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1 in 4 Deaths CANCER

Current Approaches in Metastatic Breast Cancer Edgardo Rivera, MD Chief, Breast Medical Oncology Section The Methodist Hospital/Weill Cornell University Houston, TX. 1 in 4 Deaths CANCER. Leading cause of death among women aged 40 to 79 years

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1 in 4 Deaths CANCER

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  1. Current Approaches in Metastatic Breast CancerEdgardo Rivera, MDChief, Breast Medical Oncology SectionThe Methodist Hospital/Weill Cornell UniversityHouston, TX

  2. 1 in 4 Deaths CANCER

  3. Leading cause of death among women aged 40 to 79 years • Leading cause of death among men aged 60 to 79 years

  4. Abnormal GROWTH

  5. NormalPremalignantCancer

  6. NormalDCIS/ADHBreast Ca

  7. Estimated New Cases*------------------------------------------------------------------------------------------------------------------------------- Males Females Ten Leading Cancer Types for the Estimated New Cancer Cases, by Sex, US, 2007 *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Estimates are rounded to the nearest 10.

  8. 1,444,920 Estimated New Cancer Cases

  9. Estimated Deaths------------------------------------------------------------------------------------------------------------------------------- Males Females Ten Leading Cancer Types for Estimated Deaths, by Sex, US, 2007

  10. U.S.A. 70 1950-2001 60 Lung Breast 50 Uterus 40 Annual cancer mortality / 100,000 women, ages 35 - 69* Breast 30 20 Stomach Colon & rectum 10 Uterus Lung Stomach 0 1950 1960 1990 1970 1980 2000 2010 EBCTCG Lancet 2005

  11. Declining U.S. Mortality • Behavior Modification • Early detection • Improvements in treatment

  12. Impact of Chemotherapy Ross et al., Cancer 55:341-346, 1985

  13. Survival after Recurrence Giordano et al, Cancer 100:44-52, 2004

  14. Impact of New Therapies Giordano et al, Cancer 100:44-52, 2004

  15. Historical Changes in Overall Survival (OS) _______________________________________ Median OS (days) GONOBritish Columbia Cancer Agency (NCI, Genoa, Italy) N =790 N = 2152 Cohort 1 (1983–86) 546 Cohort 1 (1991–92) 438 Cohort 2 (1987–89) 522 *Cohort 2 (1994–95) 450 Cohort 3 (1992–94) 584 ▼Cohort 3 (1997– 98) 564 *Cohort 4 (1995–97) 793 ■ Cohort 4 (1999–01) 667 Cohort 5 (1998–2001) 713 _______________________________________________________________ * Inclusion of paclitaxel in MCB regimen ▼Release of docetaxel and AI’s ■ Release of capecitabine and trastuzumab Chia, SKL. Proc ASCO, #22, 2003 Gennari, A. Proc ASCO, #634, 2004

  16. Recently FDA-Approved Drugs for Metastatic Breast Cancer • Paclitaxel 1994 • Goserelin 1995 • Anastrozole 1995 • Toremifene 1996 • Docetaxel 1996 • Pamidronate 1996 • Letrozole 1997 • Capecitabine 1998 • Trastuzumab 1998 • Exemestane 1999 • Fulvestrant 2002 • Gemcitabine 2004 • Abraxane 2005 • Lapatinib 2007

  17. Staging The process of finding out how widespread the cancer is and whether it has spread to other parts of the body AJCC Stages I – IV T-N-M

  18. Metastatic Breast Cancer • 3 – 5% of women present with metastases at time of diagnosis • 5 yr survival 5 – 15% • Therapy targeted at metastatic disease • Local therapy historically reserved for palliation for those with local progression of tumor

  19. Goals of therapy in MBC • Palliate or delay onset of symptoms • Improve quality of life • Prolong life • ?? Cure

  20. Advanced Breast Cancer Is TreatedBased on the Biology of the Tumor_______________________________________

  21. Characteristics of the Long-Term Disease-Free Survivors • Limited metastatic disease (one organ site involved) • Young age • Excellent performance status • Normal organ function • Absence of significant co-morbidity Hortobagyi GN, et al, 1996

  22. Selection of Chemotherapy for MBC • Activity • Prior therapy • Performance status • Co-morbidities • CHF, peripheral vascular disease, diabetes • Patient Considerations • Convenience vs compliance vs control • Toxicities affecting normal functioning • Peripheral neuropathy • Mucositis • Diarrhea • Patient appearance • Alopecia • IV Port

  23. Chemotherapy for MBC:Simultaneous or Sequential?The Issue • Patients with metastatic breast cancer receive multiple cytotoxic agents during their clinical course • Do combinations of two or more drugs given simultaneously give better results than each single agent given until progression and then the others given sequentially?

