1. Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content.

2. Moderator Neil Love, MD Faculty Oncology Grand Rounds Breast Cancer Nurse and Physician Investigators Discuss New Agents, Novel Therapies and Actual Cases from Practice Friday, April 29, 2016 6:00 AM – 7:30 AM Joyce O’Shaughnessy, MD Jennie Petruney, BSN, MSN, ANP Kimberly L Blackwell, MD Emily Olson, APRN, CNP, MSN

3. Oncology Grand Rounds Series

8. Oncology Grand Rounds: Themes New agents and treatment strategies: Benefits and risks Counseling patients about side effects –Practical implementation End-of-life care Psychosocial issues in patient care Supporting the supporters Job satisfaction and burnout in oncology professionals The oncology professional just entering practice The bond that heals

9. Courtesy of Christiana Care Health System

10. Initial Presentation of ATAC San Antonio Marriott Rivercenter, December 2001 Baum M, on behalf of the ATAC Trialists' Group. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) adjuvant breast cancer trial in post- menopausal women. 24th Annual San Antonio Breast Cancer Symposium 2001;Abstract 8.

11. Module 1: Neoadjuvant and Adjuvant Therapy for Patients with Localized HER2-Positive Breast Cancer

12. Discussion Topics Mechanisms of action of anti-HER2 agents Side effects and toxicities of chemotherapy/anti- HER2 agents and regimens Neoadjuvant versus adjuvant treatment of HER2- positive breast cancer Patient education issues in the early HER2-positive setting Ongoing and planned clinical trials incorporating novel HER2-directed therapies in the adjuvant and neoadjuvant settings

13. Overview of Breast Cancer Estimated number of new cases and deaths in 2016: –New cases = 249,260 –Deaths = 40,890 Stage at diagnosis (Percent of patients who present with): –Localized disease = 60% –Regional disease = 33% –Metastatic disease = 5% –Unstaged disease = 2% Five-year survival estimates (2006-2012) = 89.7% Cancer Facts and Figures 2016; American Cancer Society Surveillance Research 2011; SEER Stat Fact Sheet.

14. Breast Cancer Stage Distribution at Diagnosis Note: Distribution varies by race/ethnicity DeSantis CE et al. CA Cancer J Clin 2016;66(1):31-42. Metastatic 5% Locally Advanced 5% Local 64% Regional 26%

15. Distribution of Breast Cancer Subtypes DeSantis CE et al. CA Cancer J Clin 2016;66(1):31-42. HR+/HER2- 74% HER2+ 14% TNBC 12%

16. 35-Year-Old Woman with a ER/PR-Negative, HER2-Positive Breast Cancer (Ms Petruney) Presented with a 7-cm, ER/PR-negative, HER2-positive breast mass Enrolled in a trial of neoadjuvant trastuzumab/pertuzumab –Tumor progressed during treatment –Carboplatin/docetaxel added with excellent clinical response Lumpectomy revealed a small focus of residual disease Postoperative radiation therapy and adjuvant trastuzumab/pertuzumab She has 3 young children Experienced an episode of acute depression during the neoadjuvant therapy, which resolved

17. Case discussion points (Ms Petruney) What were some of the key patient education points that you addressed when the patient was started on neoadjuvant trastuzumab/pertuzumab? What are the most common toxicity/tolerability issues with trastuzumab/pertuzumab? How did the patient tolerate treatment with trastuzumab/pertuzumab?

18. HER signaling: The network begins with the 4 HER receptors HER2HER1/EGFRHER4HER3 Rowinsky. Oncologist 2003;8(suppl 3):5-17; Yarden et al. Nat Rev Mol Cell Biol 2001;2:127-137.

