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An Interactive Webcast Featuring Discussion of Key Presentations and Posters from the 2011 San Antonio Breast Cancer Sym

An Interactive Webcast Featuring Discussion of Key Presentations and Posters from the 2011 San Antonio Breast Cancer Symposium. Thursday, January 12, 2012 7:30 PM - 9:00 PM ET. Hope S Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials Education

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An Interactive Webcast Featuring Discussion of Key Presentations and Posters from the 2011 San Antonio Breast Cancer Sym

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  1. An Interactive Webcast Featuring Discussion of Key Presentations and Posters from the 2011 San Antonio Breast Cancer Symposium Thursday, January 12, 20127:30 PM - 9:00 PM ET

  2. Hope S Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials Education University of California, San Francisco Helen Diller Family Comprehensive Cancer Center San Francisco, California Antonio C Wolff, MD Professor of Oncology Breast Cancer Program The Johns Hopkins Kimmel Cancer Center Baltimore, Maryland Neil Love, MDResearch To Practice Miami, Florida

  3. Disclosures for Moderator Neil Love, MD Dr Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: Abbott Laboratories, Allos Therapeutics, Amgen Inc, ArQule Inc, Astellas, Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals Inc, Biodesix Inc, Biogen Idec, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, Daiichi Sankyo Inc, Dendreon Corporation, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, ImClone Systems, a wholly owned subsidiary of Eli Lilly and Company, Lilly USA LLC, Medivation Inc, Millennium: The Takeda Oncology Company, Mundipharma International Limited, Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals, Sanofi, Seattle Genetics and Teva Pharmaceuticals.

  4. Disclosures for Hope S Rugo, MD

  5. Disclosures for Antonio C Wolff, MD

  6. Agenda • Module 1: HER2-PositiveBreast Cancer • CLEOPATRA, TEACH, APHINITY, others • Module 2: Multigene/Biomarker Assays • Oncotype DX® in DCIS, RxPONDER study, PAM50, VeriStrat® • Module 3: Advanced ER-Positive Disease • SWOG-S0226, BOLERO-2, others • Module 4: HER2-Negative, BRCA1/2 Mutant • PARP inhibitors • Other chemotherapy ± biologics • Module 5: Bone-Targeted Therapy • NSABP-B-34, ABCSG-12 update, denosumab, others

  7. Module 1: HER2-Positive Breast Cancer

  8. A Phase III, Randomized, Double-Blind, Placebo-Controlled Registration Trial to Evaluate the Efficacy and Safety of Placebo + Trastuzumab + Docetaxel vs Pertuzumab + Trastuzumab + Docetaxel in Patients with Previously Untreated HER2-Positive Metastatic Breast Cancer (CLEOPATRA) Baselga J et al. SABCS 2011;Abstract S5-5. N Engl J Med 2012;366(2):109-19.

  9. Pertuzumab and Trastuzumab: Complementary Mechanisms of Action • Pertuzumab: • Inhibits ligand-dependent HER2 dimerization and signaling • Activates ADCC • Trastuzumab: • Inhibits ligand-independent HER2 signaling • Activates ADCC • Prevents HER2 ECD shedding HER1/3/4 Pertuzumab Dimerization domain HER2 Subdomain IV Trastuzumab ADCC, antibody-dependent cell-mediated cytotoxicity; ECD, extracellular domain Adapted from Baselga J et al. SABCS 2011;Abstract S5-5.

  10. R CLEOPATRA Study Design Centrally confirmed HER2-positive locally recurrent, unresectable or metastatic BC ≤1 hormonal regimen for mBC (Neo)adjuvant systemic rx, incl trastuzumab and/or taxane if DFS ≥12 mos Baseline LVEF ≥ 50%; no CHF or LVEF < 50% during or after trastuzumab Docetaxel (>6 cycles recommended) N = 406 Trastuzumab Placebo 1:1 Docetaxel (>6 cycles recommended) N = 402 Trastuzumab Pertuzumab Primary endpoint: Independently assessed progression-free survival Study dosing q3wk: Trastuzumab: 8 mg/kg loading, 6 mg/kg maint Pertuzumab: 840 mg loading, 420 mg maint Docetaxel: 75 mg/m2 (escalating to 100 mg/m2) Baselga J et al. SABCS 2011;Abstract S5-5.

