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

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Presentation on theme: "Evolving Paradigms for Optimizing Management of Metastatic Breast Cancer Investigations Innovation Clinical Application Focus on Novel Mechanisms of Action."— Presentation transcript:

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2 Evolving Paradigms for Optimizing Management of Metastatic Breast Cancer Investigations Innovation Clinical Application Focus on Novel Mechanisms of Action and Evidence-Based Therapies for Survival Prolongation in Heavily Treated Patients with MBC Focus on Novel Mechanisms of Action and Evidence-Based Therapies for Survival Prolongation in Heavily Treated Patients with MBC Program Chair Debu Tripathy, MD Professor of Medicine USC/Norris Comprehensive Cancer Center University of Southern California Los Angeles, CA

3 CME-certified symposium jointly sponsored by the Postgraduate Institute for Medicine and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from Eisai, Inc. Faculty disclosures: Listed in program syllabus This CME activity may include discussions of off-label or unapproved uses of specific agents Welcome and Program Overview

4 Program Faculty Program Chair Debu Tripathy, M.D. Professor of Medicine USC/Norris Comprehensive Cancer Center Center University of Southern California Los Angeles, CA Sara Hurvitz, MD Assistant Clinical Professor of Medicine Medicine Director, Breast Oncology Program David Geffen School of Medicine University of California, Los Angeles Los Angeles, CA Paraskevi Giannakakou, PhD Associate Professor of Pharmacology in Medicine in Medicine Weill Cornell Medical College New York, NY

5 CME Program Agenda CME Program Agenda 8:30 AM 8:45 AM Chairmans Introduction An Overview of Current Issues and Controversies Surrounding Management of Advanced and Metastatic Breast Cancer An Overview of Current Issues and Controversies Surrounding Management of Advanced and Metastatic Breast Cancer DEBU TRIPATHY, MD Program Chair Professor of Medicine USC/Norris Comprehensive Cancer Center University of Southern California Los Angeles, CA 8:45 AM 9:15 AM A Landscape Update on Metastatic Breast Cancer (MBC) What Works? What Doesnt? Strategies for Optimizing Survival: An Evidence-to-Practice Roadmap for MBC DEBU TRIPATHY, MD Program Chair Professor of Medicine USC/Norris Comprehensive Cancer Center University of Southern California Los Angeles, CA 9:15 AM 9:25 AM Question and Answer Session

6 CME Program Agenda CME Program Agenda 9:25 AM 9:50 AM Microtubules as a Target for Anticancer Drugs Multi- Mechanistic Approaches to Mitigating Metastatic Breast Disease Paraskevi Giannakakou, PhD Associate Professor of Pharmacology in Medicine Weill Cornell Medical College New York, NY 9:50 AM 10:00 AM Question and Answer Session 10:00 AM 10:30 AM Improving Overall Survival Prolongation in MBC: The Role of Nontaxane Microtubule Dynamics inhibitorsEvidence and Implications of Recent Clinical Studies Sara Hurvitz, MD Assistant Clinical Professor of Medicine Director, Breast Oncology Program David Geffen School of Medicine University of California, Los Angeles

7 CME Program Agenda CME Program Agenda 10:30 AM 10:40 AM Question and Answer Session 10:40 AM 11:05 AM Case Studies in Metastatic Breast Cancer DEBU TRIPATHY, MD Program Chair Professor of Medicine USC/Norris Comprehensive Cancer Center University of Southern California Los Angeles, CA 11:05 AM 11:15 AM Question and Answer Session

8 An Overview of Current Issues and Controversies Surrounding Management of Advanced and Metastatic Breast Cancer Evolving Paradigms and Optimizing Management of Metastatic Breast Cancer Program Chair Debu Tripathy, MD Professor of Medicine USC/Norris Comprehensive Cancer Center University of Southern California Los Angeles, CA

9 Learning Objectives Understand the treatment options for metastatic breast cancer as first-line therapy and beyond Understand the treatment options for metastatic breast cancer as first-line therapy and beyond Understand how breast cancer subtype influences treatment options and selection Understand how breast cancer subtype influences treatment options and selection Understand the side effect profile associated with different agents Understand the side effect profile associated with different agents

10 What are the Therapeutic Goals? Survival prolongation Survival prolongation Symptom palliation, delay, or preemption Symptom 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) instruments Quality of life (QOL) instruments Achieve favorable tradeoff profile (ie, efficacy vs. toxicity) Achieve favorable tradeoff profile (ie, efficacy vs. toxicity) No consistent relationship between RR/PFS and QOL No consistent relationship between RR/PFS and QOL No clinically useful tool to measure QOL or tradeoffs No clinically useful tool to measure QOL or tradeoffs Subjective assessment often made by clinicians based upon Subjective assessment often made by clinicians based 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)

11 Therapeutic Goals Live longer Live longer Prolong survival Prolong survival Live better Live better Symptom palliation or delay Symptom palliation or delay Favorable tradeoff profile Favorable tradeoff profile Toxicity Toxicity Convenience Convenience Cost Cost Complex Subjective Complex Subjective Simple Objective Simple Objective

12 Survival and FDA Approval of Oncology Drugs for Metastatic Breast Cancer 2003 (Johnson, Williams, Pazdur. J Clin Oncol 2003) 2003 (Johnson, Williams, Pazdur. J Clin Oncol 2003) There is a common misperception that … FDA … requires a survival improvement for approval of oncology drug marketing applications. There is a common misperception that … FDA … requires a survival improvement for approval of oncology drug marketing applications. Regular …approval …requires substantial evidence of efficacy… Regular …approval …requires substantial evidence of efficacy… …prolongation of life, a better life, or an established surrogate for at least one of these. …prolongation of life, a better life, or an established surrogate for at least one of these (Cortesar. Proc ASCO 2008) 2008 (Cortesar. Proc 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 is of sufficient magnitude. PFS may be an acceptable endpoint if measured properly and is of sufficient magnitude. Survival also should be measured to ensure that any new therapy does not lead to a decrement. Survival also should be measured to ensure that any new therapy does not lead to a decrement.

13 What are the Therapeutic Options? ModalitySelection Improvement in RRPFSOS Chemotherapy 1,2 ER/PR-negative, visceral mets, failed endocrine therapy Endocrine 1,2 ER and/or PR-positive Trastuzumab, lapatinib 1,2 Her2/neu-positive Bevacizumab 3,4,5 Her2/neu-negative, first-line therapy RANKL inibitors, bisphosphonates 1,2 Osteolytic bone mets 1. National Cancer Institute. Breast Cancer Treatment (PDQ®). 2. NCCN Clinical Practice guidelines in Oncology. Breast Cancer V Miller et al. N Engl J Med. 2007;357: Miles et al. Presented at the San Antonio Breast Cancer Symposium Abstract Robert N, et al. J Clin Oncol. 2009;27(15S). Abstract 1005.http://www.cancer.gov/

14 What are the Toxicities Associated with Therapeutic Options? Agent Non-hematologic toxicities Endocrine therapy Hot flushes, gynecologic symptoms Bevacizumab Hypertension, thromboembolic disease Trastuzumab Cardiac dysfunction LapatinibDiarrhea Cytotoxic agents Anthracycllnes Paclitaxel Docetaxel Ixabepilone Eribulin Vinorelbine Capecitabine Gemicitabine Cardiomyopathy Cardiomyopathy Neuropathy Neuropathy Fluid retention Fluid retention Neuropathy Neuropathy Obstipation, nueropathy Obstipation, nueropathy Hand-foot syndrome Hand-foot syndrome Fever, dyspnea Fever, dyspnea

15 Does Cytotoxic Chemotherapy Improve Survival? Chia et al. Cancer 2007; 110: Overall Survival Years Clinical trialsClinical trials –Hundreds of trials, few show OS benefit –Few that show benefit - play of chance? –More positive trials in second or greater line setting Population-based studiesPopulation-based studies –Suggests that addition of modestly effective cytotoxic agents have produced incremental improvements in OS

16 Broglio, K. R. et al. J. Natl. Cancer Inst Probability of Detecting Significant Difference in OS as a Function of Median OS Post-Progression (SPP) Median SPP (months) Probability of OS Statistical Significance (%) 80% power for PFS 85% power for PFS 90% power for PFS

17 Complete/partial response Stable disease Progressive disease Pain CRF Pain QoL Shortness of breath CRF Shortness of breath QoL Mood CRF Worry QoL Depression QoL Does Chemotherapy Palliate Symptoms ? Geels P, et al. J Clin Oncol 2000;18:

