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Clinical Application of Evolving Treatment Paradigms in Advanced Breast Cancer

Expert Review of Breast Cancer Treatment. Clinical Application of Evolving Treatment Paradigms in Advanced Breast Cancer . Clifford A. Hudis, MD Chief, Breast Cancer Medicine Service Memorial Sloan Kettering Cancer Center Professor of Medicine Weill Cornell Medical College New York, NY.

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Clinical Application of Evolving Treatment Paradigms in Advanced Breast Cancer

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  1. Expert Review of Breast Cancer Treatment Clinical Application of Evolving Treatment Paradigms in Advanced Breast Cancer Clifford A. Hudis, MD Chief, Breast Cancer Medicine Service Memorial Sloan Kettering Cancer Center Professor of Medicine Weill Cornell Medical College New York, NY

  2. Case 1 • 47 year-old woman, BRCA1 (+) with h/o stage IIa breast cancer (3-years ago) at age 44 • ER weakly positive • PR negative • HER2 negative • Treatment: dose-dense AC→T and on tamoxifen for 2+ years • Presents now with RUQ pain, 4kg weight loss, and fatigue • LFTs normal • CT with multiple hepatic metastases confirmed by biopsy c/w original tumor

  3. Case 1 Which treatment option would you recommend: • Hormone therapy • Chemotherapy • Bevacizumab

  4. Case 1 Which treatment option would you recommend: • Hormone therapy • Chemotherapy • Bevacizumab Recommended Approach: • Clinical considerations for selection of appropriate treatment will be discussed

  5. Determination of sites and extent of disease. Assessment of HER2, hormonal receptor status, disease-free interval, age, and menopausal status No life-threatening disease Hormone-responsive Hormone-unresponsive, or Life-threatening disease 1st-line hormonal therapy 1st-line chemotherapy Progression Response No Response 2nd-line chemotherapy Progression 2nd-line hormonal therapy Progression No Response Response 3rd-line chemotherapy Progression No Response Supportive care 3rd-line hormonal therapy Management of Metastatic Breast Cancer Diagnosis of Metastatic Breast Cancer

  6. Spindle toxins paclitaxel (Pac) docetaxel (Doc) vinorelbine (Vin) nab-Pac* (ABI-007) Ixabepilone (Ixa) Nucleoside analogues gemcitabine (Gem) capecitabine (Cap) 5-fluorouracil (5-FU_ Topoisomerase inhibitors CPT-11 (Topo) – doxorubicin (Dox) Platinums Antifolates methotrexate (MTX) pemetrexed (PTX) Unique delivery liposomal doxorubicin (LD) Targeted therapy HER2: trastuzumab (Trastuzumab) and lapatinib (Lap) VEGF: BVM and small-molecule TKIs (investigational) farnesyltransferase inhibitors EGFR inhibitors (investigational) Many Chemotherapy Options *Albumin-bound paclitaxel. CPT = camptothecin; VEGF = vascular endothelial growth factor; BVM = bevacizumab; mAb = monoclonal antibody; TKI = tyrosine kinase inhibitor; EGFR = epidermal growth factor receptor.

  7. Approval is Different from Common Usage Adjuvant Metastatic1 1st Line 2nd Line 3rd Line Anthracyclines (A) Taxanes (T) • Despite treatment, most advanced tumors become resistant and progress2 • Chemoresistance is the major cause of treatment failure3 1. Adapted from National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer V.2.2007. http://www.nccn.org. Accessed April 30, 2007; 2. Bernard-Marty C et al. Oncologist. 2004;9(6):617-632; 3. Longley DB, Johnson PG. J Pathol. 2005;205(2):275-292.

  8. Rationale for Combination Therapy in the Treatment of MBC

  9. Principles of Treatment With Multiple Agents • MBC-inherent drug resistance = barrier to response (cure) • There are many subpopulations of cancer cells with different types of resistance • Combination CT should reduce the different sensitive subpopulations of cancer cells, leading to an improved disease response • Improved disease response will translate into an improvement in outcome • Meta-analysis (2005): standard CT vs intensified CT (10 trials, 2126 patients) • Intensified CT associated with OR=0.60 for response • Tumor response was predictive of survival (P<0.001) • Median OS: CR=29 mon; PR=21 mon; NR=15 mon OR = odds ratio; OS = overall survival; CR = complete response; PR = partial response; NR = no response. Bruzzi P et al. J Clin Oncol. 2005;23(22):5117-5125.

