Current Approaches in Metastatic Breast Cancer Edgardo Rivera

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 -Leading cause of death among men aged 60 to 79 years

Abnormal GROWTH

Normal Premalignant Cancer

Normal DCIS/ADH Breast Ca

Estimated New Cases* ---------------------------------------------------------------Males Females Prostate 218, 89 29% 0 Breast Lung & bronchus 114, 76 15% 0 Colon & rectum 79, 130 10% Urinary bladder 50, 040 7% Non-Hodgkin 34, 200 lymphoma 4% 178, 480 26% Lung & bronchus 98, 620 15% Colon & rectum 74, 630 11% Uterine corpus 39, 080 6% Non-Hodgkin lymphoma 28, 990 4% Melanoma of the skin 26, 030 4% Thyroid 25, 480 4% Ovary 22, 430 3% 19, 600 3% 19, 440 3% 678, 060 100% Melanoma of the skin 33, 910 4% Kidney & renal pelvis 31, 590 4% Leukemia 24, 800 3% Oral cavity & pharynx 24, 180 3% Kidney & renal pelvis Pancreas 18, 830 2% Leukemia All Sites 766, 86 100 All Sites 0 % 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.

1, 444, 920 Estimated New Cancer Cases

Estimated Deaths ---------------------------------------------------------------Males Females 89, 510 31% Lung & bronchus 70, 880 26% Prostate 27, 050 9% Breast 40, 460 15% Colon & rectum 26, 000 9% Colon & rectum 26, 180 10% Pancreas 16, 840 6% Pancreas 16, 530 6% Leukemia 12, 320 4% Ovary 15, 280 6% Liver & intrahepatic bile 11, 280 duct 4% Leukemia 9, 470 4% Non-Hodgkin lymphoma 9, 060 3% Lung & bronchus Esophagus 10, 900 4% Uterine corpus 7, 400 3% Urinary bladder 9, 630 3% 5, 590 2% Non-Hodgkin lymphoma 9, 600 3% Brain & other nervous system 5, 500 2% Kidney & renal pelvis 8, 080 3% Liver & intrahepatic bile duct All Sites 289, 55 0 100 % 270, 10 0 100 % All Sites Ten Leading Cancer Types for Estimated Deaths, by Sex, US, 2007

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

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

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

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

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

Historical Changes in Overall Survival (OS) ____________________ Median OS (days) GONO (NCI, Genoa, Italy) N =790 British Columbia Cancer Agency 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

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

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

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

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

Advanced Breast Cancer Is Treated Based on the Biology of the Tumor ____________________ Advanced Breast Cancer Requiring Therapy ER and/or PR Positive Hormonal Treatments Refractory to Hormonal Therapy ER and/or PR Negative Chemotherapy HER 2 Positive Chemotherapy +Trastuzumab HER 2 Negative Chemotherapy

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

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

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?

Simultaneous vs Sequential Combinations: Advantages and Disadvantages • • • 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

E 1193 Schema Randomize Arm A DOX mg/m 2 60 q 3 wx 8 Arm B TAX mg/m 2 175 q 3 w Arm C 50 DOX mg/m 2 x 8 TAX 150 mg/m 2 PD PD TAX DOX G C S F PD 5 mg/kg d 3 -12

E 1193: Results Treatments ORR (CR) TTP Survival Doxorubicin 36 (6) 6 19. 1 Paclitaxel 34 (3) 6. 3 22. 5 Doxorubicin + paclitaxel 47* (9) 8. 2* 22. 4 Sledge G, et al, JCO 21: 588 -592, 2003

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

Novel Agents

Ixabepilone: A Novel Antineoplastic Agent • 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: Preclinical Antitumor Activity • In vitro and in vivo activity in taxane-resistant tumors 1, 2 • Synergy with capecitabine in preclinical and phase I/II settings 2 Median tumor weight (mg) Tumor response (log cell kill) Control Capecitabine 2500 Ixabepilone Combination 250 mg/kg (MTD) 2000 10 mg/kg (MTD) 1500 1000 500 (P=0. 0001) 0 10 30 50 Days post-tumor implant 1. Jordan MA, et al. Proc Amer Assoc Cancer Res. 2006; 47: abstr LB 280. 2. Lee FY, et al. J Clin Oncol. 2006; 24(18 s): abstr 12017.

ORR (%) Ixabepilone Single-Agent Activity in Metastatic Breast Cancer Roché 1 After adjuvant anthra Low 2 Taxane-pretreated MBC Conte 3 Taxane-resistant MBC Thomas 4 Multiresistant (anthra / tax / cape) MBC Baselga 5 Neoadjuvant T 2 -4, N 0 -3, M 0 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(18 S): abstr 10505. 4. Thomas E et al. J Clin Oncol. 2006; 24(18 S): abstr 660. 5. Baselga J et al. Breast Cancer Res Treat. 2005; 94(Suppl 1): S 31: abstr 305.

