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Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA PowerPoint Presentation
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Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

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Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

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  1. Strategic use of available agents through multiple lines of therapy for advanced ER/PR-negative disease:A discussion of 9 Things to Know About Metastatic Breast Cancer Beyond 1st Line Chemotherapy Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

  2. 1. Most women are candidates for multiple lines of therapy

  3. Approximately how many total lines of chemotherapy were received by the last 5 patients you treated who died of metastatic breast cancer (average of the 5 patients)? NLove, Research to Practice, 2008

  4. Duration of Chemotherapy for Advanced Breast Cancer 45 Overall 40 ER+ HER2+ 35 TN 30 25 Average Weeks on Treatment 20 15 10 5 0 1st 2nd 3rd 4th 5th 6th 7th Burstein, Litsas 2010 Unpublished data Line of Therapy

  5. Duration of Chemotherapy for Advanced Breast Cancer 45 Overall 40 ER+ HER2+ 35 TN 30 25 Average Weeks on Treatment Median # of regimens: 4 20 15 10 5 0 1st 2nd 3rd 4th 5th 6th 7th Burstein, Litsas 2010 Unpublished data Line of Therapy

  6. 2. Tumor biology / tumor subset governs outcomes –Triple negative tumors stand out as having a different trajectory

  7. Duration of Chemotherapy for Advanced Breast Cancer 45 Overall 40 ER+ HER2+ 35 TN 30 25 Average Weeks on Treatment Median # of regimens: 4 20 15 10 5 0 1st 2nd 3rd 4th 5th 6th 7th Burstein, Litsas 2010 Unpublished data Line of Therapy

  8. Duration of Chemotherapy for Advanced Breast Cancer 45 Overall 40 ER+ HER2+ 35 TN 30 25 Average Weeks on Treatment 20 15 10 5 0 1st 2nd 3rd 4th 5th 6th 7th Burstein, Litsas 2010 Unpublished data Line of Therapy

  9. Chemotherapy Outcomes in Non-TN vs TN Metastatic Breast Cancer

  10. 3. Where are we with PARP inhibitors?

  11. Gem/Carbo +/- BSI-201 in Triple Negative Metastatic Breast Cancer Gemcitabine 1000 mg/m2 d 1,8 Carbo AUC 2 d 1,8 MBC Triple Negative Prior Chemo N=120 CYCLES EVERY 21 DAYS Gemcitabine 1000 mg/m2 d 1,8 Carbo AUC 2 d 1,8 BSI-201 5.6 mg/kg d 1,4,8, 11 RESTAGE EVERY 2 CYCLES O’Shaugnessy et al, ASC0 2009

  12. Chemotherapy+/- iniparib for triple-negative breast cancer: phase II O'Shaughnessy J et al. N Engl J Med 2011;364:205-214

  13. Iniparib DataOral Presentation vs Publication Results

  14. Schema Study Design: Multi-center, randomized open-label Phase III Trial N = 519 Gem/Carbo (GC) (N= 258) Gemcitabine 1000 mg/m2 IV d 1, 8 Carboplatin AUC2 IV d 1, 8 21-day cycles Crossover allowed to GCI following Disease Progression* (central review) • Study Population: • Stage IV TNBC • ECOG PS 0–1 • Stable CNS metastases allowed • 0-2 prior chemotherapies for mTNBC • Randomization stratified by prior chemo in the metastatic setting: • 1st-line (no prior therapy) • 2nd/3rd-line (1-2 prior therapies) R Gem/Carbo + Iniparib (GCI) (N= 261) Gemcitabine - 1000 mg/m2 IV d 1, 8 Carboplatin - AUC2 IV d 1, 8Iniparib - 5.6 mg/kg IV d 1,4,8,11 21-day cycles *Prospective central radiology review of progression required prior to crossover 96% (n=152) of progressing patients crossed over to GCI at time of primary analysis NCT00938652

  15. Efficacy Endpoints – ITT population 1.0 1.0 0.9 0.9 0.8 0.8 Pre-specified alpha = 0.01 Pre-specified alpha = 0.04 0.7 0.7 0.6 0.6 0.5 Probability of Survival 0.5 Probability of Progression Free Survival 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0 0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 14 16 Months Months Since Study Entry

  16. Overall Response Rate* – ITT Population * Independent central review, RECIST 1.1 + confirmation of response 17

  17. What’s going on? • Not all exploratory studies stand up to validation in larger experience • Iniparib probably is NOT a PARP inhibitor

  18. What’s going on? • Not all exploratory studies stand up to validation in larger experience • Iniparib probably is NOT a PARP inhibitor That is to say, inadequate preliminary science

  19. 4. What are the real goals of treatment for refractory disease?