  10. Single-agent vs Combination Front-line CT in MBC • Response rate  favors combination • TTP  favors combination • Survival  ? • Toxicity  favors single agent • Quality of life  ? Very few combination trials using investigational drugs truly tested the hypothesis of combination vs sequential single-agent therapy TTP = time to progression.

  11. Single-agent vs Combination Trials Albain KS et al. J Clin Oncol. 2004;22(14) Abstract 810. O'Shaughnessy J et al. J Clin Oncol. 2002;20(12):2812-2823.

  12. E1193 Phase III Trial Dox vs Pac vs Dox + Pac Combination in MBC Results: Efficacy and Tolerability *Dox vs Dox + Pac; †Pac vs Dox + Pac. *Sledge GW et al. J Clin Oncol. 2003;21(4):588-592.

  13. 1998–2000 (N=171)(HER2 status unknown) 2000–2003 (N=406)(HER2 status known) Pac q 3 wks     Pac q wk             Pac q 3 wks + Trastuzumab         Pac 80 mg/m2 q wk –or–175 mg/m2 q 3 wks Tras 4-mg/kg load, then 2 mg/kg/wk Pac q wk + Trastuzumab             CALGB 9840: Design Seidman AD et al. J Clin Oncol. 2004;22(14 suppl): Abstract 512.

  14. Tumor Response Time to Progression HR=1.61; P=0.017 Adjusted HR=1.45; P=0.0008 Response Rate (%) Time (mon) Pac q 3 Wks(N=373) Pac Weekly(N=344) Pac q 3 Wks(N=373) Pac Weekly(N=344) Events/patients: 221/350 324/385 CALGB 9840Results (All Patients) Seidman AD et al. J Clin Oncol. 2004;22(14 suppl): Abstract 512.

  15. CALGB 9840 Conclusions • Pac once weekly is superior to Pac q 3 wks for the treatment of MBC (with respect to response rate and TTP) • Pac once weekly is associated with slightly less frequent myelosuppression but more frequent neurotoxicity than Pac q 3 wks • Trastuzumab does not improve outcome when added to Pac in HER2-neutral MBC Seidman AD et al. J Clin Oncol. 2004;22(14 suppl): Abstract 512.

  16. TAX-31: Docetaxel vs Paclitaxel s/p anthracycline / 0-1 prior chemo for MBC • *P ≤ 0.05 Jones et al. JCO 2005.

  17. New Formulations

  18. Tumor cell SPARC Tumor interstitium Leaky junction (A)Albumin, the body’s natural transporter of water-insolublenutrients Lumen of tumor microvessel (C) High tumor uptake (SPARC binding of albumin complexes) Albumin-receptor (gp60, albondin) Caveolae (vesicles) SPARC Tumor cell (B) Receptor-mediated transcytosis of albumin complexes (gp60/caveolin-1 pathway) Nab-Pac Transport & Tumor Targeting Tapping Into Biology of Albumin and Rapid Cell Growth SPARC = secreted protein and rich in cysteine.

  19. Phase III TrialAlbumin-Bound (Nab) Pac vs Pac in MBC Albumin-bound Pac: 260 mg/m2 q3w; Pac: 175 mg/m2 q3w *Median time to improvement: 22 days. Gradishar WJ et al. J Clin Oncol. 2005;23(31):7794-7803.

  20. Phase II Study of Weekly or q3wk Nab-Pac vs q3wk Doc as First-line Therapy in MBC Eligibility criteria: • Stage IV adenocarcinoma • No prior CT for metastatic disease RANDOMIZE Arm A: nab-Pac 300 mg/m2 q3wk Arm B: nab-Pac 100 mg/m2 weekly, 3 out of 4 Arm C: nab-Pac 150 mg/m2 weekly, 3 out of 4 Arm D: Doc 100 mg/m2 q3wk Gradishar W et al.SABCS 2006. Abstract 46.

  21. Where Exactly Are We? Hudis JCO 2005.

  22. Novel Microtubule Inhibitors Lee JJ, Swain SM. Semin Oncol. 2005;23(2 suppl 7):S22-26. Cortes J, Baselga J. Oncologist. 2007;12(3):271-280.