19. HER1/3/4 Pertuzumab HER2 Trastuzumab Subdomain IV Dimerization domain Trastuzumab: Inhibits ligand-independent HER2 signaling Activates ADCC Prevents HER2 ECD shedding Pertuzumab: Inhibits ligand-dependent HER2 dimerization and signaling Activates ADCC Pertuzumab and Trastuzumab: Mechanisms of Action ADCC = antibody-dependent cell-mediated cytotoxicity; ECD = extracellular domain Adapted from Harbeck N et al. Breast Care (Basel) 2013;8(1):49-55.

20. Commonly Used Adjuvant and Neoadjuvant Regimens for HER2-Positive Breast Cancer Preferred Regimens AC  taxane-trastuzumab ± pertuzumab TCH ± pertuzumab Other Regimens Docetaxel-cyclophosphamide + trastuzumab Paclitaxel + trastuzumab FEC  taxane + trastuzumab-pertuzumab Trastuzumab-pertuzumab-taxane  FEC NCCN Breast Cancer Guidelines v1.2016

21. Trastuzumab Emtansine (T-DM1): Mechanisms of Action Adapted from LoRusso PM et al. Clin Cancer Res 2011. Emtansine release Inhibition of microtubule polymerization Internalization Lysosome Nucleus HER2 T-DM1 P P P HER2 T-DM1 Immune effector cell Fcγ receptor Antibody-dependent cellular cytotoxicity (ADCC) Inhibition of HER2 signaling Inhibition of HER2 shedding P P P PI3K MAPK

22. Lapatinib: Mechanism of Action Adapted from Vogel C et al. Jap J Clin Oncol 2010;40(11):999-1013. ErbB1/EGFR Ligands ErbB2 Trastuzumab IGF-IR p95 ErbB2 Cell proliferation X X

23. Would You Recommend Neoadjuvant Chemotherapy? (2.1-3.0 cm tumor) Love N et al. SABCS 2015;Abstract P1-14-20.

25. Module 2: Management of Metastatic HER2-Positive Breast Cancer

26. Discussion Topics Common systemic regimens used in metastatic HER2-positive breast cancer: –Treatment schedules –Efficacy –Side effects and toxicities –Patient education issues Integration of endocrine treatment into the management of “triple-positive” breast cancer

27. Discussion Topics Indications for rebiopsy, variations in HER2 and ER assay results Diagnosis and management of CNS metastases in HER2-positive breast cancer New agents and treatment strategies in metastatic HER2-positive breast cancer

28. 75-Year-Old Woman with a ER/PR-Negative, HER2- Positive Metastatic Breast Cancer (Ms Olson) 4/2014: Diagnosed with ER/PR-negative, HER2-positive breast cancer and metastases in the lung and adrenal glands Docetaxel/pertuzumab/trastuzumab –Hospitalized twice with colitis –Continued dual anti-HER2 therapy 12/2015: Brain metastases, progressive lung lesions Lives independently with a supportive husband, 2 grown children Continues to travel countrywide

29. Response to Docetaxel-Trastuzumab- Pertuzumab (THP) in the Lung Prior to THPPR after 4 cycles of THP

30. Centrally confirmed HER2+ locally recurrent, unresectable or metastatic BC (MBC) ≤1 hormonal regimen for MBC Prior (neo)adjuvant systemic rx, incl chemotherapy ± trastuzumab allowed if followed by DFS ≥ 12 mo Baseline LVEF ≥ 50%; no CHF or LVEF < 50% during or after prior trastuzumab Centrally confirmed HER2+ locally recurrent, unresectable or metastatic BC (MBC) ≤1 hormonal regimen for MBC Prior (neo)adjuvant systemic rx, incl chemotherapy ± trastuzumab allowed if followed by DFS ≥ 12 mo Baseline LVEF ≥ 50%; no CHF or LVEF < 50% during or after prior trastuzumab Docetaxel + trastuzumab + placebo Docetaxel + trastuzumab + pertuzumab 1:1 N = 406 N = 402 R CLEOPATRA Study Baselga J et al. N Engl J Med 2012;366(2):109-19; Swain S et al. SABCS 2012;Abstract P5-18- 26. Trastuzumab: 8 mg/kg loading dose  6 mg/kg every 3 weeks until disease progression Docetaxel: 75 mg/m 2 every 3 weeks (increased to 100 mg/m 2 at investigator discretion) Pertuzumab: 840 mg loading dose  420 mg every 3 weeks until disease progression