  24. Simultaneous Higher response rate Higher complete response rate Longer time to progression Covers multiple mechanisms of resistance Exploits synergistic interactions Generates more adverse events Sequential Avoids additive or overlapping toxic effects Simpler scheduling Lower response rate Shorter time to progression Equivalent median survival Simultaneous vs Sequential Combinations: Advantages and Disadvantages

  25. Arm B Arm C Arm A DOX 60 mg/m2 q 3 w x 8 TAX 175 mg/m2 q 3 w DOX 50 mg/m2 x 8 TAX 150 mg/m2 GCSF PD PD PD TAX DOX 5 mg/kg d 3-12 E1193 Schema Randomize

  26. E1193: Results Sledge G, et al, JCO 21:588-592, 2003

  27. Chemotherapy for MBC:Simultaneous or Sequential?Conclusions • Both simultaneous and sequential administration of combinations of drugs represent a standard of care for different clinical situations. • Research should continue to develop more effective, potentially curative approaches for MBC • Simultaneous combinations based on potential synergy should be explored as new agents are developed

  28. Novel Agents

  29. New antineoplastic class Semisynthetic analog of epothilone B Specifically designed to overcome tumor resistance mechanisms MRP-1 and P-gp efflux pumps b (III) tubulin overexpression b tubulin mutations Ixabepilone: A Novel Antineoplastic Agent

  30. Tumor response (log cell kill) 2500 250 mg/kg (MTD) 2000 10 mg/kg (MTD) 1500 Median tumor weight (mg) 1000 500 (P=0.0001) Control Ixabepilone 0 Combination Capecitabine 10 30 50 Days post-tumor implant Ixabepilone: Preclinical Antitumor Activity • In vitro and in vivo activity in taxane-resistant tumors1,2 • Synergy with capecitabine in preclinical and phase I/II settings2 1. Jordan MA, et al. Proc Amer Assoc Cancer Res. 2006;47:abstr LB280. 2. Lee FY, et al. J Clin Oncol. 2006;24(18s):abstr 12017.

  31. Ixabepilone Single-Agent Activity in Metastatic Breast Cancer ORR (%) Roché1 After adjuvant anthra Low2 Taxane-pretreated MBC Conte3 Taxane-resistant MBC Thomas4 Multiresistant(anthra / tax / cape) MBC Baselga5 Neoadjuvant T2-4, N0-3, M0 1. Roché H et al. International Union Against Cancer World Cancer Congress, 8-12 July 2006; abstr 96-3. 2. Low et al. J Clin Oncol. 2005;23:2726–2734. 3. Conte P et al. J Clin Oncol. 2006;24(18S):abstr 10505. 4. Thomas E et al. J Clin Oncol. 2006;24(18S):abstr 660. 5. Baselga J et al. Breast Cancer Res Treat. 2005;94(Suppl 1):S31:abstr 305.

  32. Phase III Study Design N=375 Ixabepilone 40 mg/m2 IV over 3h d1 q3wk Capecitabine 2000 mg/m2/dayPO BIDd1-d14 q3wk + N=752 Stratification • Visceral liver/lung metastases • Anthracycline resistance • Prior chemo for MBC • Study site N=377 Capecitabine 2500 mg/m2/day PO BID d1-d14 q3wk Vadhat et al ASCO 2007 abstract #1006

  33. Inclusion Criteria Women ≥18 years Locally advanced or MBC Anthracycline-resistant or minimum cumulative dose Taxane-resistant KPS 70–100 Life expectancy ≥12 wk Exclusion Criteria >3 prior chemo regimens (metastatic) ≥G2 motor/sensory neuropathy Reduced hematologic/renal function ≥G2 liver function tests* No CNS metastases Patient Eligibility *Protocol amendment excluded patients with ≥G2 liver function tests regardless of liver metastases; 377 patients (33 with ≥G2 liver function tests) had been enrolled before amendment. Vadhat et al ASCO 2007 abstract #1006

  34. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 4 8 12 16 20 24 28 32 36 40 Results: Progression Free Survival Ixabepilone + Capecitabine 5.8 mo (95% CI 5.5-7.0) Capecitabine 4.2 mo (95% CI 3.8-4.5) HR: 0.75 (95% CI 0.64-0.88)* Proportion Not Progressed P=0.0003 Months Vadhat et al ASCO 2007 abstr 1006 *Adjusted for interim analysis.

