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New Developments in the Management of Advanced Breast Cancer

New Developments in the Management of Advanced Breast Cancer. Including Updates from ASCO 2007. Supported by an educational grant from Roche Laboratories. Jointly Sponsored by:. Course Objectives. At the conclusion of this course, participants should be able to:

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New Developments in the Management of Advanced Breast Cancer

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  1. New Developments in the Management of Advanced Breast Cancer Including Updates from ASCO 2007 Supported by an educational grant from Roche Laboratories Jointly Sponsored by:

  2. Course Objectives At the conclusion of this course, participants should be able to: 1. Describe the latest advances in cellular biomarkers in determining disease prognosis and predicting response to/effectiveness of therapy. 2. Review the role of chemotherapy in the management of advanced breast cancer and discuss its impact on patient outcomes. 3. Review the role of targeted therapies (eg, small molecule tyrosine kinase inhibitors and monoclonal antibodies) in the management of advanced breast cancer and discuss their impact on patient outcomes. 4. Explain the potential use of combination targeted therapies to replace, in some instances, chemotherapy.

  3. Program Agenda • Prognostic and Predictive Biomarkers of BC • Cytotoxic and Targeted Therapy • Chemotherapy • Tyrosine Kinase Inhibitors • Lapatinib Combinations • Monoclonal Antibodies • New Couplets in Advanced Breast Cancer

  4. Prognostic and Predictive Biomarkers of Breast Cancer

  5. Prognostic and Predictive Biomarkers • Prognostic biomarker • Used to identify patients with inherently good prognosis who may be cured with locoregional therapy alone and have low risk of metastatic relapse • Associated with disease-free or overall survival in the absence of adjuvant therapy • Predictive biomarker • Allows identification of individuals who will benefit from a particular drug treatment regimen

  6. Circulating Tumor Cells (CTCs) • CTCs may be predictive of prognosis and treatment efficacy in BC • Preliminary data suggest that 5 CTCs/7.5 mL blood associated with worse progression-free survival (PFS) and overall survival (OS) • Persistence of 5 CTCs/7.5 mL blood after therapy initiation predicts treatment failure1 • Prospective study conducted to measure serial CTCs in patients with MBC2 • 10-mL blood samples collected at baseline and at 3- to 4-week intervals; CTC enumeration performed using CellSearch technology • All subjects followed for PFS and OS • Clinical outcomes based on radiographic studies and physical examination in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) criteria • Cristofanilli M et al. N Engl J Med. 2004;351:781-791. • Liu MC et al. J Clin Oncol. 2007;25(Suppl 18S):10535.

  7. CTCs:Study Results • 46 of 100 subjects have been accrued; 33 have completed 1 radiographic staging evaluation (median followup 7 mo) • Treatment for 33 evaluable patients: • Cytotoxic chemotherapy (27%) • Endocrine therapy (46%) • Combination therapy with biologic agent (27%) • CTCs at baseline (per 7.5 mL blood) • 28/33 (85%) had 1 • 9/33 (27%) had 5 • Median PFS • 2.57 mo for subjects with 5 CTCs/7.5 mL at baseline • 6.77 mo for subjects with <5 CTCs/7.5 mL at baseline (P=0.02) Liu MC et al. J Clin Oncol. 2007;25(Suppl 18S):10535.

  8. CTCs in Progression of MBC:Study Design • 20 patients with MBC; 25 healthy controls • 8-mL blood samples drawn at beginning of new chemo or hormonal treatment line • Blood samples screened for presence of CTCs with quantitative PCR method using molecular probes for human mammaglobin (hMAM) and cytokeratin 19 (CK19) • Relative quantification of hMAM and CK19 RNA obtained using blood sample infected with known concentrations of MDA-MB453 cells as calibrator • Median followup 7+4.5 mo Altimari A et al. J Clin Oncol. 2007;25(Suppl 18S):21066.

  9. CTCs in Progression of MBC:Results and Conclusions • 18/20 (90%) patients CTC+ (1 marker) • 15/20 (75%) patients CK19+ • 9/20 (45%) patients hMAM+ • Disease progression • 7/14 patients with disease progression died • All 14 patients with disease progression CTC+ • 7/9 hMAM+ (78%) patients had disease progression • 11/15 (73%) patients CK19+ • Multiple- vs single-marker detection preferred for CTC blood screening in BC • Combined hMAM and CK19 evaluation might identify patients at higher risk of tumor progression and might aid in stratification and decision making in MBC Altimari A et al. J Clin Oncol. 2007;25(Suppl 18S):21066.