31. CLEOPATRA: Response and Survival Analyses EndpointPertuzumab + T + DPlacebo + T + D Median OS56.5 mo40.8 mo Median PFS18.5 mo12.4 mo ORR80.2%69.3% Baselga J et al. N Engl J Med 2012;366(2):109-19; Swain SM et al. Lancet Oncol 2013;14(6):461- 71.

32. CLEOPATRA: Overall Survival PertuzumabControl (n = 402)(n = 406) Median OS 56.5 mo40.8 mo Pertuzumab, 168 events Control, 221 events Hazard ratio: 0.68, p < 0.001 Months Overall Survival (%) Swain SM et al. N Engl J Med 2015;372(8):724-34.

33. Progressive Pulmonary Mass

34. CNS and Pulmonary Metastases MRI of CNS metsAfter completion of WBRT

35. PD Phase III EMILIA Study 1:1 HER2-positive LABC or MBC (N = 991) Prior taxane and trastuzumab Progression on metastatic treatment or within 6 months of adjuvant treatment T-DM1 3.6 mg/kg q3w IV T-DM1 3.6 mg/kg q3w IV Capecitabine 1,000 mg/m 2 PO BID, days 1–14, q3w + Lapatinib 1,250 mg/day PO qd Capecitabine 1,000 mg/m 2 PO BID, days 1–14, q3w + Lapatinib 1,250 mg/day PO qd Verma S et al. N Engl J Med 2012;367(19):1783-91. T-DM1 (n = 495) Cape-lapatinib (n = 496) Median OS30.9 mo25.1 mo Median PFS9.6 mo6.4 mo

36. EMILIA: Overall Survival Median No. of Months Lapatinib-capecitabine (n = 496) 25.1 T-DM1 (n = 495)30.9 Stratified hazard ratio, 0.68 p < 0.001 Verma S et al. N Engl J Med 2012;367(19):1783-91. Months Overall Survival (%) Lapatinib-capecitabine 51.8% 78.4% 85.2% 64.7% T-DM1

37. Case discussion points (Ms Olson) What type of end-of-life planning, if any, have you discussed with the patient? How did you respond when she inquired about physician-assisted death?

38. Module 3: Management of ER-Positive, HER2-Negative Breast Cancer

39. Discussion Topics Use of genomic assays to determine the need for chemotherapy and duration of adjuvant endocrine therapy Delayed recurrence in this disease subtype; use of pseudoadjuvant therapy for patients with local recurrence Mechanisms of action, efficacy and tolerability issues: –Endocrine agents –mTOR inhibitors –CDK4/6 inhibitors Key factors in selecting first-line systemic treatment for metastatic disease: Chemotherapy versus endocrine therapy Clinical factors affecting the sequencing of therapies in the metastatic setting

40. 45-Year-Old Woman with a ER/PR-Positive, HER2-Negative Metastatic Breast Cancer (Ms Olson) 2005: Diagnosed with ER/PR-positive, HER2-negative breast cancer (premenopausal) –Adjuvant tamoxifen x 5 years 2015: Pelvic bone pain –Bone scan: Diffuse uptake suggesting metastatic disease –Biopsy: ER/PR-positive, HER2-negative recurrence Bilateral oophorectomy Letrozole/palbociclib/zoledronic acid –Clinical complete response within 3 months, which continues currently Mother of 3 teenagers, continues to work and is experiencing a high level of anxiety about her life situation

41. PET/CT of Bone Metastases Baseline PET/CT: New mets3 months after letrozole-palbociclib

42. Annual Hazard Rates of Recurrence for Breast Cancer by ER Status Recurrence Hazard Rate Years 0.3 0.2 0.1 0 024681012 Saphner T et al. J Clin Oncol 1996;14(10):2738-46. ER-negative ER-positive