18 Is Chemotherapy more Effective than Endocrine Therapy in ER-Positive Disease? Methods Methods Meta-analysis Meta-analysis Randomized trials comparing chemotherapy alone with endocrine therapy alone in metastatic breast cancer Randomized trials comparing chemotherapy alone with endocrine therapy alone in metastatic breast cancer Results (8 trials, N=817) Results (8 trials, N=817) No difference in OS: HR 0.94 (95%CI ,P=0.5) (heterogeneity P = 0.1) No difference in OS: HR 0.94 (95%CI ,P=0.5) (heterogeneity P = 0.1) Higher RR for chemo OR 1.25 ( , P = 0.04) ((heterogeneity P= ) Higher RR for chemo OR 1.25 ( , P = 0.04) ((heterogeneity P= ) Two largest trials showed trends in opposite directions Two largest trials showed trends in opposite directions Toxicity Toxicity 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 measured QOL, concluding that it was better with chemotherapy 3 of 7 mentioned aspects of QOL, with differing results - only one trial formally measured QOL, concluding that it was better with chemotherapy Authors' conclusions Authors' conclusions In women with metastatic breast cancer and where hormone receptors are present, a policy of treating first with endocrine therapy rather than chemotherapy is recommended except in the presence of rapidly progressive disease. In women with metastatic breast cancer and where hormone receptors are present, a policy of treating first with endocrine therapy rather than chemotherapy is recommended except in the presence of rapidly progressive disease. et al. The Cochrane Database of Syst Rev 2003;(2):CD

19 What is the role for targeted agent as first line therapy or beyond? Evolving Paradigms and Optimizing Management of Metastatic Breast Cancer

20 Treatment Effect of Trastuzumab as First Line Therapy in HER2-Positive MBC 1. Slamon et al. N Engl J Med. 2001;344(11): Marty et al. J Clin Oncol. 2005;23(19): P<.001 P =.0002 P<.001 P<.0001 Chemotherapy aloneChemotherapy plus trastuzumab

21 Treatment Effect of Trastuzumab as First-Line Therapy in HER2-Positive MBC P =.046 P =.0325 Chemotherapy aloneChemotherapy plus trastuzumab 1. Slamon et al. N Engl J Med. 2001;344(11): Marty et al. J Clin Oncol. 2005;23(19):

22 Treatment Effect of Bevacizumab as First-line Therapy for MBC (Mainly HER2-Negative) P<.0001 P =.0097 P =.0054 P< Miller et al. N Engl J Med. 2001;357(26): Miles et al. J Clin Oncol May 24 [Epub ahead of Print]. 3. Robert et al. J Clin Oncol. 2009;27(15S). Abstract * * Chemotherapy alone vs chemotherapy plus 10 mg/kg bevacizumab Chemotherapy plus placebo vs chemotherapy plus 15 mg/kg bevacizumab E AVADO 2 RIBBON-1 3 Chemotherapy alone/plus placeboChemotherapy plus bevacizumab Response Rate

23 Treatment Effect of Bevacizumab as First-line Therapy for MBC (Mainly HER2-Negative) P<.001 P =.0002 P =.0001 P = Miller et al. N Engl J Med. 2001;357(26): Miles et al. J Clin Oncol May 24 [Epub ahead of Print]. 3. Robert et al. J Clin Oncol. 2009;27(15S). Abstract * E AVADO 2 RIBBON-1 3 Chemotherapy alone/plus placeboChemotherapy 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

24 Bevacizumab: Meta-analysis No bevacizumab No bevacizumabBevacizumab No ORR32%49%P<0.05 Median PFS6.7 mo9.2 mo. HR 0.64, p< Median OS26.4 mo26.7 mo.P= year survival77%82%P<0.003 OShaughnessy et al. JCO 2010; 28; 152, abst 1005

25 Second or Greater Line Biologic Agents Author & Population Experimental vs. Standard No. Median TTP/PFS (mo.)ORROS(mo.) Geyer et al. NEJM 2006 & Cameron ASCO 2007 HER2+, Trast. Resistant Lapatinib + Cap vs. Cap alone 324 HR vs % vs. 14%* HR vs Brufsky et al. SABCS, 2009 HER2-, Prior chemo Bev vs. placebo PlusChemotherapy684 HR vs % vs. 30% vs. 30% HR vs OShaughnessy et al ASCO 2009 & SABSC 2010 Triple Negative Carbo/gem +/- BSI HR vs % vs. 16% vs. 16% HR vs. 7.7 * Statistically significant difference

26 Is combination cytotoxic therapy more effective than single agent therapy as first- line therapy or beyond? Evolving Paradigms and Optimizing Management of Metastatic Breast Cancer

27 Single Agent vs Combination Chemotherapy for Metastatic Breast Cancer Methods Methods Randomized trials single agent vs. combination chemotherapy Randomized 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= , P <0.0001) & no heterogeneity HR 0.88 (95% CI= , P <0.0001) & no heterogeneity Results are similar if analysis is limited to first-line chemotherapy Results are similar if analysis is limited to first-line chemotherapy Time to disease progression Time to disease progression HR 0.78 (95% CI= , P < ) (heterogeneity (P = 0.002) HR 0.78 (95% CI= , P < ) (heterogeneity (P = 0.002) Response rate Response rate Odds ratio 1.29 (95% CI= , P <0.0001) (heterogeneity P < ) – due to varying efficacy of the comparators Odds ratio 1.29 (95% CI= , P <0.0001) (heterogeneity P < ) – due to varying efficacy of the comparators Toxicity Toxicity More neutropenia, alopecia, nausea/vomiting with combinations More neutropenia, alopecia, nausea/vomiting with combinations Carrick S, et al. The Cochrane Database of Syst Rev 2009;(2):CD The survival benefit seen in older studies not evident in more contemporary studies with availability of numerous agents and targeted therapies

28 First Line Cytotoxic Therapy for Metastatic Disease: Prior Adjuvant Anthracycline Author Combination vs. Comparator Median TTP/PFS (months)ORROS(months) Albain et al JCO 2008 Gem + Paclitaxel vs. Paclitaxel HR vs. 4.2* (TTP)41% vs. 26%* HR vs. 15.8* Sparano et al JCO 2009 PLD + Docetaxel vs. Docetaxel HR vs. 7.0* (TTP)35% vs. 26%* HR vs * Statistically significant difference * Statistically significant difference PLD – pegylated liposomal doxorubicin PLD – pegylated liposomal doxorubicin Selected Trials

29 Second or Greater Line Cytotoxic Therapy: Prior Anthracycline/Taxane Exposure Author Experimental vs. Standard No. Median TTP/PFS (mo.)ORROS(mo.) OShaughnessy et al JCO 2002 Cap+ Docetaxel vs. Docetaxel 511 HR vs. 4.2* (TTP)42% vs. 30%* vs. 30%* vs. 11.5* Thomas et al JCO 2007Ixabepilone+Cap vs. Capecitabine 752 HR vs. 4.2* (PFS)35% vs. 14%* vs. 14%* 12.9 vs Sparano et al JCO 2010Ixabepilone+Cap vs. Capecitabine 1221 HR vs. 4.2* (PFS)43% vs. 29%* vs. 29%* HR vs Twelves et al ACO 2010 Eribulin vs. Physicians Choice 762 HR vs. 2.2 (PFS) 12% vs.7%* vs. 10.7* * Statistically significant difference Selected Trials

30 Combination Chemotherapy Versus Sequential Single-agent Chemotherapy Both combinations of cytotoxic chemotherapy and single- agent chemotherapy are reasonable options as first-line systemic therapy Both combinations of cytotoxic chemotherapy and single- agent chemotherapy are reasonable options as first-line systemic therapy NCCN guidelines & ESO-mBC task force, sequential single- agent chemotherapy should be the preferred choice NCCN guidelines & ESO-mBC task force, sequential single- agent chemotherapy should be the preferred choice In absence of rapid clinical progression In absence of rapid clinical progression Life-threatening visceral metastases or Life-threatening visceral metastases or Need for rapid symptom and/or disease control Need for rapid symptom and/or disease control Guidelines did not address use of biologics in combinations Guidelines did not address use of biologics in combinations Cardoso et al. J Natl Cancer Inst. 2009;101(17):

31 Conclusions: Systemic Therapy for MBC Treatment regimen should be individualized Treatment regimen should be individualized Identify and prioritize therapeutic goals Identify and prioritize therapeutic goals Select least toxic option required to achieve therapeutic goals Select least toxic option required to achieve therapeutic goals Decision based upon multiple factors including Decision 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 factors Patient-specific factors Prior treatment history Prior treatment history Performance status Performance status Age Age Co-morbidities (eg, cardiac disease) Co-morbidities (eg, cardiac disease) Patient preference (eg, avoid alopecia) Patient preference (eg, avoid alopecia)