  10. Lymph Node-negative Breast Cancer • Presence or absence of axillary lymph node (ALN) involvement most significant prognostic indicator in early-stage BC • Untreated patients with lymph node-negative cancer have better clinical outcome than untreated patients with lymph node-positive cancer • Sentinel lymph node (SLN) biopsy is standard of care in assessing ALN status • Cianfrocca M, Goldstein LJ. The Oncologist. 2004;9:606-616.

  11. Survival in Node-negative BC Patients:SLN Biopsy vs ALN Dissection (ALND) • 355 node-negative patients with early-stage BC • Underwent either ALND (n=178) in 1990−1997 or SLN biopsy (n=177) in 1998−2004 • Primary outcome measures • Long-term disease-free and overall survival • SLN group had significantly better disease-free (P=0.012) and overall survival (P=0.04) compared with ALND group Langer I et al. J Clin Oncol. 2007;25(Suppl 18S):609.

  12. Cytotoxic and Targeted TherapyChemotherapy

  13. Ixabepilone - Background • A semisynthetic analog of epothilone B • Belongs to new class of microtubule-stabilizing agents, epothilones, derived from fermentation of myxobacterium Sorangium cellulosum1 • Epothilones bind tubulin and result in apoptotic cell death division2 • Epothilones compete with paclitaxel for binding to microtubules3 • Epothilones appear to possess several advantages over paclitaxel • Avoid development of resistance4 • Have greater polymerizing activity than paclitaxel3 • Ixabepilone has demonstrated consistent preclinical activity and seems active against various taxane-sensitive and taxane-resistant cell lines1 • Pivot X et al. Clin Breast Cancer. 2007;7:543-549. • Cortes J, Baselga J. Oncologist. 2007;12:271-280. • Kowalski RJ et al. J Biol Chem. 1997;272:2534-2541. • Bollag DM et al. Cancer Res. 1995;55:2325-2333.

  14. Capecitabine (C) + Ixabepilone (IXA) vs C Alone: Study Design • C showed ORR 9−14% in phase 3 trials for women previously treated with anthracycline and/or taxane • IXA shows synergy with C; low susceptibility to resistance mechanisms • Phase 1/2 data show activity in anthracycline/taxane pretreated tumors IXA 40 mg/m2 IV over 3 hr day 1 q3 wk + C 2000 mg/m2/day PO in 2 divided doses days 1−14 q3 wk R A N D O M I Z E D Study Eligibility • Metastatic or locally advanced BC • Resistant to taxanes or anthracyclines n=375 C 2500 mg/m2/day PO in 2 divided doses days 1−14 q3 wk n=377 Vahdat LT et al. J Clin Oncol. 2007;25(Suppl 18S):1006.

  15. Capecitabine (C) + Ixabepilone (IXA) vs C Alone: Response Rates Vahdat LT et al. J Clin Oncol. 2007;25(Suppl 18S):1006.

  16. Vinflunine - Background • A third-generation vinca alkaloid microtubule inhibitor • Binds to beta tubulin and accumulates in G2/M phase of cell cycle • Promotes cellular apoptosis • Demonstrates antiangiogenic and vascular disrupting properties • Evidence of promising activity in patients with anthracycline- and taxane-pretreated MBC • Campone M et al. Br J Cancer. 2006;95:1161-1166.

  17. Vinflunine (V) in First-line MBC:Study Design • Phase 2, open-label, multicenter, 2-arm trial • 96 patients to be enrolled (48 per cohort) • 18 patients currently enrolled; 12 evaluable for response and 13 evaluable for toxicity • HER2- • V 320 mg/m2 IV q21 days (n=3) • Patients treated until disease progression or toxicity • HER2+ (FISH) • V 280 mg/m2 IV q21 days and trastuzumab 8 mg/kg IV loading dose, followed by 6 mg/kg IV q21 days (n=10) • Patients treated with minimum of 6 cycles or until maximal tumor response, then continue with trastuzumab monotherapy until disease progression Peacock NW et al. J Clin Oncol. 2007;25(Suppl 18S):1043.

  18. Vinflunine in First-line MBCResults Peacock NW et al. J Clin Oncol. 2007;25(Suppl 18S):1043.

  19. Arm A:nab-paclitaxel 300 mg/m2 q3 wk Arm B:nab-paclitaxel 100 mg/m2weekly 3 out of 4 wk Arm C: nab-paclitaxel 150 mg/m2weekly 3 out of 4 wk Arm D: docetaxel 100 mg/m2 q3 wk Nanoparticle albumin-bound (nab)-Paclitaxel in First-line MBC: Study Design R A N D O M I Z E D Comparisons nab-paclitaxel vs docetaxel (A, B, C vs D) weekly vs q3w nab-paclitaxel (B, C vs A) Low- vs high-dose weekly nab-paclitaxel (B vs C) n=300; Arms A, C and D administered at the MTD Gradishar W et al. J Clin Oncol. 2007;25(Suppl 18S):1032.

