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May 30 - June 3, 2008 Chicago, Illinois

Breast Cancer CCO Independent Conference Coverage of the 2008 Annual Meeting of the American Society of Clinical Oncology*. May 30 - June 3, 2008 Chicago, Illinois.

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May 30 - June 3, 2008 Chicago, Illinois

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  1. Breast CancerCCO Independent Conference Coverageof the 2008 Annual Meeting of the American Society of Clinical Oncology* May 30 - June 3, 2008 Chicago, Illinois *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by an educational grant from

  2. About These Slides Our thanks to the presenters who gave permission to include their original data Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent. These slides may not be published or posted online without permission from Clinical Care Options DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

  3. Early-Stage Breast Cancer

  4. Phase III tAnGo Trial: Study Design Epirubicin 90 mg/m2 Day 1 Q3W x 4 + Cyclophosphamide 600 mg/m2 Day 1 Q3W x 4 (n = 1576) Paclitaxel 175 mg/m2 Day 1 Q3W x 4 Early breast cancer patients (N = 3152) Paclitaxel 175 mg/m2 Day 1 Q3W x 4 + Gemcitabine 1250 mg/m2 Day 1, 8 Q3W x 4 Epirubicin 90 mg/m2 Day 1 Q3W x 4 + Cyclophosphamide 600 mg/m2 Day 1 Q3W x 4 (n = 1576) Poole CJ, et al. ASCO 2008. Abstract 506.

  5. Phase III tAnGo Trial DFS: ECT vs ECGT No significant difference between treatments 100 75 Patients Surviving Disease Free (%) 50 ECT 25 ECGT HR:1.0 (95% CI: 0.8-1.2) P = .96 0 48 0 6 12 18 24 30 36 42 DFS (Mos) No. at Risk 1571 1545 1479 1392 1156 834 533 162 86 ECT ECGT 1570 1550 1488 1385 1158 813 531 154 88 Poole CJ, et al. ASCO 2008. Abstract 506.

  6. CALGB 49907 Design: CMF or AC Vs Capecitabine in EBC Pts > 65 Yrs Stratification Age 65-69,70-80,80+; PS 0-1 vs 2; HER-2 ± unk CMF 6 cycles or AC 4 cycles Capecitabine for 6 cycles CMF: C 100 mg/m2 Day 1-14 PO, M 40 mg/m2 and FU 600 mg/m2Days 1 and 8 Q4W AC: A 60 mg/m2, C 600 mg/m2Day 1 Q3W x 4 cycles 2000 Days 1-14 Q3W x 6 cycles (in 2 divided doses) Muss HB, et al. ASCO 2008. Abstract 507.

  7. CALGB 49907 Relapse-Free Survival: Multivariate Analysis N = 622; 15% events Muss HB, et al. ASCO 2008. Abstract 507.

  8. CALGB 49907: Relapse-Free Survival by Treatment Arm 1.0 0.8 0.6 Proportion Relapse Free 0.4 0.2 CMF or AC P = .0009 Capecitabine 0.0 0 1 2 3 4 5 Yrs From Study Entry No. at Risk 326 254 124 46 2 0 307 237 96 29 1 0 Muss HB, et al. ASCO 2008. Abstract 507.

  9. CALGB 49907: OS Multivariate Analysis N = 622; 10% events Muss HB, et al. ASCO 2008. Abstract 507.

  10. CALGB 49907: OS by Treatment Arm 1.0 0.8 0.6 Proportion Surviving 0.4 0.2 CMF or AC P = .019 Capecitabine 0.0 0 1 2 3 4 5 Yrs From Study Entry No. at Risk 326 297 216 117 58 7 307 279 180 90 36 8 Muss HB, et al. ASCO 2008. Abstract 507.

  11. Ovarian Suppression + TAM or ANA ± ZA: ABCSG-12 Trial Design • Accrual 1999-2006 • 1803 premenopausal breast cancer patients • Endocrine-responsive (ER and/or PgR positive) • Stage I and II, < 10 positive nodes • No chemotherapy except neoadjuvant • Treatment duration: 3 yrs Tamoxifen 20 mg/day Tamoxifen 20 mg/day + Zoledronic acid 4 mg Q6Mos Anastrozole 1 mg/day Anastrozole 1 mg/day + Zoledronic acid 4 mg Q6Mos Surgery (+RT) Goserelin 3.6 mg Q28D Gnant M, et al. ASCO 2008. Abstract LBA4.