32 Conclusions: General Principles in Selecting Therapy Cytotoxic therapy Cytotoxic therapy Usually reserved for ER-negative disease, or ER-positive disease resistant to endocrine therapy or associated with substantial symptom burden Usually reserved for ER-negative disease, or ER-positive disease resistant to endocrine therapy or associated with substantial symptom burden Use single agents rather than combinations whenever feasible Use single agents rather than combinations whenever feasible Combination cytotoxic therapy may be indicated in selected circumstances Combination cytotoxic therapy may be indicated in selected circumstances Breast cancer subtypes Breast cancer subtypes ER-Positive Disease ER-Positive Disease Use endocrine therapy (ET) as first line therapy whenever feasible Use endocrine therapy (ET) as first line therapy whenever feasible Switch to alternative ET if prolonged benefit from first or second/greater lines of ET Switch to alternative ET if prolonged benefit from first or second/greater lines of ET HER2-Positive Disease HER2-Positive Disease When chemotherapy indicated, always used in combination with anti-HER2 directed therapy When chemotherapy indicated, always used in combination with anti-HER2 directed therapy Triple-negative disease or resistant to endocrine therapy Triple-negative disease or resistant to endocrine therapy Cytototoxic therapy Cytototoxic therapy

33 A Landscape Update on Metastatic Breast Cancer (MBC): What Works? What Doesnt? Strategies for Optimizing Survival: An Evidence-to-Practice Roadmap for MBC Evolving Paradigms and Optimizing Management of Metastatic Breast Cancer Program Chair Debu Tripathy, M.D. Professor of Medicine USC/Norris Comprehensive Cancer Center University of Southern California Los Angeles, CA

34 Principles of Systemic Therapy for Advanced Metastatic Breast Cancer Evaluation includes careful history and examination with staging scans, biopsy and biomarkers (if possible) Evaluation includes careful history and examination with staging scans, biopsy and biomarkers (if possible) For ER or PR+, trial of salvage hormonal therapy For ER or PR+, trial of salvage hormonal therapy Chemotherapy for hormone-insensitive or aggressive presentations Chemotherapy for hormone-insensitive or aggressive presentations Doublets of chemotherapy – higher response and time to progression, marginal effects on survival, toxicities Doublets of chemotherapy – higher response and time to progression, marginal effects on survival, toxicities Addition of HER2 blockade to hormonal or chemotherapy (trastuzumab, lapatinib) for HER2+ disease Addition of HER2 blockade to hormonal or chemotherapy (trastuzumab, lapatinib) for HER2+ disease Addition of anti-angiogenic therapy improves time to progression, but not survival Addition of anti-angiogenic therapy improves time to progression, but not survival Newer targeted therapies in appropriate subgroups and combinations being actively studied Newer targeted therapies in appropriate subgroups and combinations being actively studied

35 Key Issues Surrounding Chemotherapy for Advanced Breast Cancer Are there specific chemotherapy agents that are superior in first or subsequent lines of therapy? Are there specific chemotherapy agents that are superior in first or subsequent lines of therapy? Should chemotherapy breaks be given in patients with stable or responsive disease? Should chemotherapy breaks be given in patients with stable or responsive disease? Should chemotherapy combinations be given instead of single agents? Should chemotherapy combinations be given 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, liposomes, immunotoxins)? Can drug delivery be improved (eg. nanoparticle, liposomes, immunotoxins)? Can one predict toxicities of single or combination therapy? Can one predict toxicities of single or combination therapy? What is the basis for individualizing treatment choices? What is the basis for individualizing treatment choices?

36 Cell Cycle-Specific Activity of Cytotoxics Antimicrotubule agents Paclitaxel Docetaxel Epothilones Eribulin Antimetabolites 5-FU, fluoropyrimidines Gemcitabine Methotrexate Cell CycleNon- Specific Agents Alkylating Agents Platinum Cyclophos- phamide Thiotepa Nitrosoureas Antibiotics Anthracycines oDoxorubicin oEpirubicin oMitoxantrone Podopyllotoxins Etoposide Camptothecins Irinotecan Vinca Alkaloids Vinorelbine Vinblastine

37 Response Rates with Single-Agent Chemotherapy in Advanced Breast Cancer First-Line Second-Line First-Line Second-Line Doxorubicin % % Epirubicin % ~28% Paclitaxel % % Docetaxel % % Capecitabine ~25% % Gemcitabine % % Vinorelbine % % Pre – Year 2000

38 Survival (Months) Proportion Alive Censored Paclitaxel 175 mg/m 2 Docetaxel 100 mg/m 2 Docetaxel vs. Paclitaxel Overall Survival P=0.03 Jones SE, et al. J Clin Oncol 2005 Intention-to-Treat Population

39 Hematologic Toxicity *For difference in grade 3 / 4 toxicities, p < 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

40 Maintenance Therapy for Advanced Hormonally 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

41 StudyTreatment SchedulesN Med TTP (mo) p Med OS (mo) p Coates A et al NEJM 1987 AC/CMF until PD AC x 3 cycles49.4 Harris AL et al Lancet 1990 Mitoxantrone until PD NS 11 NS Mitoxantrone x Muss H et al NEJM 1991 FAC x 6 CMF x < FAC x Ejlertsen B Eur J Ca 1993 FEC + TAM x < FEC + TAM x Gregory R et al Eur J Ca 1997 VAC/VEC x 6 MMM x VAC/VEC/MMM x Falkson G et al JCO 1998 A x 6 CMFPTH x < A x Nooij M et al Eur J Ca 2003 CMF until PD CMF x Trials Examining Continuous vs. Interrupted/Fixed Therapy

42 Study Treatment Schedules N Med TTP (mo) p Med OS (mo) p Gennari A et al JCO 2006 E/A + P x 6-8 P x * E/A + P x *29.0 Alba E et al ASCO 2007 A T x 6 PLD * 0.006*0.005 A T x * Trials Examining Continuous vs. Interrupted/Fixed Therapy * From time of randomization to maintenance arm E = epirubicin; A = doxorubicin; P = paclitaxel; T = docetaxel; PLD = pegylated liposomal doxorubicin Contemporary Regimens

43 Doxorubicin + Paclitaxel 36% 34% 47% QOL Median TTF Response Paclitaxel Doxorubicin 6 mos. 6 mos. 8 mos. = = = 19 mos. 22 mos. 22 mos. Median Survival Single vs. Combination vs. Sequential Chemotherapy Crossover Responses: A A T T A A T T = 22% = 20% NS Sledge G et al. J Clin Oncol 2003

44 Finnish Randomized Comparison of Single Agents vs Combinations As First- and Second-Line Chemotherapy for Metastatic Breast Cancer MCMC MCMC MCMC MCMC MCMCMCMCMCMC MCMC VV VV VV VV WeeksWeeks WeeksWeeks First -Line Second-LineSecond-LineEE EEEE EE EE EEEEEE EE EEEE EE EE EEEE EE EEEEFFFF FF FFFF CCCC CC C CCC 500 mg/m 2 60 mg/m 2 60 mg/m 2 8 mg/m 2 6 mg/m 2 8 mg/m 2 20 mg/m 2 weeklyweekly Joensuu H et al. J Clin Oncol 1998

45 Single Agents vs Combinations as 1st- and 2nd-Line Chemotherapy for MBC No significant difference in overall TTP for E M vs CEF MV (P = 0.28) No significant difference in overall TTP for E M vs CEF MV (P = 0.28) No difference in overall survival for E M vs CEF MV (P = 0.96) or survival calculated from second-line Rx (P = 0.56) No difference in overall survival for E M vs CEF MV (P = 0.96) or survival calculated from second-line Rx (P = 0.56) Less toxicity and better QOL with single agents Less toxicity and better QOL with single agents Regimen RR Response Duration CEF 55% 12 mos E 48% 10.5 mos MV 16% - M 7% - Joensuu H et al. J Clin Oncol 1998 Finnish Breast Cancer Group Study Finnish Breast Cancer Group Study

46 Combination vs. Monotherapy for MBC: No Survival Benefit (n=2,490) Dox + Paclitaxel = Single Agents Sequentially Dox + Paclitaxel = Single Agents Sequentially (Sledge, J Clin Oncol 2003) (Sledge, J Clin Oncol 2003) FEC then MV = Epirubicin then Mitomycin C FEC then MV = Epirubicin then Mitomycin C (Joensuu, J Clin Oncol 1998) (Joensuu, J Clin Oncol 1998) Taxotere > Mitomycin C + Vinblastine Taxotere > Mitomycin C + Vinblastine (Nabholtz, J Clin Oncol 1999) (Nabholtz, J Clin Oncol 1999) Taxol > CMFP Taxol > CMFP (Bishop, J Clin Oncol 1998) (Bishop, J Clin Oncol 1998) FEC = Mitoxantrone FEC = Mitoxantrone (Heidemann, Ann Oncol 2002) (Heidemann, Ann Oncol 2002) Dox + Vinorelbine = Doxorubicin Dox + Vinorelbine = Doxorubicin (Norris, J Clin Oncol 2000) (Norris, J Clin Oncol 2000) Epirubicin + Vinorelbine = Epirubicin Epirubicin + Vinorelbine = Epirubicin Ejlertsen, J Clin Oncol 2004