  20. Objective (RECIST) Investigator-confirmed Response Rates P=0.2, B vs C 70% P=0.002, B vs. DP=0.003,C vs. D P=0.016, B vs AP=0.007, C vs A 62% 43% 38% Response Rate 100 mg/m2 qw 3/4 B: n=76 150 mg/m2 qw 3/4 C: n=74 docetaxel 100 mg/m2 q3w D: n=74 300 mg/m2 q3w A: n=76 nab-paclitaxel Gradishar W et al. J Clin Oncol. 2007;25(Suppl 18S):1032.

  21. nab-paclitaxel 300 mg/m2 (n = 76)nab-paclitaxel 100 mg/m2 (n = 76)nab-paclitaxel 150 mg/m2 (n = 74)docetaxel 100 mg/m2 (n = 74) Progression-free Survival Investigator Assessments nab-paclitaxel vs docetaxel HR=0.63; P=0.046 nab-paclitaxel 300 mg/m2 q 3w vs docetaxel HR=NS; P=NS nab-paclitaxel 100 mg/m2 weekly vs docetaxel HR=0.46; P=0.002 nab-paclitaxel 150 mg/m2 weekly vs docetaxel Higher vs lower doses of nab-paclitaxel HR=0.55; P=0.009 nab-paclitaxel 150 mg/m2 weekly vs 100 mg/m2 weekly 1.00 0.75 Proportion Not Improved 0.50 0.25 75% of patients off study 0.00 0 3 6 9 12 15 18 Months Gradishar W et al. J Clin Oncol. 2007;25(Suppl 18S):1032.

  22. Cytotoxic and Targeted TherapyTyrosine Kinase Inhibitors Lapatinib Combinations

  23. Axitinib - Background • A potent oral tyrosine kinase inhibitor and selective inhibitor of vascular endothelial growth factor receptors • Previous phase I/II study identified appropriate doses of docetaxel and axitinib • Docetaxel 80 mg/m2 q3w with axitinib 5 mg bid Rugo HS et al. San Antonio Breast Cancer Symposium; December 8-11, 2005; San Antonio, Texas. Abstract 1067.

  24. Axitinib (A) + Docetaxel (D) vs Docetaxel (D) + Placebo (PL): Study Design • Randomized, double-blind, phase 2 study • Patients • Locally recurrent or metastatic HER2- BC • No prior chemotherapy for MBC • Adjuvant chemotherapy >12 months • Primary endpoint • Time to progression (TTP) Rugo HS et al. J Clin Oncol. 2007;25(Suppl 18S):1003.

  25. Axitinib (A) + Docetaxel (D) vs Docetaxel (D) + Placebo (PL): Results Response Rate by RECIST Rugo HS et al. J Clin Oncol. 2007;25(Suppl 18S):1003.

  26. Axitinib (A) + Docetaxel (D) vs Docetaxel (D) + Placebo (PL): Results Time to Progression (TTP) 1.0 A + D N=112, Median TTP= 8.2 mo 0.8 D + PL N=56, Median TTP= 7.0 mo 0.6 Proportion not Progressed Hazard ratio=0.73 (one-sided P=0.052) 95% CI: 0.49, 1.07 0.4 0.2 0.0 0 600 200 400 700 300 100 500 TTP (Days) Rugo HS et al. J Clin Oncol. 2007;25(Suppl 18S):1003.

  27. Lapatinib (L) + Capecitabine (C):Study Design • Recently published results of a phase 3, randomized, open-label study demonstrated that L+C improved time to progression (TTP)1 • Current study conducted to update efficacy data and results of correlative studies2 • To determine if gene expression levels in 5-FU and HER pathways associated with clinical benefit in L+C • Tumor blocks available on 217/399 patients; tumors evaluated for expression of: • HER 1−4 • Thymidylate synthase • Thymidine phosphorylase • PTEN (tumor suppressor protein) • cMYC 1. Geyer CE et al. N Engl J Med. 2006;355:2733-2743. 2. Geyer CE et al. J Clin Oncol. 2007;25(Suppl 18S):1035.

  28. Lapatinib (L) + Capecitabine (C):Results* *Updated efficacy results through April 3, 2006 • Preliminary analysis of first 64 samples indicates that elevated baseline mRNA expression of HER2 associated with higher RR and longer TTP with L+C • Elevated HER2 mRNA expression predicted poorer outcome in C arm • Efficacy results confirm prior demonstrated benefit of L+C vs C alone and suggests a correlation between elevated HER2 mRNA levels and RR/TTP Geyer CE et al. J Clin Oncol. 2007;25(Suppl 18S):1035.

