Evolving Paradigms for Optimizing Management of Metastatic Breast Cancer Investigations Innovation Clinical Application Focus on Novel Mechanisms of Action

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


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


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


Program ChairProgram Chair Debu Tripathy, MDDebu Tripathy, MDProfessor of MedicineProfessor of Medicine



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.

http://www.cancer.gov/

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

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Overa

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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

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(%

)Pro

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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

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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?



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?



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


(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.


(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



Program ChairProgram Chair Debu Tripathy, M.D.Debu Tripathy, M.D.Professor of MedicineProfessor of Medicine



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



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



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



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)


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


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



Any

Minimum cumulative Minimum cumulative dosedose

Doxorubicin: Doxorubicin: 240 mg/m240 mg/m22

Epirubicin: 360 mg/mEpirubicin: 360 mg/m22


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


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.


046/048 Phase III Trials:046/048 Phase III Trials:Overall SurvivalOverall Survival

Outcome

Study 046Study 046 Study 048Study 048


CapeCapeN=377N=377


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


046/048 Planned 046/048 Planned Subset AnalysesSubset Analyses



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


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


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


Halichondrin B Analogue Halichondrin B Analogue (E7389)(E7389)

after Anthracyclines, Taxanes after Anthracyclines, Taxanes and Capecitabine: and Capecitabine:



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

))


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


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


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


EMBRACE: Exploratory Subgroup EMBRACE: Exploratory Subgroup Analysis of Overall SurvivAnalysis of Overall Survivalal


EMBRACE Overall Incidence of AEsEMBRACE Overall Incidence of AEs

Adverse event (AE), %Adverse event (AE), % EribulinEribulin(n=503)(n=503)


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)


EribulinEribulin(n=503) (n=503)


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


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


► 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.


► 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.


► 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


► 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.


► 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.



► 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


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



► 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


► 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



► 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



► 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


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


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



► 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)


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



► 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


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



► 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)



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