  11. CLEOPATRA: Efficacy Endpoints * Interim analysis of OS did not cross O’Brien-Fleming stopping boundary; therefore, results are exploratory and nonsignificant (n = 165 OS events, 19.3 mo follow-up). ** Response evaluation prespecified to occur after OS; therefore, results are exploratory. Baselga J et al. SABCS 2011;Abstract S5-5.

  12. Prior Therapy for Breast Cancer Baselga J et al. SABCS 2011;Abstract S5-5.

  13. Primary Endpoint: Independently Assessed PFS (n = 433 PFS events) • Median PFS, pertuzumab + trastuzumab + docetaxel: 18.5 mos • Median PFS, placebo + trastuzumab + docetaxel: 12.4 mos • Hazard ratio = 0.62 • p < 0.0001 Baselga J et al. SABCS 2011;Abstract S5-5.

  14. Overall Survival: Predefined Interim Analysis (Median Follow-Up: 19.3 Months, n = 165 OS Events) • Pertuzumab + trastuzumab + docetaxel, 69 events • Placebo + trastuzumab + docetaxel, 96 events • Hazard ratio = 0.64 • p = 0.005 Interim analysis of OS did not cross O’Brien-Fleming stopping boundary; therefore, results are exploratory and nonsignificant Baselga J et al. SABCS 2011;Abstract S5-5.

  15. Adverse Events Baselga J et al. SABCS 2011;Abstract S5-5.

  16. Adjuvant Pertuzumab and Herceptin IN Initial TherapY in Breast Cancer: APHINITY (BIG 4-11/BO25126/TOC4939g) von Minckwitz G et al. SABCS 2011;Abstract OT1-02-04.

  17. Phase II Trial of Adjuvant TC (Docetaxel/Cyclophosphamide) plus Trastuzumab (HER TC) in HER2 Positive Early Stage Breast Cancer Patients Jones S et al. SABCS 2011;Abstract PD07-03.

  18. Survival and Select Adverse Events (AEs) DFS, disease-free survival; OS, overall survival; ESBC, early-stage breast cancer Jones S et al. SABCS 2011;Abstract PD07-03.

  19. Results of the TEACH Trial. Lapatinib in Women with Early-Stage HER2-Overexpressing Breast Cancer: A Double-Blind, Placebo-Controlled, Phase III Trial Goss P et al. SABCS 2011;Abstract S4-7.

  20. TEACH Study Design Eligibility: Stage I-IIIC HER2+ local ICH3+ or FISH+ No prior trastuzumab Neo(adjuvant) CMF, anthracycline or taxane Appropriate endocrine therapy N = 3,147 from 33 countries Lapatinib 1500 mg qd x 1 y Adjuvant chemo R Diagnosis Placebo qd x 1 y Median time since initial diagnosis: 2.7 y Primary endpoint: Disease-free survival Goss P et al. SABCS 2011;Abstract S4-7.

  21. Survival Analysis: ITT and Centrally Confirmed FISH+ (Median F/U: 4 Years) Goss P et al. SABCS 2011;Abstract S4-7.

  22. Common Adverse Events: Maximum NCI CTC Toxicity Grades 1 6 5 18 19 Percentage of Patients (%) 1 37 1 1 1 35 1 3 3 2 3 1 3 1 13 14 13 10 12 10 Lap Plac Lap Plac Lap Plac Lap Plac Diarrhea Rash Nausea Fatigue Goss P et al. SABCS 2011;Abstract S4-7.

  23. Phase II Study Evaluating Lapatinib in Combination with nab®-Paclitaxel in Women Who Have Received ≤1 Chemotherapy Regimen for HER2-Overexpressing Metastatic Breast Cancer Yardley DA et al. SABCS 2011;Abstract P1-12-10.

  24. Efficacy Analysis and Adverse Events Yardley DA et al. SABCS 2011;Abstract P1-12-10.

  25. AVEREL, A Randomized Phase III Trial to Evaluate Bevacizumab in Combination with Trastuzumab + Docetaxel as First-Line Therapy for HER2-Positive Locally Recurrent/ Metastatic Breast Cancer Gianni L et al. SABCS 2011;Abstract S4-8.

  26. Efficacy Endpoints * Unstratified ** Stratified, censored for nonprotocol therapy Gianni L et al. SABCS 2011;Abstract S4-8.