  29. Lapatinib (L) + Capecitabine (C):Safety Results Most Frequent Grade 3/4 Adverse Events PPE=palmar-plantar erythrodysesthesia Geyer CE et al. J Clin Oncol. 2007;25(Suppl 18S):1035.

  30. Lapatinib (L) + Paclitaxel (P):Study Design • Phase 3, randomized, double-blind study • 580 patients with incurable ABC at first diagnosis or relapse • Enrollment predominantly from countries with limited HER2 testing capacity • 55% patients received prior adjuvant chemotherapy or anti-hormonal therapy • No patients received prior trastuzumab • Patients stratified by metastatic site and randomized 1:1 to • L 1500 mg QD + P 175 mg/m2 every 3 weeks or • Placebo QD + P 175 mg/m2 every 3 weeks Di Leo A et al. J Clin Oncol. 2007;25(Suppl 18S):1011.

  31. Lapatinib (L) + Paclitaxel (P):Efficacy Results • 579 patients analyzed; 87% presented with Stage IV BC • At time of analysis, 561 patients (97%) progressed or otherwise withdrew • Median TTP 25 weeks • ORR 30% • Blinded analyses of HER2, ER, and PR are ongoing • Final biomarker evaluations will be presented with unblinded efficacy data Di Leo A et al. J Clin Oncol. 2007;25(Suppl 18S):1011.

  32. Lapatinib (L) + Paclitaxel (P):Safety Results* *579 patients analyzed At time of analysis, 561 (97%) patients progressed or otherwise withdrew Di Leo A et al. J Clin Oncol. 2007;25(Suppl 18S):1011.

  33. Cytotoxic and Targeted TherapyMonoclonal Antibodies

  34. Pertuzumab (P) and Trastuzumab (T): Background • P and T are monoclonal antibodies that target different epitopes of HER receptor • P is first of a new class of HER2 inhibitors (HER dimerization inhibitors) that binds to dimerization domain of HER2 receptor1 • T binds to extracellular domain of HER2 receptor and blocks intracellular signalling1 • Preclinical models support hypothesis that complementary mechanisms of action for P and T could result in augmented efficacy when these agents are used in combination2 • Bianco AR. J Chemother. 2004;16(Suppl 4):52-54. • Arpino G et al. J Natl Cancer Inst. 2007;99:694-705.

  35. Pertuzumab (P) + Trastuzumab (T):Study Design • 2-phase study • Recruitment into stage 1 complete; recruitment into stage 2 in progress • Criteria to proceed to stage 2 • 2 partial responses or • 1 partial response and 12 stable diseases or • 13 stable diseases • Inclusion criteria • 24 patients with measurable, centrally-tested HER2+ breast cancer • Up to 3 lines of prior chemotherapy plus T • Disease progression during T therapy • Baseline left ventricular ejection fraction (LVEF) 55% and no decrease of LVEF below 50% during prior T therapy Baselga J et al. J Clin Oncol. 2007;25(Suppl 18S):1004.

  36. Pertuzumab (P) + Trastuzumab (T):Study Design (cont.) • Dosing • T 2 mg/kg IV weekly or 6 mg/kg IV q3 weeks (with reloading dose if required) plus P 420 mg IV q3 weeks following loading dose of 840 mg Baselga J et al. J Clin Oncol. 2007;25(Suppl 18S):1004.

  37. Pertuzumab (P) + Trastuzumab (T):Results • Response status • 5 confirmed partial responses (21%) • 12 stable disease (50%) • Adverse events (AEs) • Most mild to moderate and none treatment limiting • Main AEs • Diarrhea (71%) • Fatigue (46%) • Nausea/vomiting (38%) • Rash (25%) • No clinical cardiac events; no cases of LVEF decrease 10% and to ≤50% Baselga J et al. J Clin Oncol. 2007;25(Suppl 18S):1004.

  38. Bevacizumab (B) + Trastuzumab (T):Study Design • To assess pathologic complete response (pCR) in patients with doxorubicin/cyclophosphamide (A/C)-resistant and AC-sensitive inflammatory BC • 106 patients with Stage II-IV BC on neoadjuvant studies • Treated with either 2 or 4 cycles of dose-dense A/C neoadjuvant chemotherapy (2 cycles if AC-resistant; 4 cycles if AC-sensitive) • If HER2-, with or without B • If HER2+, with T Mehta RS et al. J Clin Oncol. 2007;25(Suppl 18S);591.