  23. Epothilones in Clinical Developmentfor Breast Cancer Goodin S et al. J Clin Oncol. 2004;22(10):2015-2025. Kolman A. Curr Opin Investig Drugs. 2005;6(6):616-622. Schmid P et al. J Clin Oncol. 2005;23(16 suppl): Abstract 2051.

  24. O S OH N HN O O OH Ixabepilone (Ixa) First in the New Class of Epothilones • Naturally occurring epothilone Bchemically modified to improvemetabolic activity, proteinbinding, and antitumor activity1 • Tubulin-binding mode distinctfrom other microtubule-stabilizing agents1 • Active against multiple tumor xeno grafts, including drug-resistant types that overexpressP-gP, MRP-1, and b-III tubulinisoforms1 • Active in taxane-resistant disease2,3 IxabepiloneSemi-synthetic analogof epothilone B 1. Ixempra (ixabepilone) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2007. 2. Perez E et al. J Clin Oncol. 2007;25(23):3407-3414. 3. Thomas E et al. J Clin Oncol. 2007;25(23):3399 3406.

  25. Extracellular Ixa MRP-1 P-gP Intracellular Ixa Tubulin ß-tubulin ßIII-tubulin Ixa: Mechanism of Action • Poor substrate for efflux pumps, eg, P-gP and MRP-11 • P-gP and MRP-1 are involved in drug resistance2 • Binds multiple ß-tubulin isoforms, including ßIII-tubulin to inhibit microtubule dynamics1 • Overexpression of ßIII is associated with in vivo and clinical resistance to taxanes3,4 1. Ixempra (ixabepilone) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2007. 2. Lee JJ, Swain SM. Semin Oncol. 2005;32(6 suppl 7):S22-S26. 3. Kamath K et al. J Biol Chem. 2005;280(13):12902-12907. 4. Mozzetti S et al. Clin Cancer Res. 2005;11:298-305.

  26. Phase II Trial Ixa in Anthracycline-, Taxane-, and Capecitabine-Resistant MBCEfficacy Single-agent Ixa 40 mg/m2 IV over 3 hrs q3w until disease progression Perez E et al. J Clin Oncol. 2007;25(23):3407-3414.

  27. Combination therapy: Ixa 40 mg/m2 IV over 3 h q 21 days +Cap 2000 mg/m2/d PO Days 1–14 MBC Demonstratedresistance toanthracyclineand taxaneN=752 Primary Endpoint PFS (IRR) Monotherapy: Cap 2500 mg/m2/d PO Days 1–14 Ixa Study 046Design Ixa in Combination With Cap in Patients Resistant to an Anthracycline and a Taxane • Strict resistance criteria prospectively defined as • Disease progression = 3 mon of the last anthracycline dose in the metastaticsetting –OR– recurrence = 6 mon in the adjuvant or neoadjuvant setting • –AND– • Disease progression = 4 mon of the last taxane dose in the metastatic setting –OR–recurrence = 12 mon in the adjuvant or neoadjuvant setting *Pts who received a minimum cumulative dose of 240 mg/m2 of Dox or 360 mg/m2 of epirubicin were also eligible. RR = independent radiologic review. Imprexa (ixabepilone) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2007. Thomas ES et al. J Clin Oncol. 2007; 25(33):5210-5217.

  28. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Ixa + Cap Cap P=0.0003† Proportion not Progressed 0 4 8 12 16 20 24 28 32 36 40 Months Ixabepilone Study 046Significant Improvement in Median PFS* *Based on IRR of ITT population; †Stratified by visceral metastasis in liver/lung, prior CT in metastatic setting, and anthracycline resistance.. Thomas ES et al. J Clin Oncol. 2007; Early online release; 0: JCO.2007.12.6557v1.

  29. Ixabepilone+ Capecitabine (N=369) 80 Capecitabine (N=368) 60 % of Patients 40 20 23 18 17 9 9 8 0 6 4 3 3 3 3 2 2 2 0.3 0 0 Fatigue Myalgia Nausea Diarrhea Hand-foot syndrome Vomiting Peripheral neuropathy Mucositis Arthralgia Grade 3/4 Non-hematologic Toxicities

  30. What About Anti-angiogenics?

  31. RANDOMI ZE • Stratify: • DFI ≤24 mon vs >24 mon • <3 vs ≥3 metastatic sites • Adjuvant CT: yes vs no • ER(+) vs ER(–) vs ER unknown Pac + Bev Pac 28-day cycle Pac 90 mg/m2 D1, 8, and 15 BVM 10 mg/kg D1 and 15 E2100 Study Design DFI = disease-free interval. Miller KD et a. SABCS 2005. Abstract 3.