47 Single vs Combination Chemotherapy: Recent Positive Trials in MBC - Overall Survival O'Shaughnessy J et al J Clin Oncol 2002 Albain K et al J Clin Oncol Hazard ratio = Log-rank p= Capecitabine/docetaxel Docetaxel Survival Gemcitabine + Paclitaxel (n=267) Paclitaxel (n=262) 12 mo70.7%60.9% 18 mo50.7%41.9% Log rank P=0.018 HR 0.78 ( ) Months 100% 72%14.5 (12.3–16.3) 79%11.5 (9.8–12.7) EventsMedian (CI)

48 Capecitabine plus Docetaxel: Most Common (>5%) Grade 3/4 Treatment-Related Toxicities Patients (%) Capecitabine/docetaxel (n=251) Diarrhea Stomatitis Hand-foot syndrome Nausea Fatigue/ asthenia Neutropenic fever Docetaxel (n=255) Grade 3 Grade 4 Grade 3 Grade 4 O'Shaughnessy J, et al J Clin Onocol 2002

49 Combination vs. Single-Agent Therapy for MBC: Meta-Analysis of Randomized Trials Combination betterSingle agent better Efficacy: (p= ) 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) Total (deaths/patients) AV A + DBD A + MMC VAC CF + P ± V A + ETO AV + MMC E + VDS FEC 75 CMF + VBL CMF CMFV + P CF + P ± V FEC / / /990 A A A A AA A A E E C PAM F CCNU I E 649/ / /996 Fossati R et al. J Clin Oncol 1998

50 = paclitaxel 80 mg/m 2 * qw vs 175 mg/m 2 q 3w = trastuzumab 4mg/kg load, 2 mg/kg/w Paclitaxel: Dose/Schedule Comparison Paclitaxel: Dose/Schedule Comparison CALGB 9840 q3w P q1w P (n=171; HER2 unknown) q3wP+T q1wP+T (n=406; HER2 known) H E R 2 (+) H E R 2 (-) *first 116 pts at 100 mg/m 2 /wk x 6, then all pts 80 mg/m 2 q wk Seidman A, et al. J Clin Oncol 2008

51 Paclitaxel: Dose/Schedule Comparison Paclitaxel: Dose/Schedule Comparison CALGB 9840 Seidman A, et al. J Clin Oncol 2008

52 Pegylated Liposomal Doxorubicin (PLD) Prolonged half life (>55 hours) Prolonged half life (>55 hours) - Pegylation reduced uptake by reticuloendothelial system Preferential tumor penetration Preferential tumor penetration - Compromised vasculature in tumor tissue Reduced volume of distribution Reduced volume of distribution - Limited exposure to normal tissue, e.g. heart. Doxorubicin Liposomal doxorubicin Pegylated liposomal doxorubicin Gabizon A et al. Clin Pharmacokinet 2003

53 Phase III trial: Pegylated liposomal doxorubicin (PLD) plus Docetaxel vs. Docetaxel RandomizeRandomize PLD (30 mg/m 2 ) + Docetaxel (60 mg/m 2 ) day 1 every 21 days Docetaxel (75 mg/m 2 ) day 1 every 21 days N=751 Eligibility: - Advanced breast cancer - Relapsed 1 year following neo/adjuvant anthracyclines (180 and 360 mg/m 2 ) Primary endpoint: TTP Secondary endpoints: OS, ORR, overall safety, cardiac safety N=378 N=373 Sparano J et al. JCO 2009 Alone in Advanced Breast Cancer

54 Docetaxel PLD + Docetaxel HRP-Value Median TTP7.0 months9.8 months ORR26%35% Median OS*20.7 months20.6 months PLD plus Docetaxel vs. Docetaxel Alone in Advanced Breast Cancer Sparano J et al. JCO 2009 Select Grade 3/4 Adverse Events Docetaxel (N=373) PLD + Docetaxel (N=377) Neutropenia59%57% Febrile Neutropenia6%7% Hand-Foot syndrome024%* Stomatitis1%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%)

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56 Randomized nab-Paclitaxel Trial Design: CA012 Albumin-bound paclitaxel 260 mg/m 2 iv over 30 min q3w No standard premedication Paclitaxel 175 mg/m 2 iv over 3 hrs q3w Standard premedication with dexamethasone and antihistamines MBC with prior anthracycline and no prior taxane for MBC Randomisation (1:1) n = 460 Gradishar et al. J Clin Oncol 2005

57 Randomized nab-Paclitaxel Trial Response Rates Albumin-bound paclitaxel Paclitaxel n ORR (± 95% CI) % 42.3% 18.7% 27.0% 26.5% 13.2% 34.1% 18.3% 33.5% 18.7% P = 0.001P = 0.029P = 0.006P = Gradishar et al. J Clin Oncol 2005

58 Nab-Paclitaxel: Different Dose/Schedules vs. Docetaxel Gradishar W et al. JCO 2009 Response Rates 100 mg/m 2 q3w n = mg/m 2 q3w n = mg/m 2 qw 3/4 n = mg/m 2 qw 3/4 n = 74 Docetaxel Nab-Paclitaxel

59 Capecitabine ± Ixabepilone in Taxane and Anthracyline-Resistant MBC % Response Investigator Independent Radiology Review Ixabepilone + Capecitabine (N=375) (N=375)Capecitabine (N=377) (N=377) Ixabepilone + Capecitabine (N=375)Capecitabine(N=377) ORR (CR + PR) P < Stable Disease Median Progression-Free Survival: by IRR (95% CI) Ixabepilone + capecitabine: 5.8 months ( ) Capecitabine: 4.2 months ( ) Hazard ratio: 0.75 ( ); P= Vahdat L et al. JCO 2007

60 Median95% CI Ixabepilone + Capecitabine 5.8 mo(5.5–7.0) Capecitabine4.2 mo(3.8–4.5) Progression-free Survival by Independent Radiologic Review P= HR: 0.75 (0.64–0.88) Proportion Progression Free Months Vahdat L et al. JCO 2007

61 Basal subtype % of tumors 2. ER/PR/HER2-negative 3. very proliferative 4. EGFR, c-kit, c-myc + 5. includes BRCA1 mutations HER2+ subtype % of tumors 2. prognostic/predictive 2. proliferation 3. two types (ER -/+) Luminal A and B (ER+) 1. continuum 2. prognostic/predictive 3. ER-GATA3-HNF3a-XBP1 4. proliferation (mutant p53) 5. cyclin D1 and BCL2 + Ki-67, STK6, Survivin, Cyclin B1 and MYBL2 Gene Expression Profiling Reveals Distinct Clusters Sorlie T et al. PNAS 2003

62 p < p <0.001 Sorlie T et al. PNAS 2003

63 Where are We Today with Chemotherpy for Advanced Breast Cancer ? No clear single agent stands out as superior, but certain comparisons have been noted No clear single agent stands out as superior, but certain comparisons have been noted First line (eg. docetaxel > paclitaxel) First line (eg. docetaxel > paclitaxel) Late line (eg. eribulin > several single agents after 2 or more chemotherapy regimens for MBC) Late line (eg. eribulin > several single agents after 2 or more chemotherapy regimens for MBC) Combinations are superior for response and TTP, so may be indicated for symptoms or high visceral burden Combinations are superior for response and TTP, so may be indicated for symptoms or high visceral burden Dose and schedule matter, particularly for taxanes Dose and schedule matter, particularly for taxanes Certain combinations may be synergistic in preclinical models, but difficult to prove in the clinic Certain combinations may be synergistic in preclinical models, but difficult to prove in the clinic Molecular diagnostics and pharmacogenomics may point the way to individualizing chemotherapy for efficacy and toxicity Molecular diagnostics and pharmacogenomics may point the way to individualizing chemotherapy for efficacy and toxicity

64 Microtubules as a Target for Anticancer Drugs Multi-Mechanistic Approaches to Mitigating Metastatic Breast Disease The Role of Nontaxane Microtubule Dynamics Inhibitors – Evidence and Implications of Recent Clinical Studies Evolving Paradigms and Optimizing Management of Metastatic Breast Cancer Paraskevi Giannakakou, PhD Associate Professor of Pharmacology in Medicine Weill Cornell Medical College New York, NY

65 Improving Overall Survival in Metastatic Breast Cancer The Role of Nontaxane Microtubule Dynamics Inhibitors – Evidence and Implications of Recent Clinical Studies Evolving Paradigms and Optimizing Management of Metastatic Breast Cancer Sara Hurvitz, MD Assistant Clinical Professor of Medicine Director, Breast Oncology Program David Geffen School of Medicine University of California, Los Angeles Los Angeles, CA