Phase III Study Design N=375 Ixabepilone N=752 Stratification • Visceral liver/lung metastases • Anthracycline resistance • Prior chemo for MBC • Study site 40 mg/m 2 IV over 3 h d 1 q 3 wk + Capecitabine 2000 mg/m 2/day PO BID d 1 -d 14 q 3 wk N=377 Capecitabine 2500 mg/m 2/day PO BID d 1 -d 14 q 3 wk Vadhat et al ASCO 2007 abstract #1006

Patient Eligibility Inclusion Criteria Exclusion Criteria • Women ≥ 18 years • >3 prior chemo regimens (metastatic) • Locally advanced or MBC • Anthracycline-resistant or minimum cumulative dose • Taxane-resistant • KPS 70– 100 • Life expectancy ≥ 12 wk • ≥G 2 motor/sensory neuropathy • Reduced hematologic/ renal function • ≥G 2 liver function tests* • No CNS metastases *Protocol amendment excluded patients with ≥G 2 liver function tests regardless of liver metastases; 377 patients (33 with ≥G 2 liver function tests) had been enrolled before amendment. Vadhat et al ASCO 2007 abstract #1006 37

Results: Progression Free Survival 1. 0 Ixabepilone + Capecitabine 5. 8 mo (95% CI 5. 5 -7. 0) Proportion Not Progressed 0. 9 0. 8 Capecitabine 4. 2 mo (95% CI 3. 8 -4. 5) 0. 7 0. 6 HR: 0. 75 (95% CI 0. 64 -0. 88)* 0. 5 P=0. 0003 0. 4 0. 3 0. 2 0. 1 0. 0 0 4 8 12 16 20 24 28 32 36 40 Months Vadhat et al ASCO 2007 abstr 1006 *Adjusted for interim analysis.

Results: Response Rate ORR – % (95% CI) Ixabepilone + Capecitabine N=375 Capecitabine N=377 35 (30– 40) 14 (11– 18) P<0. 0001 CR – % PR SD PD Not evaluable Vadhat et al ASCO 2007 abstr 1006 0. 3 34 41 15 9 0 14 46 27 12

Enhanced Anti-tumor Activity of ABI-007 vs Taxol in Mice Human MX-1 Mammary Carcinoma (n = 5/group); Dose: 5 Daily Tumor Volume (mm 3) Control nab-Paclitaxel 30 mg/kg/dose Cremophor®-EL Paclitaxel 30 mg/kg/dose* 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 # A 3

ABI-007 Q 3 W regimen in MBC PHASE I DOSE- FINDING STUDY N=19 PHASE II 175 MG/M 2 DOSE STUDY N=41 • Overall Response Rate 40% • 1 st Line Response 45% • Well Tolerated Without Steroids • 0% Grade ¾ Neuropathy • No routine premedication required • DLTs at 375 mg/m 2: keratitis, neuropathy-sensory, stomatitis • MTD: 300 mg/m 2 • Bi-exponential distribution, linear PK PHASE II 300 MG/M 2 DOSE STUDY N=63 • Overall Response Rate 48% • 1 st Line Response 64% • Well Tolerated Without Steroids • 11% Grade ¾ Neuropathy PIVOTAL PHASE III STUDY 260 MG/M 2 ABI-007 DOSE VS 175 MG/M 2 TAXOL DOSE N=460 (3, 4) Ibrahim, et al. , Clin Cancer Res. 2002; 8: 1038 -1044. O’Shaughnessy, et al. , SABCS. 2003; Abstract #44

Phase III Trial Design ABI-007 versus Taxol ABI-007 260 mg/m 2 paclitaxel IV over 30 min q 3 wk No Premedication Randomization (1: 1) N = 460 Taxol® 175 mg/m 2 paclitaxel IV over 3 hrs q 3 wk Standard Premedication with Dexamethasone and Anti-histamines O'Shaughnessy, et al. , SABCS 2003. Abstract #44

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.

Phase III Overall Response Rates (ORR): ABI-007 vs Taxol All treated patients First-line patients ABI-007 n=229 Taxol n=225 ABI-007 n=97 Taxol n=89 CR+PR 33% 19% 42% 27% 95% CI 27 -39% 14 -24% 32 -52% 18 -36% p-Value* p<0. 001 *Cochran-Mantel-Haenszel test. O’Shaughnessy, et al. , SABCS. 2003; Abstract #44. p=0. 029

Phase III: Time to Disease Progression (All Patients) Proportion not progressed 1. 00 ABRAXANETM (n=229) TAXOL® (n=225) 0. 75 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 P=value=0. 002 HR = 0. 726 (95% CI 0. 589 – 0. 895) 16 24 32 40 48 56 64 72 80 88 96 104 112 120 Week O’Shaughnessy, et al. , SABCS. 2003; Abstract #44.