  20. Goals of Chemotherapy for Advanced Breast Cancer • Relieve symptoms associated with advanced cancer, such as pain, fatigue, or dyspnea • Prevent symptomatic progression of tumor • Prolong survival • Enhance quality of life • To make advanced breast cancer a “chronic” condition

  21. Does Chemotherapy Palliate Refractory Breast Cancer? • 3rd line chemotherapy: • 30% had improvement in emotional status • 34% had major improvement in HRQL scores • 6% had objective clinical response • Tumor response correlated with more energy, diminished distress, and functional improvement • Not all “benefit” was seen in responders, and not all “responders” benefit McLachlan SA, Pintilie M, Tannock IF. Breast Cancer Res Treatment 1999;54:213

  22. Cumulative Incidence of Adverse Symptom Events over Time as Reported by Patients versus Clinicians at Successive Office Visits. Clinical teams under-report symptoms relative to patients Survey of consecutive office visits among 467 cancer patients at MSKCC Basch E. N Engl J Med 2010;362:865-869.

  23. Trade-offs • Cancer-related symptoms • Benefits of chemotherapy • Side effects of chemotherapy, especially chronic side effects (fatigue, neuropathy, GI discomfort) • The tyranny of the infusion room • The hope that comes with doing something

  24. 5. There are a lot of choices once you get beyond 1st or 2nd line,but there really aren’t much data

  25. Chemotherapy Outcomes in Refractory Breast Cancer

  26. Typical Clinical Outcomeswith Single-agent Chemotherapy for Advanced Breast Cancer

  27. 6. Newer options: ixabepilone

  28. Overview: Mechanism of action of microtubule-targeting drugs Vinca alkaloids / eribulin Taxanes / epothilones Destabilizers Stabilizers  Polymerization  Polymerization

  29. Ixabepilone: Epothilone B Analog • Furthest developed agent in a new class of antineoplastics, the epothilones • Epothilones bind to microtubules resulting in polymerization and apoptosis • Novel microtubule-stabilizing agent with tubulin-binding mode distinct from other agents S.cellulosum Epothilone B Ixabepilone Lee JJ, Swain SM. Semin Oncol. 2005;32(suppl 7):S22-S26; Kamath K et al. J Biol Chem. 2005;280:12902-12907; Mozzetti S et al. Clin Cancer Res. 2005;11:298-305.

  30. Ixabepilone in MBC: Summary of Single-Agent Phase II Trials 100 90 83 77 80 70 26 57 60 53 35 SD Percentage (%) 50 RR 40 35 41 30 57 42 20 22 10 12 N=65 N=23 N=37 N=49 0 After Adjuvant Anthracycline1 (40 mg/m2 q3w) Taxane Pretreated MBC3 (6 mg/m2 daily X 5) Taxane Resistant MBC4 (40 mg/m2 q3w) Taxane Naïve MBC2 (6 mg/m2 daily X 5) • Roche H et al. J Clin Oncol. 2007;23:3415-3420. 3. Low et al. J Clin Oncol 2005;23:2726–2734. • 2. Denduluri N et al. J Clin Oncol. 2007;23:3421-3427. 4. Thomas E et al. J Clin Oncol. 2007;23:3399-3406.

  31. Capecitabine +/- ixabepilone after anthracyclines and taxanes . Thomas E S et al. JCO 2007;25:5210-5217 ©2007 by American Society of Clinical Oncology

  32. Time to resolution of neuropathy Thomas E S et al. JCO 2007;25:5210-5217 ©2007 by American Society of Clinical Oncology

  33. . Ixabepilone After Anthracyclines, Taxanes and Capecitabine Perez E A et al. JCO 2007;25:3407-3414 ©2007 by American Society of Clinical Oncology

  34. Ixabepilone After Anthracyclines, Taxanes and Capecitabine Perez E A et al. JCO 2007;25:3407-3414 ©2007 by American Society of Clinical Oncology

  35. Capecitabine ± Ixabepilone in Triple Negative MBC 37 Pooled triple negative subgroup (n = 443) Rugo H, et al. SABCS 2008. Abstract 3057.