66 Microtubule Targeting Agents Taxanes Taxanes Docetaxel, paclitaxel, nab-paclitaxel Docetaxel, paclitaxel, nab-paclitaxel Vinca alkaloids Vinca alkaloids Vinorelbine, vinflunine Vinorelbine, vinflunine Epothilones Epothilones Ixabepilone, KOS 862 (EPO D), ZK-EPO, patupilone Ixabepilone, KOS 862 (EPO D), ZK-EPO, patupilone Halichondrin B analogue Halichondrin B analogue Eribulin (E7389) Eribulin (E7389)

67 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

68 Destabilizers Stabilizers Polymerization Vinca alkaloids Taxanes/Epothilones Mitotic spindle formation blocked MT Bundling Multipolar spindles MT Bundling Multipolar spindles Graphic courtesy of Harold J. Burstein, MD, PhD. Mechanisms of action of microtubule-targeted agents

69 Sorangium cellulosum Myxobacteria Myxobacteria Secondary metabolites (epothilones/fungicides) Secondary metabolites (epothilones/fungicides) Zambezi river

70 Ixabepilone (BMS ) Epothilone B Ixabepilone Semisynthetic analog of epothilone B (aza- epothilone B) Semisynthetic analog of epothilone B (aza- epothilone B) Molecular difference between ixabepilone and epothilone because of amine vs ester moiety Molecular difference between ixabepilone and epothilone because of amine vs ester moiety

71 Conclusions: Preclinical Ixabepilone Ixabepilone Semisynthetic analog of epothilone B Semisynthetic 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 paclitaxel Tubulin polymerizing activity 2-10 x greater than paclitaxel Have activity in tumors that use MDR as a resistance mechanism Have activity in tumors that use MDR as a resistance mechanism Active in multiple in vivo tumor models Active in multiple in vivo tumor models Similar mechanism of action (G2/M arrest, Bax conformational change) Similar mechanism of action (G2/M arrest, Bax conformational change) Linear pharmacology Linear pharmacology Ixabepilone + other agents Ixabepilone + other agents Synergy with capecitabine, cetuximab, trastuzumab Synergy with capecitabine, cetuximab, trastuzumab Greater in vivo synergy with bevacizumab than paclitaxel Greater in vivo synergy with bevacizumab than paclitaxel

72 Ixabepilone: Preclinical Activity (P=0.0001) Days post-tumor implant Median tumor weight (mg) ControlIxabepilone Capecitabine Combination mg/kg (MTD) 10 mg/kg (MTD) Capecitabine Synergy Days Post-Tumor Implant Pat-21 Xenograft Ixabepilone Paclitaxel Control Median Tumor Weight (mg) Paclitaxel Rx (36 mg/kg/inj) Ixabepilone Rx (10 mg/kg/inj) N = 8 Activity in Paclitaxel Resistance Bevacizumab IP 4 mg/kg Ixabepilone IV Control Bevacizumab Ixabepilone Combined Median Tumor Weight (mg) Days Post-Tumor Implant L2987 Human Lung Carcinoma Bevacizumab Synergy Rx Median tumor weight (mg) Control Trastuzumab Ixabepilone Combined Trastuzumab Synergy Days Post-Tumor Implant HER2 receptor positive KPL4 Human breast Carcinoma Xenografts Data on file. Bristol Myers Squibb Company; Princeton, NJ

73 Ixabepilone in Metastatic Breast Cancer: Summary of Single-Agent Phase II Trials Roche H et al. J Clin Oncol. 2007;23: ; Denduluri N et al. J Clin Oncol. 2007;23: ; Low et al. J Clin Oncol 2005;23:2726–2734; Thomas E et al. J Clin Oncol. 2007;23:

74 PD or unacceptable toxicity Max 18 cycles Phase II Study 081: Ixabepilone in Triple Refractory MBC Primary end point: ORR Prior therapy with anthracycline, taxane, and capecitabine (N=126) Ixabepilone 40 mg/m 2 IV q3w 1 Resistance Criteria Neoadjuvant or Adjuvant: 6 months of last doseNeoadjuvant or Adjuvant: 6 months of last dose Metastatic: 8 weeks of last doseMetastatic: 8 weeks of last dose Progression during or after discontinuation of trastuzumab in HER2+ patientsProgression during or after discontinuation of trastuzumab in HER2+ patients Perez E, et al. J Clin Oncol. 2007;23:

75 Phase II Study 081: Ixabepilone in Triple Refractory MBC Characteristic Patients, no. (%) (N=126) Median age (min-max) in years 51 (30–78) Visceral disease (liver and/or lung) 108 (86) No. of disease sites: 3– (49) 62 (49) 19 (15) 19 (15) ER-, PR-, HER2- 42 (33) 42 (33) Prior neoadjuvant/adjuvant chemotherapy 95 (75) No. of prior chemotherapy regimens for metastatic disease (12) 51 (40) 60 (48) No. of prior taxane-containing regimen Any (100) 38 (30) 7 (6) Perez E, et al. J Clin Oncol. 2007;23:

76 Phase II Study 081: Efficacy Outcome Response-Evaluable (n=113) Tumor response rate, % (95% CI) IRR assessment12.4( ) Investigator assessment18.6( ) Median response duration, mo (95% CI)6.0( ) Stable disease rate, % Median duration of stable disease, mo (95% CI) (3.7–6.0) Treated Patients (n=126) Median PFS, mo (95% CI)3.2( ) Median survival, mo (95% CI)9.0( ) IRR = independent radiology review. Perez E, et al. J Clin Oncol. 2007;23:

77 Phase II Study 081: Safety Grade 3/4 Toxicity % of Patients (n=126) Hematologic Neutropenia54 Febrile neutropenia 2 Leukopenia49 Anemia8 Thrombocytopenia7 Nonhematologic Peripheral sensory neuropathy14 Fatigue13 Myalgia/arthralgia8 Stomatitis6 Perez E, et al. J Clin Oncol. 2007;23:

78 Conclusions This is the first large prospective trial in triple therapy refractory metastatic breast cancer This is the first large prospective trial in triple therapy refractory metastatic breast cancer Ixabepilone demonstrates efficacy in patients with anthracycline-taxane and capecitabine refractory MBC Ixabepilone demonstrates efficacy in patients with anthracycline-taxane and capecitabine refractory MBC Overall population Overall population Median PFS 3.2 months Median PFS 3.2 months Median overall survival 9 months Median overall survival 9 months Response rate 18% (investigator assessment) Response rate 18% (investigator assessment) Safety profile is acceptable Safety profile is acceptable In summary, ixabepilone represent a new choice in patients with patients with triple-therapy refractory MBC In summary, ixabepilone represent a new choice in patients with patients with triple-therapy refractory MBC

79 Capecitabine Ixabepilone Study 046: Clinical Eligibility Criteria for Resistance Strict definition: patients whose tumors rapidly progressed in the adjuvant or metastatic setting after receiving both anthracyclines and taxanes SettingAnthracyclineTaxane Metastatic 3 months of last dose 4 months of last dose Neo/adjuvant 6 months of last dose 12 months of last dose Any Minimum cumulative dose Doxorubicin: 240 mg/m 2 Epirubicin: 360 mg/m 2 Perez E, et al. J Clin Oncol. 2007;23:

80 046/048 Phase III MBC Trials: Ixabepilone and Capecitabine Combination Pivotal trial CA Pivotal trial CA Patients prospectively defined using a strict definition of resistance to previous anthracycline and taxane therapy Patients prospectively defined using a strict definition of resistance to previous anthracycline and taxane therapy Confirmatory trial CA Confirmatory trial CA Patients with metastatic disease who were pretreated with or resistant to an anthracycline and a taxane Patients with metastatic disease who were pretreated with or resistant to an anthracycline and a taxane 50% met strict resistance criteria in pivotal trial 50% met strict resistance criteria in pivotal trial

81 Ixabepilone (40 mg/m 2 IV over 3 hr d1 q3wk) + Capecitabine (2000 mg/m 2 /day BID 14 days q3wk) Capecitabine (2500 mg/m 2 /day BID 14 days q3wk) Metastatic / locally advanced breast cancer pretreated with or resistant to taxanes and anthracyclines and anthracyclines 046/048 Phase III MBC Trials: Study Design Hortobagyi GN et al ASCO Breast 2008

82 046/048 Phase III Trials: Progression Free Survival Outcome Study 046Study 048 Ixa + Cape N=375 Cape N=377 Ixa + Cape N=480 Cape N=480 Median PFS, months Hazard ratio (95.17% CI) 0.78 (0.67 – 0.91) 0.79 (0.69 – 0.90) Stratified log- rank P-value Roche et al. BCRT 2010

83 046/048 Phase III Trials: Objective Response Rate Outcome Study 046*Study 048 Ixa + Cape N=375CapeN=377 N=462CapeN=462 Objective response rate, % % CI37.1 – – – – 33.2 Best Response, N (%) Complete response12 (3)3 (1)16 (3)11 (2) Partial response146 (39)82 (22)184 (40)122 (26) Stable disease136 (36)144 (38)170 (37)182 (39) Progressive disease51 (14)109 (29)57 (12)111 (24) Unable to determine30 (8)39 (10)35 (8)36 (8) *ORR in 046 presented by investigator assessment. Roche et al. BCRT 2010