  12. Inhibition of Multiple Steps in Tumor Cell Metastasis Primary tumor Angiogenesis Invasion Decreases matrix invasion Inhibits angiogenesis Stimulates immune surveillance Synergy with anticancer drugs Induces tumor cell apoptosis Decreases adhesion to bone Metastases Micrometastases Adhesion and extravasation Arrest in distant capillary Gnant M, et al. ASCO 2008. Abstract LBA4.

  13. DFS: ZA vs No ZA 0 12 24 36 48 60 72 84 100 90 80 70 60 DFS (%) 50 No. of Events HR (95% CI) Events vs No ZA 40 30 ZA 0.643 (0.46-0.91); P = .011 54 20 No ZA 83 10 0 Time Since Randomization (Mos) No. at Risk 904 838 735 565 441 265 161 60 No ZA ZA 899 851 744 573 434 270 131 59 Gnant M, et al. ASCO 2008. Abstract LBA4.

  14. Secondary Endpoints: ZA Vs No ZA No. of Events HR (95 % CI) Events vs No ZA ZA 16 0.595 (0.32-1.11), P = .101 No ZA 26 904 832 714 538 403 241 145 47 899 846 730 555 414 257 123 54 RFS OS 100 100 90 90 No. of Events HR (95 % CI) 80 80 Events vs No ZA 70 70 ZA 54 0.653 (0.46-0.92), P = .014 60 60 No ZA 82 Recurrence-Free Survival (%) Overall survival, % 50 50 40 40 30 30 20 20 10 10 0 0 0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 84 Time Since Randomization (Mos) Time Since Randomization (Mos) No. at risk 904 838 735 565 441 265 161 60 No ZA 899 851 744 573 434 270 131 59 ZA Gnant M, et al. ASCO 2008. Abstract LBA4.

  15. ZA-Mediated Mechanisms Contributing to Improved DFS Direct antitumor activity Immune activation Bone mets recurrence Nonbone mets recurrence Contralateral recurrence Locoregional mets recurrence DFS Gnant M, et al. ASCO 2008. Abstract LBA4.

  16. Effect of Zoledronic Acid on BMD: CALGB 79809 Trial Design “Early” ZA 4 mg IV Q3Mos + Calcium/Vit D Calcium/Vit D Premenopausal women ≤ 40 yrs with stages I-III; last menstrual period ≤ 6 mos prior to entry Mos 1 122436 Stratified by stage, tamoxifen ZA 4 mg IV Q3Mos + Calcium/Vit D Calcium/Vit D “Late” Shapiro CL, et al. ASCO 2008. Abstract 512.

  17. Chemo-induced OF 50-70% of women Increasing age Distinct from amenorrhea that reverses No standard definition Bone loss due to estrogen deprivation CALGB 79809 Study Rationale: Chemotherapy Decreases Bone Density 1.0 None Chem Only 0.8 Horm Only Both 0.6 Estimated Probability 0.4 0.2 0.0 25 30 35 40 45 50 55 Age at Diagnosis Shapiro CL, et al. ASCO 2008. Abstract 512.

  18. CALGB 79809 Mean Percent Change in BMD ± Tamoxifen at 12 Mos 4 2.2 2.0 2 ZA-tamoxifen 0 Control-tamoxifen ZA -2 % ∆ Control -4 4.3 -6 -8 -10 9.5 -12 Shapiro CL, et al. ASCO 2008. Abstract 512.

  19. Frequency of Vitamin D Deficiency at Breast Cancer Diagnosis: Background Diet/supplements Skin synthesis Liver Vitamin D 25-OHase 25(OH)D Kidneys Breast Tissue Endocrine Autocrine/paracrine 25(OH)D 25(OH)D 25(OH)D 1α-OH-ase 1α-OH-ase 1,25(OH)2D 1,25(OH)2D 1,25(OH)2D Calcium Differentiation Circulation homeostasis Proliferation Goodwin PJ, et al. ASCO 2008. Abstract 511.

  20. Vitamin D Deficiency in Breast Cancer Cellular Effects in Breast Cancer VDR – Vitamin D receptor, nuclear VDRE – Vitamin D response element cAMP – Cyclic AMP PKA – Protein kinase A PKC – Protein kinase C PLC – Phospholipase C RAS – GTPase, pathway RXR – Retinoid X receptor Vitamin D G-protein RXR PLC nuc VDR cAMP Ca fluxes PKC PKA RAS VDRE Rapid response Nucleus Cell cycle arrest Apoptosis E-cadherin expression Goodwin PJ, et al. ASCO 2008. Abstract 511.

