a CT scan revealed the presence of liver and bone revealed the presence of liver and bone metastasesmetastases
► 1st line metastatic chemotherapy: weekly 1st line metastatic chemotherapy: weekly paclitaxel 80 mg/m² + Zoledronic Acid 4 mg every paclitaxel 80 mg/m² + Zoledronic Acid 4 mg every 28 days28 days
► Side effects: two episodes G2 neutropeniaSide effects: two episodes G2 neutropenia
► After 8 weeks of treatment, Partial Response at CT After 8 weeks of treatment, Partial Response at CT scanscan
► She continued paclitaxel for further 16 weeks and She continued paclitaxel for further 16 weeks and experienced G2-3 peripheral neuropathy experienced G2-3 peripheral neuropathy (paresthesia) as main side effect.(paresthesia) as main side effect.
► December 2009: stable disease at CT scan; she December 2009: stable disease at CT scan; she stopped chemo and started Examestane as stopped chemo and started Examestane as hormonal therapyhormonal therapy
Case Study 6Case Study 6
Courtesy of Giuseppe Galletti, MD Weill Cornell Medical College
► July 2010: onset of dispnea and July 2010: onset of dispnea and headaches; evidence of right headaches; evidence of right pleural effusion, increase in size pleural effusion, increase in size of liver mets and presence of of liver mets and presence of brain lesions at CT scanbrain lesions at CT scan
► July-August 2010: stereotactic July-August 2010: stereotactic radiation therapy on brain mets radiation therapy on brain mets followed by complete regression followed by complete regression of the two lesions on subsequent of the two lesions on subsequent MRIMRI
► August 2010: patient started August 2010: patient started Ixabepilone 40 mgIxabepilone 40 mg
Case Study 6Case Study 6
Thomas E et al. JCO 2007; 25(33): 5210-17
► After the 2nd cycle, a Total Body CT scan showed After the 2nd cycle, a Total Body CT scan showed stable diseasestable disease
► Chemotherapy continued for further 4 cyclesChemotherapy continued for further 4 cycles
► At the end of the 3rd administration, patient At the end of the 3rd administration, patient referred G3 peripheral neuropathy (paresthesia referred G3 peripheral neuropathy (paresthesia and sensory loss tp lower limbs), partially and sensory loss tp lower limbs), partially recoveredrecovered
► December 2010: A total body CT scan confirmed December 2010: A total body CT scan confirmed the stable diseasethe stable disease
► Currently relapse free and under 3rd lineCurrently relapse free and under 3rd line
Case Study 6Case Study 6
Courtesy of Giuseppe Galletti, MD Weill Cornell Medical College
► Microtubule targeting agents as backbone of Microtubule targeting agents as backbone of breast cancer chemotherapy in the adjuvant and breast cancer chemotherapy in the adjuvant and metastatic settingmetastatic setting
► Taxanes fundamental to improve disease free Taxanes fundamental to improve disease free survival and overall survival in the adjuvant survival and overall survival in the adjuvant strategiesstrategies
► Ixabepilone still active against a very taxane-Ixabepilone still active against a very taxane-resistant diseaseresistant disease
► Neurological toxicitiy as main side effects of Neurological toxicitiy as main side effects of almost all microtubule targeting agents (eribulin almost all microtubule targeting agents (eribulin seems to better tolerated)seems to better tolerated)
Case Study 6Case Study 6
Courtesy of Giuseppe Galletti, MD Weill Cornell Medical College
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