84 046/048 Phase III Trials: Overall Survival Outcome Study 046 Study 048 Ixa + Cape N=375CapeN=377 N=609CapeN=612 Median overall survival, months No. of events Hazard ratio (95.17% CI) 0.90 (0.77 – 1.05) 0.90 (0.78 – 1.03) Stratified log-rank P- value Roche et al. BCRT 2010

85 046/048 Planned Subset Analyses Evolving Paradigms and Optimizing Management of Metastatic Breast Cancer

86 Pooled Subgroup Analyses: Objective Response Rates Patients With Ixa + Cape, % Cape, % Triple negative tumors3115 Taxane resistant tumors3922 Poor KPS (70-80)3519 Roche et al. BCRT 2010

87 Pooled Subgroup Analyses: Median Progression Free Survival Patients With Ixa + Cape, months Cape, months P value Triple negative tumors Taxane resistant tumors Poor KPS (70-80) Roche et al. BCRT 2010

88 046/048 Phase III Trials: Summary Ixabepilone + capecitabine demonstrated clinically meaningful efficacy (increase in PFS and ORR) in a large heavily pretreated patient population (~2000) with limited treatment options Ixabepilone + capecitabine demonstrated clinically meaningful efficacy (increase in PFS and ORR) in a large heavily pretreated patient population (~2000) with limited treatment options The difference in median overall survival favored the combination: this difference did not reach statistical significance The difference in median overall survival favored the combination: this difference did not reach statistical significance Ixabepilone plus capecitabine treatment showed consistent clinical benefit in difficult to treat sub-populations, including triple receptor MBC Ixabepilone plus capecitabine treatment showed consistent clinical benefit in difficult to treat sub-populations, including triple receptor MBC Study 048 reinforced the manageable safety profile of ixabepilone Study 048 reinforced the manageable safety profile of ixabepilone Similar profile as study 046 Similar profile as study 046 Low frequency of toxicity related deaths (<1%) in both arms Low frequency of toxicity related deaths (<1%) in both arms Roche et al. BCRT 2010

89 Halichondrin B Analogue (E7389) after Anthracyclines, Taxanes and Capecitabine: Evolving Paradigms and Optimizing Management of Metastatic Breast Cancer

90 Microtubule stabilization De-polymerize Polymerize Paclitaxel Eribulin Inhibits Microtubule Assembly Non-productive aggregates Microtubule dynamics E7389-induced formation of tubulin aggregates No drug 1 µM E µM E7389 M.A. Jordan et al, Mol Cancer Ther 4:1086, 2005 Eribulin (E7389): Mechanism of Action

91 Eribulin: Tubulin-based Antimitotic Mechanism 0 μM 1.5 μM 3 μM 5 μM 7.5 μM 15 μM Inhibition of tubulin polymerization in vitro U937 cells, 100 nM G2/M cycle blocks DU 145 cells, 3xIC 20 h Control Eribulin Disruption of mitotic spindles (DAPI/β-tubulin) Towle et al., Cancer Research, 61: , 2001

92 Eribulin: Preclinical Activity Across a Range of Models Control Eribulin LOX melanoma Towle MJ unpublished results, ERI, 2007 MDA-MB-435 Human Breast Cancer MWFx4, i.v Control ER mg/kg ER mg/kg Paclitaxel 20 mg/kg Average tumor volumes (µl) Day COLO 205 Human Colon Cancer MWFx4, i.p. OVCAR-3 Human Ovarian Cancer MWFx3, i.v. LOX Human Melanoma Q1Dx5[x2], i.p. Human tumor xenografts ( mg/kg) Average tumor volume (mm 3 ) Towle et al., Cancer Research, 61: , 2001

93 Summary of Eribulin Phase II Studies in 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/m 2 (n = 70) over 2-5 mins on Days 1, 8, 15 q4w Eribulin IV 1.4 mg/m 2 (n = 70) over 2-5 mins on Days 1, 8, 15 q4w Assessments 1. Vahdat LT, et al. J Clin Oncol. 2009;27: Vahdat LT, et al. ASCO Abstract *MBC patients with progression of disease 6 mos of last chemotherapy, if present, preexisting neuropathy grade 2. Eribulin IV 1.4 mg/m 2 (n = 33) over 2-5 mins on Days 1, 8 q3w Eribulin IV 1.4 mg/m 2 (n = 33) over 2-5 mins on Days 1, 8 q3w Eribulin IV 1.4 mg/m 2 over 2-5 min on Days 1, 8 q3w Eribulin IV 1.4 mg/m 2 over 2-5 min on Days 1, 8 q3w ORR with independent review Response duration, PFS, and OS Adverse events

94 ITT Efficacy Summary of Phase II Eribulin Breast Cancer Studies Characteristic/Response 201 Trial 1 (N = 103) 211 Trial 2 (N = 269) Previous regimens, median n 44 Response rate,* % Clinical benefit rate, % Duration of response, median mos Vahdat LT, et al. J Clin Oncol. 2009;27: Vahdat LT, et al. ASCO Abstract *CR + PR. CR+ PR + SD for 6 mos.

95 Summary of Eribulin Phase II Study Grade 3/4 Adverse Events Adverse Events, % 201 Trial [1] (N = 103) 211 Trial [2] (N = 291) Neutropenia6454 Febrile neutropenia46 Thrombocytopenia21 Mucositis11 Peripheral neuropathy56 1.Vahdat l, et al. J Clin Oncol. 2009;27: Vahdat LT, et al. ASCO Abstract 1084.

96 Additional Studies of Eribulin in Metastatic Breast Cancer EMBRACE Study (305)* Phase III Eribulin IV on Days 1, 8, q21 Days Physicians choice (monotherapy) OS ASCO Study Phase III Eribulin Capecitabine MBC Phase II Eribulin IV on Days 1, 8, q21 Days Ixabepilone 40 mg/m 2 IV q3w Development of peripheral neuropathy PFS, OS completed Primary endpoints: *Third-line breast cancer treatment. Second-line breast cancer treatment. ClinicalTrials.gov. NCT ; NCT ; NCT

97 A Phase III study (EMBRACE*) of eribulin mesylate vs. treatment of physicians choice in patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane Dr Chris Twelves Professor of Clinical Cancer Pharmacology and Oncology University of Leeds & St Jamess University Hospital, Leeds, UK On behalf of the abstract co-authors and EMBRACE investigators *Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus Eribulin (E7389) EMBRACE

98 Locally recurrent or MBC 2-5 prior chemotherapies Progression 6 months of last chemotherapy Neuropathy grade 2 ECOG 2 Eribulin mesylate 1.4 mg/m 2, 2-5 min IV Day 1, 8 q21 days Treatment of Physicians Choice (TPC) Any monotherapy (chemotherapy, hormonal, biological)* or supportive care only Randomization 2:1 PFS ORR Safety Overall survival Primary endpoint Secondary endpoints EMBRACE Study Design Stratification: –Geographical region, prior capecitabine, HER2/neu status Global, randomized, open-label Phase III trial (Study 305) Patients (N=762) 2 for advanced disease Prior anthracycline and taxane * Approved for treatment of cancer Or palliative treatment or radiotherapy administered according to local practice, if applicable ECOG, Eastern Cooperative Oncology Group; IV, intravenous; PFS, progression-free survival; HER2/neu, human epidermal growth factor receptor 2

99 EMBRACE Patient Characteristics Characteristic Eribulin (n=508) TPC(n=254) TOTAL (n=762) Median age (range) 55 (28-85) 56 (27-81) 55 (27-85) ECOG, % Missing Geographic region, % I North America, Western Europe, Australia II Eastern Europe, Russia, Turkey III Latin America, South Africa Prior capecitabine, % Yes No Median no. prior chemotherapy regimens (range)4 (1-7)4 (2-7)4 (1-7) ITT population

100 EMBRACE Disease Characteristics Characteristic Eribulin (n=508) TPC(n=254) TOTAL (n=762) ER positive, %6667 PR positive, % HER2/neu status, % Positive16 Negative Unknown109 Triple (ER/PR/HER2) negative, % No. organs involved, % > Sites of disease,* % Liver Lung Bone ITT population; *Clinically relevant sites of disease; ER, estrogen receptor; PR, progesterone receptor

101 EMBRACE: Demographic and Baseline Characteristics Cortes J, et al. The Lancet, Early Online Publication, 3 March 2011 Hormone Therapy Eribulin (n=508) TPC (n=254) Overall (n=762) Previous hormone therapy430 (85%)210 (83%)640 (84%) Number of previous hormone regiments 1220 (43%)96 (38%)316 (41%) 2109 (21%)65 (26%)174 (23%) 360 (12%)23 (9%)83 (11%) >441 (8%)26 (10%)67 (9%)