  21. Freq of Vit D Deficiency at BC Diagnosis & Risk of Recurrence: Study Design Patients with locoregional breast cancer T1-3, N0-1, M0diagnosed 1989-1996 (Toronto - latitude 43 40')(N = 512 women in cohort) Blood frozen at -80C*; diet, physical activity, clinical data Systemic Treatment (if any) Annual follow-up to 2007 • Distant recurrence • Death Mean 11.6 yrs *Analysed for 25-OH vitamin D in 2007. Goodwin PJ, et al. ASCO 2008. Abstract 511.

  22. Distant DFS by Vitamin D Level in EBC Distant DFS 1.0 Sufficient 0.8 Insufficient Deficient 0.6 Proportion Distant Disease Free 0.4 0.2 P = .02 0.0 0 2 4 6 8 10 12 Yrs Since Diagnosis Goodwin PJ, et al. ASCO 2008. Abstract 511.

  23. Metastatic Breast Cancer

  24. Studying Molecular Changes in Primary Vs Metastatic Lesions: Study Design Schema Patients identified with biopsy-proven relapses from the BCOU database from 1986-1992 Patient linked to current large TMA cohort series (n = 4444) of primary breast cancers Additional TMA was created of relapsed/metastatic tumors IHC performed for ER, PR, HER2 281 cases linked between BCOU database and TMA series 160 had adequate tumor for analysis MacFarlane R, et al. ASCO 2008. Abstract 1000.

  25. Changes in Primary Vs Metastatic Lesions: Results and Summary Results 160 tumor blocks with adequate tissue 115 (72%): no changes in ER/PgR or HER2 status Of the 45 (28%) tumors with changes in receptor status 11(7%): local recurrence 34 (21%): regional or distant relapse 11 went from ER/PgR+ to ER/PgR- 14 went from ER/PgR- to ER/PgR+ 3 went from HER2- to HER2+ 6 went from HER2+ to HER2- Summary Biopsies of relapsed/metastatic breast cancer should be performed routinely because of changes in ER/PgR or HER2 receptor status MacFarlane R, et al. ASCO 2008. Abstract 1000.

  26. MUC4 HER1 - HER3 HER1 - HER2 HER2 - HER2 HER1 - HER4 HER1 - HER1 PTEN PTEN p95 HER2 - HER3 PI3K HER2 - HER4 PI3K SOS SOS Akt RAS RAS Akt RAF RAF MEK MEK MAPK MAPK Cell proliferation Cell survival Cell mobility and invasiveness Transcription Total Blockade of HER2 May Provide Greater Antitumor Activity and Overcome Resistance O’Shaughnessy J, et al. ASCO 2008. Abstract 1015.

  27. Phase III Study to Test if Total HER2 Blockade Improves Clinical Outcome Key inclusion • HER2+ (FISH+/IHC3+) MBC • Progression on • Anthracycline • Taxane • Trastuzumab • Progression on most recent trastuzumab regimen Lapatinib 1500 mg/day PO (N = 148) Crossover if PD after 4-wk therapy (N = 73) Stratification factors • Visceral disease • Hormone receptor Lapatinib 1000 mg/day PO Trastuzumab 4 2 mg/kg IV QW (N = 148) O’Shaughnessy J, et al. ASCO 2008. Abstract 1015.

  28. Treatment Efficacy: Lapatinib vs Lapatinib + Trastuzumab *Confirmed CR + PR. †CR + PR + SD ≥ 6 mos. O’Shaughnessy J, et al. ASCO 2008. Abstract 1015.

  29. PFS: Lapatinib vs Lapatinib + Trastuzumab 100 80 60 Cumulative Percentage Alive Without Progression 40 28% 6 Mo PFS 20 13% 0 0 10 20 30 40 50 60 Time From Randomization (Wks) Subjects at Risk Lapatinib Lapatinib +Trastuzumab 148 148 53 73 21 42 13 27 5 8 0 2 O’Shaughnessy J, et al. ASCO 2008. Abstract 1015.