  36. 7. New options: eribulin

  37. Eribulin mesylate (E7389) • Synthetic analogue of halichondrin B • Binds to unique site on tubulin • Suppresses microtubule polymerization • Sequesters tubulin into nonfunctional aggregates • Creates irreversible mitotic block • Inhibition of breast cancer cell line growth in vitro MCF7 Jordan M A et al. Mol Cancer Ther 2005;4:1086-1095

  38. Eribulin: Phase II Results in A- and T-Treated MBC Dosing 1.4 mg/m2 days 1, 8, 15 q28d or days 1,8 q21 days Response rate (n=103) Overall 11% ER+ 15% TN 7% HER2+ 8% Grade 3 or 4 side effects neutropenia 64% febrile neutropenia 4% fatigue 5% neuropathy 5% Vahdat, L. T. et al. J Clin Oncol; 27:2954-2961 2009

  39. EMBRACE study design • Global, randomized, open-label Phase III trial (Study 305) Eribulin mesylate 1.4 mg/m2, 2-5 min IVDay 1, 8 q21 days Patients (N=762) Primary endpoint • Locally recurrent or MBC • 2-5 prior chemotherapies • Progression ≤6 months of last chemotherapy • Neuropathy ≤grade 2 • ECOG ≤2 • Overall survival • ≥2 for advanced disease • Prior anthracycline and taxane Randomization 2:1 Secondary endpoints Treatment of Physician’s Choice (TPC) Any monotherapy (chemotherapy, hormonal, biological)* or supportive care only† • PFS • ORR • Safety • Stratification: • Geographical region, prior capecitabine, HER2/neu status * Approved for treatment of cancer †Or palliative treatment or radiotherapy administered according to local practice, if applicable ECOG, Eastern Cooperative Oncology Group; IV, intravenous; PFS, progression-free survival;HER2/neu, human epidermal growth factor receptor 2

  40. EMBRACE Trial OS PFS RR: Eribulin 12%, TPC 5% Cortest, et al. 2011:377; 914-923

  41. 7. Angiogenesis inhibition in TN BC

  42. Progression-free Survival Overall Survival Miller K et al. N Engl J Med 2007;357:2666-2676

  43. E2100: Bevacizumab andTriple Negative Breast Cancer KD Miller, et al. NEJM 2007

  44. RIBBON-2 trial design Investigator’s choice of chemotherapy Treat to disease progression; crossover after progression permitted HER2-negative LR/mBC, one prior line of CT, no prior anti-VEGF therapy (n=684) 2:1 BEV + CT Taxane or gemcitabine or capecitabine or vinorelbine R PLA + CT • Taxane (paclitaxel 90 mg/m2 d1, 8, 15 q4w or paclitaxel 175 mg/m2, nab-paclitaxel 260 mg/m2, or docetaxel 75–100 mg/m2 q3w) • Gemcitabine (1250 mg/m2 d1, 8 q3w) • Capecitabine (1000 mg/m2 bid d1–14 q3w) • Vinorelbine (30 mg/m2 d1, 8, 15 q3w) • BEV or PLA (15 mg/kg q3w or 10 mg/kg q2w, depending on CT regimen) • Stratification factors: CT regimen; interval from LR/MBC diagnosis to 1st progression; ER and PgR status ER = estrogen receptor; PgR = progesterone receptor; PLA = placebo; R = randomization

  45. Summary of efficacy in RIBBON-2 (all patients) aStratified analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression, ER/PgR receptor status) bNot significant at prespecified α=0.01 Brufsky et al. SABCS 2009

  46. Baseline characteristics

  47. TNBC population: PFS Estimated probability 1.0 0.8 0.6 0.4 0.2 0 aStratified analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression) 2.7 6.0 0 5 10 15 20 25 Time (months) No. at risk: BEV + CT 112 65 26 8 4 Placebo + CT 47 11 4 2

  48. TNBC population: Interim OS Estimated probability 1.0 0.8 0.6 0.4 0.2 0 aStratified analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression) 12.6 17.9 0 5 10 15 20 25 30 Time (months) No. at risk: BEV + CT 112 92 73 27 14 5 Placebo + CT 47 38 25 14 4 2 1