102 EMBRACE 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=44 n=38 n=24 n=25 n=9 No patient received best supportive care or biological therapies only

103 Response Independent review Investigator review Eribulin(n=468)TPC(n=214)Eribulin(n=468)TPC(n=214) ORR (CR+PR), % p-value SD, % PD, % NE, % Clinical benefit rate (CR + PR + SD 6 months),% EMBRACE Best Overall Response Response evaluable population CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, non-evaluable

104 EMBRACE: ITT Progression-Free Survival 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

105 EMBRACE: Per-Protocol Population Progression- Free Survival by Independent Review Cortes J, et al. The Lancet, Early Online Publication, 3 March 2011

106 Overall survival (months) Survival probability EMBRACE Overall Survival Eribulin Median months TPC Median months HR* 0.81 (95% CI 0.66, 0.99) p-value = 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

107 EMBRACE: Overall Survival in an Updated Analysis Cortes J, et al. The Lancet, Early Online Publication, 3 March 2011

108 EMBRACE: Exploratory Subgroup Analysis of Overall Surviv al Cortes J, et al. The Lancet, Early Online Publication, 3 March 2011

109 EMBRACE Overall Incidence of AEs Adverse event (AE), % Eribulin (n=503) TPC (n=247) All AEs Serious AEs AEs leading to Interruption Discontinuation Dose reduction Dose delay Fatal AEs Fatal AEs (treatment-related)1.00.8

110 Adverse Events Grade 3 Grade 4 Eribulin (n=503) TPC (n=247) Eribulin (n=503) TPC (n=247) Hematologic events, % Neutropenia Leukopenia Anemia Febrile neutropenia Non-hematologic events, % Asthenia / fatigue Peripheral neuropathy Nausea Dyspnea Mucosal inflammation Hand-foot syndrome EMBRACE Grade 3 and 4 AEs* *>2% incidence; Neuropathy peripheral, neuropathy, paresthesia, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, peripheral sensorimotor neuropathy, demyelinating polyneuropathy

111 Phase 3 Trials in MBC Patients Previously Treated with an Anthracycline and a Taxane Cortes J, et al. The Lancet, Early Online Publication, 3 March 2011

112 EMBRACE: Conclusions EMBRACE is the first Phase III single-agent study in heavily pre- treated MBC to meet its primary endpoint of prolonged overall survival EMBRACE is the first Phase III single-agent study in heavily pre- treated MBC to meet its primary endpoint of prolonged overall survival Eribulin demonstrated a statistically significant improvement in overall survival Eribulin demonstrated a statistically significant improvement in overall 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 patients Clinically meaningful in heavily pretreated patients Overall response rate and progression-free survival also favored eribulin Overall response rate and progression-free survival also favored eribulin These benefits were achieved with a manageable safety profile These benefits were achieved with a manageable safety profile

113 Conclusions Ixabepilone and eribulin are new therapeutic options for metastatic breast cancer Ixabepilone and eribulin are new therapeutic options for metastatic breast cancer Approved for pretreated breast cancer Approved for pretreated breast cancer Neutropenia and neuropathy are most common adverse events Neutropenia and neuropathy are most common adverse events

114 Case Study 1 43-year-old Army wife and mother of 5 children presents with a 6 cm, 5/12 + LN, ER+, PR+, Her2 nonamplified breast cancer in early year-old Army wife and mother of 5 children presents with a 6 cm, 5/12 + LN, ER+, PR+, Her2 nonamplified breast cancer in early No PMH other than postpartum depression No PMH other than postpartum depression No medications No medications Staging studies including a bone scan, CT/PET scan and cardiac echo are within normal limits Staging studies including a bone scan, CT/PET scan and cardiac echo are within normal limits

115 Patient receives 6 cycles of TAC followed by tamoxifen at an outside institution. Tolerates well. Patient receives 6 cycles of TAC followed by tamoxifen at an outside institution. Tolerates well. One year after completing her chemotherapy, patient develops midthoracic pain. Bone scan reveals metastatic disease at T8 and L1. CT scan reveals no visceral disease. One year after completing her chemotherapy, patient develops midthoracic pain. Bone scan reveals metastatic disease at T8 and L1. CT scan reveals no visceral disease. Bone biopsy confirms ER+ and HER2- recurrence Bone biopsy confirms ER+ and HER2- recurrence Case Study 1

116 Patient receives radiation to L1 spine with good pain relief. Undergoes laparascopic oophorectomy followed by enrollment on a clinical trial of Exemestane and a IGFR mAb. Zoledronic acid is initiated. Patient receives radiation to L1 spine with good pain relief. Undergoes laparascopic oophorectomy followed by enrollment on a clinical trial of Exemestane and a IGFR mAb. Zoledronic acid is initiated. Does well until early 2009 when staging studies reveal new bony mets. LFTs remain normal. Bone scan is stable. Patient receives fulvestrant. Does well until early 2009 when staging studies reveal new bony mets. LFTs remain normal. Bone scan is stable. Patient receives fulvestrant. Case Study 1

117 Patient does well until late 2009 when staging studies reveal multiple new liver lesions. LFTs remain normal. Bone scan is stable. Patient does well until late 2009 when staging studies reveal multiple new liver lesions. LFTs remain normal. Bone scan is stable. Case Study 1

118 Capecitabine is initiated at 900 mg/m2, po, bid. Patient requires dose reduction to 700 mg/m2, po, bid secondary to diarrhea and hand foot syndrome after first cycle. Capecitabine is initiated at 900 mg/m2, po, bid. Patient requires dose reduction to 700 mg/m2, po, bid secondary to diarrhea and hand foot syndrome after first cycle. Initial scans show a near complete response in the liver Initial scans show a near complete response in the liver Case Study 1

119 In the middle of 2010, patient demonstrated progression within the liver on single agent Capecitabine after 8 months and Bevacizumab was added. In the middle of 2010, patient demonstrated progression within the liver on single agent Capecitabine after 8 months and Bevacizumab was added. Restaging after 6 weeks of combination therapy demonstrated further progression. LFTs still normal. Patient wants additional therapy. Restaging after 6 weeks of combination therapy demonstrated further progression. LFTs still normal. Patient wants additional therapy. Case Study 1

120 Patient was placed on single agent eribulin. Her scans have shown a near complete response in the liver after 3 cycles. Patient was placed on single agent eribulin. Her scans have shown a near complete response in the liver after 3 cycles. Last cycle, patient reported an increase in peripheral neuropathy and she was dose reduced per package insert. Last cycle, patient reported an increase in peripheral neuropathy and she was dose reduced per package insert. Case Study 1

121 Case Study 2 64-year-old retired bookkeeper 64-year-old retired bookkeeper Stage II ER+, PR-, HER2- breast cancer, dose dense AC-T Stage II ER+, PR-, HER2- breast cancer, dose dense AC-T Developed cough 5 years later on anastrazole Developed cough 5 years later on anastrazole Bilateral pulmonary nodules Bilateral pulmonary nodules CT guided biopsy positive CT guided biopsy positive – ER+, PR-, HER2- disease Bone scan positive Bone scan positive –Lytic lesions on CT –No symptoms Other factors Other factors –ECOG PS 1 –Non-insulin dependent diabetes –Hypertension

122 Your choice for initial systemic therapy is: 1.Chemotherapy 2.Chemotherapy plus bevacizumab 3.Endocrine therapy What will you recommend?

123 Received fulvestrant with SD for 9 months, then develops increasing cough and bone pain. What chemotherapy regimen do you recommend? Received fulvestrant with SD for 9 months, then develops increasing cough and bone pain. What chemotherapy regimen do you recommend? 1.Single agent capecitabine 2.Single agent taxane 3.Paclitaxel or docetaxel + bevacizumab 4.Paclitaxel + gemcitabine 5.Docetaxel + capecitabine 6.Carboplatin + gemcitabine 7.Other What will you recommend?

124 Received paclitaxel with bevacizumab with response, then progression 12 months later. What chemotherapy regimen do you recommend? 1.Single agent capecitabine 2.Ixabepilone 3.Ixabepilone + capecitabine 4.Eribulin What will you recommend?

125 Case Study 3 44-year-old unemployed investment banker with T3N2M0 triple negative invasive breast cancer 44-year-old unemployed investment banker with T3N2M0 triple negative invasive breast cancer –In 2006, received adjuvant docetaxel/doxorubicin/ cyclophosphamide –Abdominal cramping and distention. CT scan: omental caking, peritoneal nodularity and a moderate amount of ascites; the ovaries and adnexae appeared normal. 6 bilateral pulmonary nodules, and a small right pleural effusion was noted. CT scan: omental caking, peritoneal nodularity and a moderate amount of ascites; the ovaries and adnexae appeared normal. 6 bilateral pulmonary nodules, and a small right pleural effusion was noted. Serum CA-125: normal. Serum CA-125: normal. Serum CA 15-3: elevated at 235. Serum CA 15-3: elevated at 235. Abdominal paracentesis: straw colored fluid Abdominal paracentesis: straw colored fluid Cytologic examination: adenocarcinoma cells morphologically similar to her prior primary invasive breast cancer. Cytologic examination: adenocarcinoma cells morphologically similar to her prior primary invasive breast cancer.