  39. Bevacizumab (B) + Trastuzumab (T):Results Pathologic Complete Response Rates in BC Subsets • 38 of 85 (45%) accessable tumors had pathologic complete response • 56 of 84 (67%) tumors were reduced to ≤5 mm Mehta RS et al. J Clin Oncol. 2007;25(Suppl 18S);591.

  40. Bevacizumab (B) + Capecitabine (C) in First-Line MBC (XCaliBr Trial):Study Design C: 1000 mg/m2 BID days 1−15 B: 15 mg/kg IV day 1, repeated q3 weeks until progression First-lineHER2- MBC (n=106) PD Second-line: Chemotherapy with B Sledge G et al. J Clin Oncol. 2007;25(Suppl 18S):1013.

  41. Bevacizumab (B) + Capecitabine (C):Efficacy Results • Primary TTP endpoint was met (extension from 4 to > 5.6 months) • Combination of C + B was tolerable • Combination appears to be more active in ER+ patients Sledge G et al. J Clin Oncol. 2007;25(Suppl 18S):1013.

  42. Bevacizumab (B) + Capecitabine (C):1Safety Results • Lower incidence of adverse events compared with previous study2 • 1250 mg/m2 bid dose used • Most common adverse events: • Diarrhea • Stomatitis • HFS • DVT • PE • 22 non–drug-related deaths • 2 drug-related deaths (cerebral hemorrhage, sepsis) • Sledge G et al. J Clin Oncol. 2007;25(Suppl 18S):1013. • Miller KD et al. J Clin Oncol. 2005;23:792-799.

  43. Bevacizumab (B) + Albumin-bound (nab) Paclitaxel: Study Design • Retrospective analysis of patient records (March 2005 to December 2006) to obtain patients treated consecutively with: • nab-paclitaxel 80−125 mg/m2 days 1, 8, 15 or 170−200 mg/m2 every 14 days on a 28-day cycle + • B 10 mg/kg every 14 days • 40 patients identified • All patients had received minimum of 3 prior chemotherapy regimens (including anthracyclines 34/40 and taxanes 35/40) • Patients monitored for response using RECIST criteria on PE and PET/CT imaging Link JS et al. J Clin Oncol. 2007;25(Suppl 18S):1101.

  44. Bevacizumab (B) + (nab) Paclitaxel: Results • Response rates • 20 women (50%) had objective responses to B/nab-paclitaxel. • 3 complete responses • 17 partial responses • 7 women had stable disease for average duration of >200 days. • Objective response rate + stable disease = 67% • Mean time to progression = 132 days • Regimen well tolerated with acceptable toxicity. • Fatigue, neuropathy, anemia, hypertension most common AEs. • 2 patients discontinued because of CNS hemorrhage into metastatic brain lesion. Link JS et al. J Clin Oncol. 2007;25(Suppl 18S):1101.

  45. New Coupletsin Advanced Breast Cancer

  46. Gemcitabine (G) + Paclitaxel (P) or Docetaxel (D) in First- or Second-Line MBC:1Study Design • Combination of G + P2 and combination of G + D3 have shown efficacy in treatment of MBC • 50 patients with locally advanced or MBC randomized to • G 1250 mg/m2 IV Days 1 and 8 + P 175 mg/m2 IV Day 1 (n=25) or • G 1000 mg/m2 IV Days 1 and 8 + D 75 mg/m2 IV Day 1 (n=25) • Primary outcome measure • Tumor response using RECIST criteria • Boccia RV et al. J Clin Oncol. 2007;25(Suppl 18S):1046. • Delfino C et al. Oncology. 2004;66:18-23. • O’Shaunessey JA et al. Clin Breast Cancer. 2006;6:505-510.

  47. Gemcitabine (G) + Paclitaxel (P) or Docetaxel (D): Efficacy Results Boccia RV et al. J Clin Oncol. 2007;25(Suppl 18S):1046.

  48. Gemcitabine (G) + Paclitaxel (P) or Docetaxel (D): Safety Results a5 grade 4; b8 grade 4; c2 grade 4 Boccia RV et al. J Clin Oncol. 2007;25(Suppl 18S):1046.

  49. Course Summary • CTCs now show more evidence as predictive markers in MBC and could be used more often • SLN is the superior and less invasive surgical method in lymph node-negative BC patients • New chemotherapeutic agents and treatment regimens are emerging, and a few of these will soon be available to our patients • New biologic agents (eg, small molecules and monoclonal antibodies) show promising activity and add good efficacy in combinations with other agents, with relative modest toxicity

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