43. Progression-Free Survival (Investigator Assessed): Palbociclib-Fulvestrant versus Placebo-Fulvestrant Turner NC et al. Proc ASCO 2015;Abstract LBA502. NEJM 2015;373(3):209. Hazard ratio, 0.42 P < 0.001 Palbociclib-fulvestrant (N = 347) Median progression-free survival, 9.2 mo Placebo-fulvestrant (N = 174) Median progression-free survival, 3.8 mo

44. Key Toxicities Associated with Palbociclib- Fulvestrant Turner NC et al. Proc ASCO 2015;Abstract LBA502. NEJM 2015;373(3):209-19. AE Palbociclib + Fulvestrant (n = 345) Placebo + Fulvestrant (n = 172) Any GradeGrade 3Grade 4 Any GradeGrade 3Grade 4 Neutropenia79%53%9%4%0%<1% Leukopenia46%25%<1%4%0%<1%

45. Abemaciclib Monotherapy in Advanced or Metastatic Breast Cancer Tolaney SM et al. SABCS 2014;Abstract 763. Change in tumor size at best response ORR (all): 12/47 (25.5%) ORR (HR+): 12/36 (33.3%) ORR (HR-): 0/9 (0%) 3 nonevaluable patients are not shown. All patients were required to have measurable disease. † Patient progressing on endocrine therapy before study entry and continued on that specific therapy * Indicates HER2+ HR statusNegativePositiveUnknown % Change from Baseline 100 80 60 40 20 0 -20 -40 -60 -80 -100 * * * * * *********** †† †† † † † † † †

46. Best Change in Tumor Size from Baseline with Abemaciclib Combined with Other Therapies Tolaney SM et al. Proc ASCO 2015;Abstract 522. * For this patient, change in tumor size is greater than 100%. Part A letrozole Part B anastrozole Part C tamoxifen Part E exemestane + everolimus Part D exemestane Patients Change from baseline (%) * 20% increase 30% decrease

47. MONARCH 3: Phase III Study of First-Line Abemaciclib with a Nonsteroidal Aromatase Inhibitor (NSAI) Goetz MP et al. Proc ASCO 2015;Abstract TPS624. Clinicaltrials.gov; NCT02246621 Abemaciclib + NSAI until PD R Placebo + NSAI until PD Postmenopausal women with HR+, HER2- locoregionally recurrent or metastatic breast cancer with disease-free interval >12 mo following (neo)adjuvant ET or presenting de novo with metastatic disease (N = 450) 2:1 Primary endpoint: Progression-free survival (PFS) Stratification Factors: Nature of disease (visceral metastases versus bone-only metastases versus other) Prior (neo)adjuvant endocrine therapy (AI therapy versus other versus no prior endocrine therapy)

48. Package inserts for ipilimumab, nivolumab, pembrolizumab (4/2016) 1981: Mastectomy for early breast cancer 2009: HR-positive, HER2-negative recurrence, primarily in bone –Exemestane/zoledronic acid (ZDA) x 2 years –Fulvestrant/ZDA x 15 months –Tamoxifen/everolimus/ZDA x 3+ years  disease progression –Letrozole x 3 months  disease progression –Nab paclitaxel every 3 weeks with very poor tolerance PET scan showed significant improvement Continued at 50% dose reduction — just completed 5 th cycle with very good tolerance Now able to participate fully in activities of daily living 72-Year-Old Woman with HR-Positive, HER2-Negative Metastatic Breast Cancer (Ms Petruney)

49. Case discussion points (Ms Olson) In general, what are some of the key patient education points that you address when a patient with ER-positive metastatic breast cancer is starting on everolimus? What are the most common toxicity/tolerability issues with everolimus? In general, what is your approach to prevention and management of mucositis associated with everolimus?