  35. Results: Response Rate Vadhat et al ASCO 2007 abstr 1006

  36. Enhanced Anti-tumor Activity of ABI-007 vs Taxol in Mice Human MX-1 Mammary Carcinoma (n = 5/group); Dose: 5  Daily Control nab-Paclitaxel 30 mg/kg/dose Cremophor®-EL Paclitaxel 30 mg/kg/dose* Tumor Volume (mm3) Days Post-implant *30 mg/kg/day of Cremophor®-EL paclitaxel causes 20% mortality; no death with nab paclitaxel. Hawkins, et al.,AACR. 2003; Abstract Poster # A3

  37. ABI-007 Q3W regimen in MBC • No routine premedication required • DLTs at 375 mg/m2: keratitis, neuropathy-sensory, stomatitis • MTD: 300 mg/m2 • Bi-exponential distribution, linear PK PHASE I DOSE- FINDING STUDY N=19 PHASE II 300 MG/M2 DOSE STUDY N=63 PHASE II 175 MG/M2 DOSE STUDY N=41 • Overall Response Rate 40% • 1st Line Response 45% • Well Tolerated Without Steroids • 0% Grade ¾ Neuropathy • Overall Response Rate 48% • 1st Line Response 64% • Well Tolerated Without Steroids • 11% Grade ¾ Neuropathy PIVOTAL PHASE III STUDY 260 MG/M2 ABI-007 DOSE VS 175MG/M2 TAXOL DOSE N=460 (3,4) Ibrahim,et al.,Clin Cancer Res. 2002;8:1038-1044. O’Shaughnessy, et al., SABCS. 2003; Abstract #44

  38. Phase III Trial Design ABI-007 versus Taxol ABI-007 260 mg/m2 paclitaxel IV over 30 min q 3 wk No Premedication Randomization (1:1)N = 460 Taxol® 175 mg/m2 paclitaxel IV over 3 hrs q 3 wk Standard Premedication with Dexamethasone and Anti-histamines O'Shaughnessy, et al., SABCS 2003. Abstract #44

  39. Phase III Trial ABI-007 versus Taxol Study Objectives PRIMARY ENDPOINTS: • Objective response rates (RR) • All treated patients and first line (planned analysis) • RECIST criteria • Safety and tolerability SECONDARY ENDPOINTS: • Time to tumor progression (TTP) • Overall survival (OS) O’Shaughnessy, et al., SABCS. 2003; Abstract #44.

  40. Phase III Overall Response Rates (ORR): ABI-007 vs Taxol *Cochran-Mantel-Haenszel test. O’Shaughnessy, et al., SABCS. 2003; Abstract #44.

  41. 1.00 ABRAXANETM (n=229) TAXOL® (n=225) 0.75 Proportion not progressed 0.50 Median = 23.0 weeks (95% CI = 19.4 -26.1) 0.25 Median = 16.6 weeks (95% CI = 15.1 – 20.1) 0 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 Week Phase III:Time to Disease Progression (All Patients) P=value=0.002 HR = 0.726 (95% CI 0.589 – 0.895) O’Shaughnessy, et al., SABCS. 2003; Abstract #44.

  42. 1.00 ABRAXANETM (n=229) TAXOL® (n=225) 0.75 P = 0.322 HR = 0.899 (95% CI 0.728 –1.110) Median = 65.0 weeks (53.4 – 76.9) Probability of survival 0.50 Median = 55.3 weeks (48.0 – 66.4) 0.25 0 16 0 32 48 64 80 96 112 128 144 8 24 40 56 72 88 104 120 136 Week Phase III Randomized Trial:Survival (All Patients) Note: P-value from log-rank test.American BioScience, Inc., Data on file, 2005. .

  43. Lapatinib: Targeting EGFR and HER-2 • Lapatinib oral tyrosine kinase inhibitor of ErbB1 and ErbB2 • Blocks signaling through EGFR and HER-2 homodimers and heterodimers • May also prevent signaling between ErbB1/ErbB2 and other ErbB family members Phospholipid cell membrane Lapatinib PTEN Ras Shc P13K Grb2 Raf So8 pAkt pErk Rusnak DW, et al. Mol Cancer Ther. 2001;1:85-94; Xia W, et al. Oncogene. 2002;21:6255-6263.

  44. EGF100151: Lapatinib + Capecitabine in Advanced Breast Cancer Lapatinib 1250 mg daily +Capecitabine 2000 mg/m2 dailyfor days 1-14, 3-week cycles(n=160) Refractory, progressive metastatic or locally advanced HER-2+ breast cancer previously treated with anthracycline, taxane, or trastuzumab (N=528 planned*) Follow-up:until progressionor unacceptabletoxicity Capecitabine 2500 mg/m2 dailyfor days 1-14, 3-week cycles(n=161) *Study enrollment terminated early by IDMC due to superiority of combination arm in primary endpoint; Geyer CE, et al. ASCO 2006. Clinical Science Symposium.

  45. Lapatinib + Capecitabine Vs Capecitabine Alone in HER2+ MBC * Exploratory Analysis Cameron et al. ASCO 2007 Abstract 1035

  46. Agents Targeting VEGF *Approved in RCC and GIST. **Approved in RCC

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