  27. PFS According to Baseline Plasma VEGF-A H + DOC low VEGF-A (n = 45)H + DOC high VEGF-A (n = 37) H + DOC + BEV low VEGF-A (n = 36)H + DOC + BEV high VEGF-A (n = 43) Estimated probability 0.2 0.5 1 2 5 HR 16.616.5 8.5 13.6 Time (months) With permission from Gianni L et al. SABCS 2011;Abstract S4-8.

  28. A 42-year-old premenopausal woman presents 1 year after completing adjuvant TCH for ER-negative, HER2-positive IDC with asymptomatic lung mets. Your likely recommendation:

  29. A 42-year-old premenopausal woman presents 1 year after completing adjuvant TCH for an ER-negative, HER2-positive IDC with asymptomatic lung mets. Your likely recommendation: Trastuzumab (T) alone 4% Paclitaxel/T 34% Nanoparticle albumin-bound (nab) paclitaxel/T 10% 10% Lapatinib/capecitabine Lapatinib/trastuzumab 31% Chemotherapy/trastuzumab/bevacizumab 4% Other 7% 0% 5% 10% 15% 20% 25% 30% 35%

  30. A 42-year-old premenopausal woman with an ER-positive, HER2-positive tumor presents 1 year after completing adjuvant TCH, on tamoxifen with asymptomatic lung mets. Your likely recommendation:

  31. A 42-year-old premenopausal woman with an ER-positive, HER2-positive tumor presents 1 year after completing adjuvant TCH, on tamoxifen with asymptomatic lung mets. Your likely recommendation:

  32. Module 2: Multigene/Biomarker Assays

  33. A Quantitative Multigene RT-PCR Assay for Predicting Recurrence Risk after Surgical Excision Alone without Irradiation for Ductal Carcinoma in Situ (DCIS): A Prospective Validation Study of the DCIS Score from ECOG E5194 Solin LJ et al. SABCS 2011;Abstract S4-6.

  34. Methods for DCIS Score Validation Study • Patients with DCIS from ECOG-E5194 (n = 670) • Treated with surgical excision (≥3-mm negative margins) without irradiation • Some received tamoxifen (n = 96) • DCIS grade: low/intermediate ≤2.5 cm or high ≤1 cm • Oncotype DX assay by RT-PCR on formalin-fixed, paraffin-embedded tumors • (n = 327) • Calculated: DCIS score, Recurrence Score® • DCIS score based on an optimized gene expression algorithm • DCIS score calculated in 2 ways: • Continuous variable • 3 prespecified risk groups: low (<39), intermediate (39-54), high (≥55) Solin LJ et al. SABCS 2011;Abstract S4-6.

  35. 10-Year IBE Outcomes with the New Oncotype DX DCIS Score Primary Endpoint: Any IBE Secondary Endpoint: Invasive IBE Log rank p = 0.02 Log rank p = 0.01 Solin LJ et al. SABCS 2011;Abstract S4-6.

  36. SWOG S1007: A Phase III, Randomized Clinical Trial of Standard Adjuvant Endocrine Therapy +/- Chemotherapy in Patients with 1-3 Positive Nodes, Hormone Receptor (HR)-Positive and HER2-Negative Breast Cancer with Recurrence Score (RS) of 25 or Less Gonzalez-Angulo AM et al. SABCS 2011;Abstract OT1-03-01.

  37. SWOG-S1007 (RxPONDER) Study Design Chemotherapy*; appropriate endocrine therapy** HR-positive, HER2-negative, nodes 1-3+ early breast cancer with RS ≤ 25 (N = 4,000) 1:1 R No chemotherapy*; appropriate endocrine therapy** * Various 2nd- or 3rd-generation regimens (physician/patient choice) ** Various options, dependent on menopausal status (physician/patient choice) Primary Objective Determine the effect of chemo in patients with node-positive BC who do not have high RS by Oncotype DX 1. DFS for patients treated with chemo compared to no chemo and dependence on the magnitude of RS 2. Determine the optimal cut-point for recommending chemo or not Gonzalez-Angulo AM et al. SABCS 2011;Abstract OT1-03-01.

  38. Impact of the Recurrence Score on Adjuvant Decision-Making in ER-Positive Early Breast Cancer — Results of a Large Prospective Multicentre Decision Impact Study in Node Negative and Node Positive Disease Rezai M et al. SABCS 2011;Abstract P2-12-26.