  30. GBG 26/BIG 3-05 Phase III Study Design: Cape vs Cape + Trastuzumab Capecitabine 2500 mg/m² Days 1-14 Q21D Pathologically confirmed, HER2+, locally advanced or metastatic breast cancer that progressed during treatment with trastuzumab with or without adjuvant first-line metastatic chemo; ≤ 1 chemotherapy palliation allowed; LVEF ≥ 50% in prestudy cardiac monitoring (N = 156) Capecitabine 2500 mg/m² Days 1-14 Q22D and continuation ofTrastuzumab 6 mg/kg Q21D Von Minckwitz G, et al. ASCO 2008. Abstract 1025.

  31. GBG 26/BIG 3-05 Phase III Clinical Response (RECIST): X vs XT 100 90 2-sided P value OR: .011 CB: .0068 80 70 75.3% (64.2-84.4) 60 NC> 24 wks Patients (%) 50 54 (42.1-65.7) 40 30 48.0 (36.5-59.7) CR: 7.7% PR: 40.3% CR + PR 20 27.0 (17.3-38.6) CR: 2.7% PR: 24.3% 10 0 X XT OR = CR + PR CB = CR + PR + NC > 24 wks Von Minckwitz G, et al. ASCO 2008. Abstract 1025.

  32. Trastuzumab and Pertuzumab: Distinct Epitopes on HER2 Extracellular Domain Potent inhibitor of HER2-mediated signaling pathways Activates antibody-dependent cellular cytotoxicity Inhibits shedding and, thus, formation of p95 I I II II III III Trastuzumab Pertuzumab IV IV • Prevents receptor dimerization • Potent inhibitor of HER-mediated signaling pathways Gelmon KA, et al. ASCO 2008. Abstract 1026.

  33. Phase II Trastuzumab + Pertuzumab: Simon-Type 2-Stage Study Design Main patient eligibility criteria ≥ 3 previous cytotoxic therapies and/or trastuzumab (including adjuvant) PD during trastuzumab as most recent treatment for metastatic disease Study treatment initiated within 9 weeks of the last dose of trastuzumab Baseline LVEF ≥ 55% and no decrease of LVEF to < 50% during previous trastuzumab Stage 2 (n = 66) Yes ≥ 2 R or 1 R + 12 SDor 13 SD Safety evaluationfor IDSMB Stage 1 (n = 24)Trastuzumab +Pertuzumab No Stop trial Trastuzumab 4 mg/kg loading dose  2 mg/kg QW or 8 mg/kg loading dose  6 mg/kg Q3W + pertuzumab 840 mg loading dose  420 mg Q3W Gelmon KA, et al. ASCO 2008. Abstract 1026.

  34. Phase II Trastuzumab + Pertuzumab: Efficacy Data: Overall Response *Median duration of response = 25.1 weeks (12.4-66.6). Gelmon KA, et al. ASCO 2008. Abstract 1026.

  35. Hsp90 Inhibitor Tanespimycin + Trastuzumab: Study Rationale • Hsp90 function necessary for proper protein folding • Inhibition of Hsp90 chaperone function induces proteasomal degradation of numerous client proteins • One of the most sensitive client proteins to inhibition of Hsp90 function is the HER2 receptor • Preclinical data supports the combination therapy of a Hsp90 inhibitor with trastuzumab in patients with HER2 positive breast cancer[1] • Phase I data using the combination of tanespimycin and trastuzumab demonstrated 1 confirmed PR and 4 additional patients with tumor regressions (20% to 29% by RECIST) in patients with documented progression of disease on a trastuzumab-containing regimen[2] 1. Solit DB, et al. Cancer Res. 2003;63:2139-2144. 2. Modi S, et al. J Clin Oncol. 2007;25:5410-5417.

  36. Phase II Trial of Tanespimycin + Trastuzumab: Study Design Eligibility: Metastatic breast cancer with HER2 amplification by FISH or 3+ HER2 overexpression by IHC: PD within 3 mos following last dose of adjuvant trastuzumab or PD following initial therapy for metastatic disease with trastuzumab • Trastuzumab 4 mg/kg if loading dose required then 2 mg/kg maintenance • Tanespimycin 450 mg/m2 • 2 hours for Cremophor-based Injection formulation (antihistamines and steroids premedications precede trastuzumab) or • 1 hour for suspension formulation Modi S, et al. ASCO 2008. Abstract 1027.

  37. Phase II Trial of Tanespimycin + Trastuzumab: Overall Response *1 unconfirmed as of May 15, 2008; patient remains active on study. Modi S, et al. ASCO 2008. Abstract 1027.