126 1.Single agent capecitabine 2.Single agent taxane 3.Paclitaxel or docetaxel + bevacizumab 4.Paclitaxel + gemcitabine 5.Docetaxel + capecitabine 6.Carboplatin + gemcitabine 7.Other What will you recommend?

127 Received paclitaxel with bevacizumab with response and then PD at 12 months, then capecitabine with progression at 6 months. What chemotherapy regimen do you recommend? Received paclitaxel with bevacizumab with response and then PD at 12 months, then capecitabine with progression at 6 months. What chemotherapy regimen do you recommend? 1.Carboplatin + gemcitabine 2.Ixabepilone 3.Ixabepilone + capecitabine 4.Eribulin 5.Other What will you recommend?

128 Case Study 4 A 62-year-old woman is treated with modified radical mastectomy 5 years prior, for a T2N0M0 ER/PR/HER- negative infiltrating ductal cancer. A 62-year-old woman is treated with modified radical mastectomy 5 years prior, for a T2N0M0 ER/PR/HER- negative infiltrating ductal cancer. She is treated with doxorubicin and cyclophosphamide for four cycles. She is treated with doxorubicin and cyclophosphamide for four cycles. She now is noted on a routine chest x-ray to have 4 pulmonary nodules in the right and left lungs, with CT and bone scans showing no other disease other than several rib metastases. She now is noted on a routine chest x-ray to have 4 pulmonary nodules in the right and left lungs, with CT and bone scans showing no other disease other than several rib metastases. A CT-directed biopsy of the lung shows infiltrating ductal cancer, ER/PR/HER-negative, and TTF-1-negative. She has no symptoms and ECOG performance score of 0. A CT-directed biopsy of the lung shows infiltrating ductal cancer, ER/PR/HER-negative, and TTF-1-negative. She has no symptoms and ECOG performance score of 0.

129 At this point, which strategy would you recommend? 1.Single agent paclitaxel every 3 weeks 2.Single agent paclitaxel weekly 3.Docetaxel plus gemcitabine 4.Ixabepilone What will you recommend?

130 Case Study 5 This patient is treated with docetaxel plus capecitabine for 3 cycles and exhibits a response, but subsequently required dose reductions of both drugs do to fatigue, delayed count recovery and hand-foot syndrome. This patient is treated with docetaxel plus capecitabine for 3 cycles and exhibits a response, but subsequently required dose reductions of both drugs do to fatigue, delayed count recovery and hand-foot syndrome. After 6 months, scans show progression in the lung and three new liver metastases, 1-2 cm in size After 6 months, scans show progression in the lung and three new liver metastases, 1-2 cm in size Apart from fatigue, she has no symptoms, but has reduced her work to part time. Blood work and serum chemistries are normal except for a mild anemia. ECOG performance score is 1 Apart from fatigue, she has no symptoms, but has reduced her work to part time. Blood work and serum chemistries are normal except for a mild anemia. ECOG performance score is 1

131 At this point, which strategy would you recommend? 1.Paclitaxel plus gemcitabine 2.Albumin-bound paclitaxel plus gemcitabine 3.Albumin-bound paclitaxel alone 4.Ixabepilone What will you recommend?

132 Patient M.C., 61 years old, female No Family Hx for cancer No Family Hx for cancer No hormone replacing therapy No hormone replacing therapy Annual screening mammography, always negative Annual screening mammography, always negative 2004: during self palpation, she notices a non-tender mass in her left breast 2004: during self palpation, she notices a non-tender mass in her left breast No skin changes, no palpable adenopathies in the omolateral axilla No skin changes, no palpable adenopathies in the omolateral axilla Mammography: presence of a 2,3 cm density, with irregular edges Mammography: presence of a 2,3 cm density, with irregular edges Case Study 6 Courtesy of Giuseppe Galletti, MD Weill Cornell Medical College

133 FNA of the lesion: Invasive Ductal Carcinoma No evidence of metastatic disease at PET/CT scan No evidence of metastatic disease at PET/CT scan April 2004: lumpectomy and SLN (positive) followed by omolateral axillary lymph node dissection April 2004: lumpectomy and SLN (positive) followed by omolateral axillary lymph node dissection Pathology results: Invasive Ductal Carcinoma Pathology results: Invasive Ductal Carcinoma pT2 (2,7 cm) pN1a (3/18 positive nodes) M0 Stage IIB pT2 (2,7 cm) pN1a (3/18 positive nodes) M0 Stage IIB Case Study 6 Courtesy of Giuseppe Galletti, MD Weill Cornell Medical College

134 May-June 2004: adjuvant chemotherapy Doxorubicin 60 mg/m2 + Cyclophosphamide 600 mg/m2 x 4 Docetaxel 75 mg/m2 x 4 Trastuzumab for 1 year May-June 2004: adjuvant chemotherapy Doxorubicin 60 mg/m2 + Cyclophosphamide 600 mg/m2 x 4 Docetaxel 75 mg/m2 x 4 Trastuzumab for 1 year Left breast irradiation (50 Gy + 10 Gy boost) Left breast irradiation (50 Gy + 10 Gy boost) Case Study 6 NCCN Guideline Version Clinical

135 June 2009: increase of Ca 15-3 levels; a CT scan revealed the presence of liver and bone metastases June 2009: increase of Ca 15-3 levels; a CT scan revealed the presence of liver and bone metastases 1st line metastatic chemotherapy: weekly paclitaxel 80 mg/m² + Zoledronic Acid 4 mg every 28 days 1st line metastatic chemotherapy: weekly paclitaxel 80 mg/m² + Zoledronic Acid 4 mg every 28 days Side effects: two episodes G2 neutropenia Side effects: two episodes G2 neutropenia After 8 weeks of treatment, Partial Response at CT scan After 8 weeks of treatment, Partial Response at CT scan She continued paclitaxel for further 16 weeks and experienced G2-3 peripheral neuropathy (paresthesia) as main side effect. She continued paclitaxel for further 16 weeks and experienced G2-3 peripheral neuropathy (paresthesia) as main side effect. December 2009: stable disease at CT scan; she stopped chemo and started Examestane as hormonal therapy December 2009: stable disease at CT scan; she stopped chemo and started Examestane as hormonal therapy Case Study 6 Courtesy of Giuseppe Galletti, MD Weill Cornell Medical College

136 July 2010: onset of dispnea and headaches; evidence of right pleural effusion, increase in size of liver mets and presence of brain lesions at CT scan July 2010: onset of dispnea and headaches; evidence of right pleural effusion, increase in size of liver mets and presence of brain lesions at CT scan July-August 2010: stereotactic radiation therapy on brain mets followed by complete regression of the two lesions on subsequent MRI July-August 2010: stereotactic radiation therapy on brain mets followed by complete regression of the two lesions on subsequent MRI August 2010: patient started Ixabepilone 40 mg August 2010: patient started Ixabepilone 40 mg Case Study 6 Thomas E et al. JCO 2007; 25(33):

137 After the 2nd cycle, a Total Body CT scan showed stable disease After the 2nd cycle, a Total Body CT scan showed stable disease Chemotherapy continued for further 4 cycles Chemotherapy continued for further 4 cycles At the end of the 3rd administration, patient referred G3 peripheral neuropathy (paresthesia and sensory loss tp lower limbs), partially recovered At the end of the 3rd administration, patient referred G3 peripheral neuropathy (paresthesia and sensory loss tp lower limbs), partially recovered December 2010: A total body CT scan confirmed the stable disease December 2010: A total body CT scan confirmed the stable disease Currently relapse free and under 3rd line Currently relapse free and under 3rd line Case Study 6 Courtesy of Giuseppe Galletti, MD Weill Cornell Medical College

138 Microtubule targeting agents as backbone of breast cancer chemotherapy in the adjuvant and metastatic setting Microtubule targeting agents as backbone of breast cancer chemotherapy in the adjuvant and metastatic setting Taxanes fundamental to improve disease free survival and overall survival in the adjuvant strategies Taxanes fundamental to improve disease free survival and overall survival in the adjuvant strategies Ixabepilone still active against a very taxane-resistant disease Ixabepilone still active against a very taxane-resistant disease Neurological toxicitiy as main side effects of almost all microtubule targeting agents (eribulin seems to better tolerated) Neurological toxicitiy as main side effects of almost all microtubule targeting agents (eribulin seems to better tolerated) Case Study 6 Courtesy of Giuseppe Galletti, MD Weill Cornell Medical College


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