  32. Pac. + Bev. 11.4 mos 1.0 Paclitaxel 6.11 mos 0.8 HR = 0.51 (0.43-0.62) Log Rank Test P < 0.0001 0.6 PFS Probability 0.4 0.2 0.0 0 6 12 18 24 30 Months First-line Therapy of Metastatic Breast Cancer with Bevacizumab Added to Paclitaxel Improved PFS 484 events reported Miller K, NEJM 2007.

  33. AVADODouble-blind, Placebo-controlled Trial Primary endpoint: Progression-free survival Secondary endpoints:Overall response rate, duration of response, time to treatment failure, overall survival, safety, quality of life Treat withplacebo/bevacizumabto diseaseprogression All patientsgiven optionto receive bevacizumabwith2nd linechemotherapy • 1st line locally recurrent or mBC (N=705) • Stratification factors: • region • prior taxoid/time to relapse since adjuvant chemo • measurable disease • hormone receptor status Docetaxel* 100mg/m2+ placebo q3w Docetaxel* + bevacizumab 7.5mg/kg q3w Docetaxel* + bevacizumab 15mg/kg q3w *Docetaxel was administered for a maximum of 9 cycles, but earlier discontinuation was permitted

  34. Placebo +docetaxel (n=241) Bev 15† +docetaxel (n=247) Placebo +docetaxel (n=241) Bev 7.5† +docetaxel (n=248) HR + 95% CI (unstratified) HR + 95% CI (unstratified) 0.72 (0.57–0.90)P = 0.0036 0.79 (0.63–0.98)P = 0.0318 HR + 95% CI (stratified*) HR + 95% CI (stratified*) 0.61 (0.48–0.78)P < 0.0001 0.69 (0.54–0.89)P = 0.0035 8.0 8.8 8.0 8.7 Median Median 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 PFS estimate PFS estimate 0 6 12 18 0 6 12 18 Months Months †mg/kg q3w *Data censored for non-protocol therapy prior to PD Progression-free Survival(ITT population)

  35. Tumour cell Endothelial cell or pericyte VEGF Autocrine loop PDGF-b Paracrine stimulation EGF/IGF PDGFR-b VEGFR-2 Apoptosis RAS RAF Mcl-1 RAF Angiogenesis: Mitochondria RAS Mitochondria Differentiation HIF-2 MEK Proliferation EGF/TGF-a Migration Apoptosis MEK ERK Tubule formation PDGF VEGF Nucleus ERK Nucleus Proliferation Survival Sorafenib Sorafenib Targets Both Tumor-cell Proliferation and Angiogenesis PDGF = platelet-derived growth factor EGF = epidermal growth factorVEGF = vascular endothelial growth factor TGF-a = transforming growth factor-alpha Mcl-1 = myeloid cell leukemia-1 Wilhelm SM, et al. Cancer Res 2004;64:7099–109.

  36. Paclitaxel Dr. GRADISHAR (Northwestern, ACORN) Started Jun 07 Capecitabine* Dr. BASELGA (SOLTI) Started Aug 07 TRIALS INVESTIGATING THE EFFECTS OF SORAFENIB IN BREAST CANCER Gemcitabine*3 Drs. HUDIS & SCHWARTZBERG (MSKCC/ ACORN) Started Jun 07 Triplet2 Dr. SLEDGE (HOG) Planned Aromatase Inhibitors*1 Dr. PEREZ (MCCRC) Planned Docetaxel or Letrozole Dr. GIANNI (Michelangelo) Planned Sorafenib in Breast CancerSix Randomized, Double-blind, Placebo-controlled Phase 2b Trials *includes 2nd line patients 1. Letrozole, anastrozole, or exemestane 2. Paclitaxel/bevacizumab +/- sorafenib 3. Bevacizumab-progressors

  37. Conclusions • Newly approved and other novel agents for the treatment of patients with MBC continue to improve outcomes • The addition of biologics may make a substantial impact • There is a clear and immediate need for larger, better designed clinical trials to assess the role of these new agents • As monotherapy • As combination therapy • As additions to therapies employing a growing number of biologics

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