  38. T-DM1 combines biological activity of trastuzumab with targeted delivery of DM1 to HER2-expressing cells DM1 binds tubulin competitively with vinca alkaloids, 20-100 times more potently compared with vincristine T-DM1 administered once/cycle as a 30- to 90-min IV infusion Cycle = 21 days Trastuzumab-DM1 in Advanced HER2+ Breast Cancer: 2 Clinical Studies Beeram M, et al. ASCO 2008. Abstract 1028. Holden SN, et al. ASCO 2008. Abstract 1029.

  39. Trastuzumab-DM1 in Advanced HER2+ BC: Pts With Objective Responses Beeram M, et al. ASCO 2008. Abstract 1028. Holden SN, et al. ASCO 2008. Abstract 1029.

  40. Primary endpoint: PFS AVADO: Double-Blind, Placebo-Controlled Trial: Design Docetaxel* 100mg/m2+ Placebo Q3W Treat withplacebo/bevacizumabuntil diseaseprogression All patientsgiven optionto receive bevacizumabwithsecond-linechemotherapy First-line locally recurrent or MBC (N = 705) Stratified by region, previous taxoid/time to relapse, since adjuvant chemo, measurable disease,hormone receptor status Docetaxel* +Bevacizumab 7.5 mg/kg Q3W Docetaxel* +Bevacizumab 15 mg/kg Q3W *Docetaxel was administered for a maximum of 9 cycles, but earlier discontinuation was permitted Miles D, et al. ASCO 2008. Abstract LBA1011.

  41. AVADO Trial PFS: by Bevacizumab Dose Placebo +docetaxel (n = 241) Bev 7.5† + docetaxel (n = 248) Placebo +docetaxel (n = 241) Bev 15† + docetaxel (n = 247) HR + 95% CI (unstratified) HR + 95% CI (unstratified) 0.72 (0.57-0.90)P = .0036 0.79 (0.63-0.98)P = .0318 HR + 95% CI (stratified*) HR + 95% CI (stratified*) 0.61 (0.48-0.78)P < .0001 0.69 (0.54-0.89)P = .0035 8.0 8.8 8.0 8.7 Median, mos Median, mos 1.0 1.0 0.8 0.8 0.6 0.6 PFS Estimate PFS Estimate 0.4 0.4 0.2 0.2 0 0 0 6 12 18 0 6 12 18 Mos Mos *Data censored for non-protocol therapy prior to PD. †mg/kg Q3W. Miles D, et al. ASCO 2008. Abstract LBA1011.

  42. Pazopanib + Lapatinib vs Lapatinib Alone in HER2+ MBC: Phase II Study Design Screening Lapatinib 1500 mg +Pazopanib 300 mgQD Randomize/stratify Lapatinib1500 mg QD Lapatinib 1000 mg +Pazopanib 400 mgQD Week-12 disease assessment Trastuzumab available Trastuzumab not available CR or PRmay continue with reconsent SD or PDmust discontinue PDmust discontinue CR, PR, or SDmay continue Slamon D, et a. ASCO 2008. Abstract 1016.

  43. PFS During 12-Week Treatment Period 1.0 0.8 Estimates of 12-Week Progressive Disease Rate* 0.6 15.9% Lapatinib + pazopanib Lapatinib monotherapy 36.8% 84.1% Proportion Progression Free HR: 0.41 (95% CI: 0.21-0.3)P = .0091 (difference between treatments) 0.4 0.2 Lapatinib 1000 mg + pazopanib 400 mg Lapatinib 1500 mg 63.2% 0.0 0 2 4 6 12 14 8 10 Wks *Investigator-assessed data for the 114 patients for which 12 week scans were available. Slamon D, et a. ASCO 2008. Abstract 1016.

  44. Breast Cancer: Summary • Conventional combination adjuvant therapy is effective • Capecitabine is not sufficient for older patients • Gemcitabine does not appear to add benefit • Zoledronic acid may have an expanding role • HER2 is an important target even after progression on trastuzumab • VEGF/VEGFR inhibition provides additional benefit

  45. Go Online for More CCO Coverage of This Conference! Capsule Summaries of all the key data, plus Expert Analysis panel discussions exploring the clinical implications Expert and Video Highlights:download mp3 files and listen to our experts review thehighlights of this conference Expert Recap (slides and audio) plus downloadable PowerPoint slides clinicaloptions.com/Chicago2008

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