50. Crosstalk between ER and PI3K/AKT/mTOR Signaling: Rationale for Dual Inhibition PI3K AKT PTEN mTOR RAS RAF MEK MAPK ER target gene transcription P P EGFR HER2 E E ER E E E mTOR activates ER in a ligand-independent manner Estradiol suppresses apoptosis induced by mTOR blockade Hyperactivation of the mTOR pathway is observed in endocrine therapy–resistant breast cancer cells mTOR is a rational target to enhance the efficacy of hormonal therapy Adapted from: Di Cosimo S, Baselga J. Nat Rev Clin Oncol 2010;7:139-47.

51. BOLERO-2: PFS with Exemestane-Everolimus in HR-Positive Advanced Breast Cancer Baselga J et al. N Engl J Med 2012;366(6):520-9. Placebo plus exemestane median PFS, 4.1 mo Everolimus plus exemestane median PFS, 10.6 mo Hazard ratio, 0.36 p < 0.001 Probability of Event (%) Weeks

52. Case discussion points (Ms Petruney) In general, what are some of the key patient education points that you address when a patient with breast cancer is starting on docetaxel or nab paclitaxel? What are the most common toxicity/tolerability issues with these agents? In general, how do you explain the difference between nab paclitaxel and the other taxanes?

54. Module 4: Management of Triple-Negative Breast Cancer (TNBC)

55. Discussion Topics Global rationale for neoadjuvant treatment of breast cancer: Potential advantages in local tumor control Role of platinum-based neoadjuvant treatment in TNBC Common treatment sequences in metastatic TNBC New approaches to TNBC: –Androgen receptor assays and antiandrogens –BRCA, BRCAness and the rationale for PARP inhibitors –Anti-PD-1/PD-L1 checkpoint inhibitors in TNBC –Genomic assays for patients who have received all approved therapies

56. 54-Year-Old Oncology Infusion Nurse with Triple- Negative Early Breast Cancer (Ms Petruney) Presented with a large breast mass and positive axillary nodes –Biopsy: ER/PR-negative, HER2-negative infiltrating ductal carcinoma Clinical trial: Neoadjuvant paclitaxel/carboplatin followed by AC Mastectomy: Small focus of DCIS, no evidence of invasive cancer Axillary node dissection and postoperative radiation therapy Currently 3 years out and faring well Greatly affected by her experience as an oncology nurse Quit work and is travelling the country with her husband Places a high value on experiencing life

58. Novel Treatment Approaches to TNBC Androgen receptor assays and antiandrogens BRCA, BRCAness and the rationale for PARP inhibitors Anti-PD-1/PD-L1 checkpoint inhibitors in TNBC Genomic assays for patients who have received all approved therapies

59. MDV3100-11: Clinical Benefit According to PREDICT AR Traina TA et al. Proc ASCO 2015;Abstract 1003. CR, complete response; PR, partial response; PFS, progression-free survival; CBR, clinical benefit rate PREDICT AR-PREDICT AR+ Time (weeks) PREDICT AR- PREDICT AR+ Total, n (%)62 (53%)56 (47%) CBR16, % n 11% n = 7 39% n = 22 CBR24, % n 6% n = 4 36% n = 20 CR or PR, % n 3% n = 2 9% n = 5 Median PFS (ITT) 8.1 wks16.1 wks nn = 62n = 56 Time (weeks) 0-1 prior lines 2+ prior lines Active Confirmed CR or PR

60. OLYMPIA Study Design Tutt NJ et al. Proc ASCO 2015;Abstract TPS1109.

61. Pembrolizumab in TNBC: ORR (N = 27) and Maximum Percentage Change from Baseline in Target Lesions (N = 23) Nanda R et al. SABCS 2014;Abstract S1-09. ORR = 18.5% Confirmed complete response (nodal disease) Confirmed partial response Stable disease Progressive disease Change form Baseline in Sum of Longest Diameter of Target Lesion, %