Phase III Randomized Trial: Survival (All Patients) 1. 00 Probability of survival 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) 0. 50 Median = 55. 3 weeks (48. 0 – 66. 4) 0. 25 0 0 8 16 24 32 40 48 56 64 72 80 88 96 104112120128136144 Week Note: P-value from log-rank test. American Bio. Science, Inc. , Data on file, 2005.

Lapatinib: Targeting EGFR and HER-2 • Lapatinib oral tyrosine kinase inhibitor of Erb. B 1 and Erb. B 2 – Blocks signaling through EGFR and HER-2 homodimers and heterodimers – May also prevent signaling between Erb. B 1/Erb. B 2 and other Erb. B family members Phospholipid cell membrane PTEN P 13 K Lapatinib Shc Grb 2 Ras Raf So 8 p. Akt p. Erk Rusnak DW, et al. Mol Cancer Ther. 2001; 1: 85 -94; Xia W, et al. Oncogene. 2002; 21: 6255 -6263.

EGF 100151: Lapatinib + Capecitabine in Advanced Breast Cancer Refractory, progressive metastatic or locally advanced HER-2+ breast cancer previously treated with anthracycline, taxane, or trastuzumab (N=528 planned*) Lapatinib 1250 mg daily + Capecitabine 2000 mg/m 2 daily for days 1 -14, 3 -week cycles (n=160) Capecitabine 2500 mg/m 2 daily for days 1 -14, 3 -week cycles (n=161) Follow-up: until progression or unacceptable toxicity *Study enrollment terminated early by IDMC due to superiority of combination arm in primary endpoint; Geyer CE, et al. ASCO 2006. Clinical Science Symposium.

Lapatinib + Capecitabine Vs Capecitabine Alone in HER 2+ MBC Capecitabine + Lapatinib N=201 N=198 HR P-Value Time to Progression 4. 3 mo 6. 2 mo 0. 57 . 00013 Overall Survival 15. 3 mo 15. 6 mo 0. 78 . 177 14% 24% - . 017 13 (6%) 4 (2%) - . 045 Overall Response Rate Brain Mets as Site of First Progression* N (%) * Exploratory Analysis Cameron et al. ASCO 2007 Abstract 1035

Agents Targeting VEGF Class Examples Stage of Development Targets Agents targeting the VEGF ligand Antibodies Bevacizumab VEGF Soluble receptors VEGF-TRAP VEGF and Pl. GF Company Phase III Genentech Phase II Regeneron/Sanofi Aventis Agents targeting the VEGF Receptors Small molecule inhibitors Sunitinib VEGFR-2, PDGFR, c-Kit Phase II/III* Pfizer Axitinib VEGFR-2, PDGFR Phase II Pfizer SU 014813 VEGFR 1, 2; c-Kit Phase I/II Pfizer Pazopanib VEGFR 1, 2; PDGFR, c-Kit Phase I/II GSK Sorafenib PTK-787 Raf, VEGFR 1, 2; c-Kit VEGFR-1/2 PDGFR, c-Kit Phase II** Phase II/III Bayer/Onyx Novartis AEE 788 VEGFR 1, 2; Erb. B 1, 2 Phase II Novartis Vandetinib VEGFR-2/EGFR Phase II Astra Zeneca AZD 2171 VEGFR, c-Kit Phase II Astra Zeneca AMG 706 VEGFR 1, 2; PDGFR, c-Kit Phase I/II Amgen *Approved in RCC and GIST. **Approved in RCC

Bevacizumab and Paclitaxel in Metastatic Breast Cancer Paclitaxel (n=339) Paclitaxel + bevacizumab (n=341) P-value HR (95% CI) Response, % All patients 13. 9 29. 9 <0. 0001 – Measurable disease 16 37. 7 <0. 0001 – PFS, months 6. 11 11. 4 <0. 0001 0. 51 (0. 43 -0. 62) OS, months 25. 2 28. 4 0. 12 0. 84 (0. 64 -1. 05) Outcome Miller KD, et al. SABCS 2005. Abstract 3.

Sunitinib • SU 11248 is an oral TKI of: – VEGFR – PDGFR – Kit – Flt-3 • Phase II study in heavily pretreated MBC • 50 mg: 4 weeks on, 2 weeks off N=64 Partial Response 7 (11%) Stable disease > 6 months 3 (5%) Overall clinical benefit 10 (16%) • Toxicity – 34% grade 3 NTP – 16% grade 2 thrombocytopenia – Fatigue, diarrhea, anorexia, mouth pain – 38% dose reduction, 53% dose interruption Miller et al, SABCS 2005

Conclusions • Understanding of breast cancer as a molecular disease is leading to novel therapies – Improved survival and response rate in early stage and metastatic breast cancer • However, newer therapies have led to newer toxicity issues that require further evaluation as well as longer follow up

The Balancing Act Control of Disease Quality of Life