  39. Summary • 366 evaluable German patients with N0 and N+ (1-3 positive nodes) early breast cancer and no contraindication to chemo. • Physician recommendations assessed before and after Oncotype DX assay. • Initial treatment recommendation changed in 33.1% of all cases: • 30.3% in N0 disease • 38.5% in N+ disease • Treatment recommendations predominantly changed from chemoendocrine therapy to endocrine therapy alone: • 18.4% in N0 disease • 27.9% in N+ disease Rezai M et al. SABCS 2011;Abstract P2-12-26.

  40. About how many patients, if any, do you have in your practice with metastatic disease who had DCIS as their original diagnosis?

  41. About how many patients, if any, do you have in your practice with metastatic disease who had DCIS as their original diagnosis? None 63% 26% 1 2 9% 3-5 2% 6-10 0% >10 0% 0% 10% 20% 30% 40% 50% 60% 70%

  42. For how many patients with node-positive disease in your practice have you ordered an Oncotype DX assay?

  43. For how many patients with node-positive disease in your practice have you ordered an Oncotype DX assay? None 33% 11% 1 2 16% 3-5 27% 6-10 10% >10 3% 0% 5% 10% 15% 20% 25% 30% 35%

  44. Module 3: Advanced ER-Positive Breast Cancer

  45. A Phase III Randomized Trial of Anastrozole Versus Anastrozole and Fulvestrant as First-Line Therapy for Postmenopausal Women with Metastatic Breast Cancer: SWOG S0226. Mehta RS et al. SABCS 2011;Abstract S1-1.

  46. SWOG-S0226 Study Design Anastrozole - 1 mg PO daily Treatment until progression; crossover to fulvestrant strongly encouraged after progression Postmenopausal, ER/PR-positive metastatic breast cancer (N = 690) R Anastrozole – 1 mg PO daily First cycle of 28 days: Fulvestrant – 500 mg IM (2x5mL) Day 1 Fulvestrant – 250 mg IM (1x5mL) Day 14 Fulvestrant – 250 mg IM (1x5mL) Day 28 Fulvestrant – 250 mg IM (1x5mL) Day 28 Primary endpoint: Progression-free survival Subsequent cycles of 28 days: Treat until progression Mehta RS et al. SABCS 2011;Abstract S1-1.

  47. Primary Endpoint: Progression-Free Survival Anastrozole + Fulvestrant (268 events) Anastrozole (297 events) Stratified log-rank p = 0.0070 Median PFS Anastrozole 13.5 mos (95% CI 12.1-15.1) Combination 15.0 mos (95% CI 13.2-18.4) HR = 0.80 (95% CI 0.68-0.94) With permission from Mehta RS et al. SABCS 2011;Abstract S1-1.

  48. Secondary Endpoint: Overall Survival Median OS Anastrozole 41.3 mos (95% CI 37.2-45.0) Combination 47.7 mos (95% CI 43.4-55.7) HR = 0.81 (95% CI 0.65-1.00) Anastrozole + Fulvestrant (154 deaths) Anastrozole (176 events)Stratified log-rank p = 0.049 With permission from Mehta RS et al. SABCS 2011;Abstract S1-1.

  49. SWOG-S0226 Study Design Anastrozole - 1 mg PO daily Treatment until progression; crossover to fulvestrant strongly encouraged after progression Postmenopausal, ER/PR-positive metastatic breast cancer (N = 690) R Anastrozole – 1 mg PO daily First cycle of 28 days: Fulvestrant – 500 mg IM (2x5mL) Day 1 Fulvestrant – 250 mg IM (1x5mL) Day 14 Fulvestrant – 250 mg IM (1x5mL) Day 28 Fulvestrant – 250 mg IM (1x5mL) Day 28 Primary endpoint: Progression-free survival Subsequent cycles of 28 days: Treat until progression Mehta RS et al. SABCS 2011;Abstract S1-1.

  50. Everolimus for Postmenopausal Women with Advanced Breast Cancer: Updated Results of the BOLERO-2 Phase III Trial Hortobagyi GN et al. SABCS 2011;Abstract S3.7. Baselga J et al. N Engl J Med 2011;[Epub ahead of print].

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