1. Expert Guidance on Selecting Treatment and Management Approaches in Metastatic Breast Cancer Jointly sponsored by the Annenberg Center for Health Sciences at Eisenhower and Clinical Care Options, LLC This program is supported by educational grants from Image: T & L/BSIP/Copyright©2013 Corbis Corporation. All Rights Reserved

2. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer About These Slides  Be sure to review the slide notes field for each slide for insightful commentary from the expert faculty  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 Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (e-mail permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care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. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Faculty Kimberly L. Blackwell, MD Director, Breast Cancer program Duke Cancer Institute Durham, North Carolina Kathy D. Miller, MD Associate Professor Indiana University Melvin and Bren Simon Cancer Center Indianapolis, Indiana Nicholas J. Robert, MD Associate Chair, Breast Committee US Oncology Virginia Cancer Specialists Fairfax, Virginia

4. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Disclosures Kimberly L. Blackwell, MD, has disclosed that she has received consulting fees from Novartis and Sandoz; contracted research from Celgene, Genentech, and Roche; and has been on the speakers’ bureau for Genomic Health. Kathy D. Miller, MD, has disclosed that she has received consulting fees from Antigen Express, Clovis, and Nektar, and research grants from Clovis, Entremed, Genentech, ImClone, Merrimack, Syndax, and Taiho. Nicholas J. Robert, MD, has disclosed that he has received contracted research from Genentech.

5. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Treating Metastatic Breast Cancer: Considerations  Goals of treatment –Palliation of symptoms, increase QoL –Prolong survival –Tumor response  Previous therapy, DFI  Tumor biology –ER, HER2  Underlying medical and social issues  Patient considerations –Convenience vs compliance –Toxicities affecting normal functioning

6. Estrogen Receptor–Positive Metastatic Breast Cancer

7. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Diagnosis of metastatic breast cancer Determination of sites and extent of disease Assessment of HER2, hormonal receptor status, disease-free interval, age, and menopausal status No life-threatening disease or hormone-responsive Hormone-unresponsive or life-threatening disease 1st-line hormonal therapy 1st-line chemotherapy Response No Response 2nd-line hormonal therapy 2nd-line chemotherapy Progression 3rd-line hormonal therapy Response No Response 3rd-line chemotherapy Supportive care Metastatic Breast Cancer: Management

8. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer ER+ MBC, Case 1: Presentation  A 67-year-old woman presents to the emergency room with right facial droop. Physical examination finds: –Peripheral seventh nerve deficit (Bell’s palsy) –7-cm left breast mass with slight skin dimpling but no inflammatory changes –Mobile, nontender, left axillary adenopathy  On closer questioning, she reports that the left breast mass had been present for “a few years” and had caused no trouble  She has no other chronic medical problems –Has not seen a physician in 20-30 yrs

9. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer ER+ MBC, Case 1: Evaluation  Breast imaging –Large mass in left breast with microcalcifications and suspicious adenopathy; no abnormality in the right breast  FNA of the left breast and axilla –Grade I IDC, ER 90%, PR 80%, HER2 negative  Chest/abdomen CT and bone scan –Widespread uptake in axillary skeleton, pelvis, and skull –Mixed sclerotic/lytic lesions on bone scan  Brain MRI –Mild atrophy and bone lesions, otherwise negative

10. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer MBC Interactive Decision Support Tool www.clinicaloptions.com/Oncology/Treatment Updates/MBC Insight 2013/tool/mbc_tool

11. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer First-line Letrozole vs Tamoxifen, Then Crossover Median OS Letrozole: 34 mos Tamoxifen: 30 mos Time to Crossover Letrozole: 17 mos Tamoxifen: 14 mos Mouridsen H, et al. J Clin Oncol. 2003;21:2101-2109. P =.53 (log-rank test) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 06121824303642485460 Mos Proportion of Patients Alive Letrozole 1stTamoxifen 1st

12. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer FIRST Study: TTP at Follow-up Analysis 0 0.2 0.4 0.6 0.8 1.0 06121824 Mos 30364248 Fulvestrant 500 mg Anastrozole 1 mg Proportion of Patients Alive and Progression Free HR: 0.66 (95% CI: 0.47-0.92; P =.01) Patients at Risk, n Fulvestrant 500 mg Anastrozole 1 mg 102 103 74 69 65 55 52 39 45 30 34 21 20 8 6262 0000 Robertson JF, et al. Breast Cancer Res Treat. 2012;136:503-511.

13. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer LEA: Endocrine Therapy ± Bevacizumab as First-line Treatment of MBC  Binational, multicenter, open-label, randomized phase III trial Endocrine Therapy (Letrozole or Fulvestrant)* + Bevacizumab 15 mg/kg q3 wks (n = 191) Endocrine Therapy (Letrozole or Fulvestrant)* (n = 189) Patients with unresectable locally advanced or metastatic, HR+, HER2- breast cancer (N = 380) Until disease progression Stratified by adjuvant AI (yes vs no), number of lesions (1 vs multiple), measurable lesions (yes vs no), country (Spain vs Germany) *Letrozole: 2.5 mg/day; fulvestrant: 250 mg q28 days. Martin M, et al. SABCS 2012. Abstract S1-7.

14. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer LEA: PFS With First-line Endocrine Therapy ± Bevacizumab Martin M, et al. SABCS 2012. Abstract S1-7. Median PFS ET + bev (n = 191): 18.4 mos ET alone (n = 189): 13.8 mos HR: 0.83 (95% CI: 0.65-1.06; P =.14) Probability of Survival Without Progression Mos 1.0 0.8 0.6 0.4 0.2 0 01020304050

15. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer FACT: Phase III Study of First-line Anastrozole ± Fulvestrant in HR+ MBC Fulvestrant 500 mg on Day 1, then 250 mg on Days 15, 29, then every 4th wk Anastrozole 1 mg/day PO (n = 258) Anastrozole 1 mg/day PO (n = 256) Post- or premenopausal women receiving GnRH agonist, ER- or PgR-positive, in first relapse after treatment for localized disease (N = 514) Bergh J, et al. J Clin Oncol. 2012;30:1919-1925. Primary endpoint: TTP Secondary endpoints: ORR, TTF, DoR, clinical benefit rate, OS Treat until progression or undue toxicity

16. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer FACT Phase III Study of Anastrozole ± Fulvestrant in HR+ MBC: TTP Median TTP Anastrozole (n = 256): 10.2 mos Anastrozole + fulvestrant (n = 258): 10.8 mos HR: 0.99 (95% CI: 0.81-1.20; P =.91) Bergh J, et al. J Clin Oncol. 2012;30:1919-1925. Probability of Survival Without Progression Mos 1.0 0.4 0.3 0.2 0.1 0 03036424854 0.9 0.8 0.7 0.6 0.5 6121824

17. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Postmenopausal women with HR+ MBC (N = 707) Anastrozole 1 mg/day PO + Fulvestrant 500 mg on Day 1, 250 mg on Days 14 and 28, 250 mg q28 days thereafter (n = 355) Anastrozole 1 mg/day PO (n = 352) Treatment until disease progression Stratified by previous adjuvant tamoxifen Women with progression encouraged to cross over to receive fulvestrant SWOG S0226: Phase III Study of First-line Anastrozole ± Fulvestrant in HR+ MBC  Primary endpoint: PFS  Secondary endpoints: OS, clinical benefit rate, ORR Mehta RS, et al. N Engl J Med. 2012;367:435-444.

18. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Mehta RS, et al. N Engl J Med. 2012;367:435-444. S0226 Study of First-line Anastrozole ± Fulvestrant in HR+ MBC: PFS and OS 1.00 0.75 0.50 0.25 0 0 12 24 36 48 60 Anastrozole (297 events) Anastrozole + Fulvestrant (268 events) Median PFS Combination: 15.0 mos (95% Cl: 13.2-18.4) Anastrozole: 13.5 mos (95% Cl: 12.1-15.1) PFS Mos Since Randomization HR: 0.80 (95% Cl: 0.68-0.94; P =.007 by stratified log-rank test) 1.00 0.75 0.50 0.25 0 Anastrozole (176 deaths) HR: 0.81 (95% Cl: 0.65-1.00; P =.049 by stratified log-rank test) Anastrozole + Fulvestrant (154 deaths) Median OS Combination: 47.7 mos (95% Cl: 43.4-55.7) Anastrozole: 41.3 mos (95% Cl: 37.2-45.0) OS 0 12 24 36 48 60 72 Mos Since Randomization

19. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer S0226: PFS and OS Overall and by Previous Adjuvant Tamoxifen EndpointAnastrozole + Fulvestrant AnastrozoleHR (95% CI)P Value Median PFS (n = 694), mos15.013.50.80 (0.68-0.94).007  No previous adjuvant tamoxifen (n = 414) 17.012.60.74 (0.59-0.92).0055  Previous adjuvant tamoxifen (n = 280) 13.514.10.89 (0.69-1.15).37 Median OS (n = 694), mos47.741.30.81 (0.65-1.00).049  No previous adjuvant tamoxifen (n = 414) 47.739.70.74 (0.56-0.98).0362  Previous adjuvant tamoxifen (n = 280) 49.644.50.91 (0.65-1.28).59 Mehta RS, et al. N Engl J Med. 2012;367:435-444.

20. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer First-line Anastrozole ± Fulvestrant in HR+ MBC: FACT vs SWOG S0226 FACT [1] SWOG S0226 [2] Patients, n514707 De novo metastatic disease, %1339 Prior adjuvant chemotherapy, %4533 Previous adjuvant endocrine therapy (tamoxifen), % 6840 Mean PFS range, mos10-1113-15 PFS benefitNoYes 1. Bergh J, et al. J Clin Oncol. 2012;30:1919-1925. 2. Mehta RS, et al. N Engl J Med. 2012;367:435-444.

21. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Meta-analysis: Chemotherapy vs Endocrine Therapy in MBC Methods –Randomized trials of chemotherapy alone vs endocrine therapy alone Results –No significant difference for OS in 6 trials (N = 692): HR: 0.94 (95% CI: 0.79-1.12; P =.5) –Significant difference favoring chemotherapy for ORR in 8 trials (N = 817): HR: 1.25 (95% CI: 1.01-1.54; P =.04) –However, the 2 largest trials demonstrated trends in opposite directions –Toxicity: Little information available on adverse events and QoL –Increased toxicity with chemotherapy (nausea, vomiting, alopecia) –3 of 7 trials noted QoL aspects with differing results Authors’ Conclusions –“In women with metastatic breast cancer and where hormone receptors are present, a policy of treating first with endocrine therapy rather than chemotherapy is recommended except in the presence of rapidly progressive disease.” Wilcken N, et al. Cochrane Database Syst Rev. 2003:CD002747.

22. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer ER+ MBC, Case 2: Presentation and Initial Treatment  A 58-yr-old postmenopausal ICU nurse presents with a palpable mass in upper, outer quadrant of left breast –Mild hypertension; no other comorbidities –Last mammogram 18 mos ago  Mammogram and ultrasound confirm suspicious lesion  Core biopsy reveals IDC  Primary treatment: left lumpectomy and SLNB –Pathology: IDC: 2.5 cm, G3, 1/3 SLNs positive for micrometastases –ER+ (75%), PgR+ (20%); HER2 (2+ by IHC), FISH ratio 1.3 –OncotypeDx recurrence score: 39  Adjuvant treatment: AC → wkly paclitaxel x 12, followed by anastrozole starting 4 wks after completing chemo (concurrent with RT)

23. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer ER+ MBC, Case 2: 25 Mos After First-line Therapy  Patient presents with mild but persistent right rib pain unresponsive to NSAIDs; CBC and CMP are normal  ECOG performance status: 0  Physical examination: new positive 1 x 1 cm left SCLN; mild percussion tenderness over lateral 6th rib on right; otherwise negative  Bone scan: 2 rib lesions, 1 in area of pain; additional lesions in T4 and L1  CT scan –Mixed lytic/blastic lesions in ribs: T4, L1 –2-cm left hilar and subcarinal nodes –Tiny left pleural effusion

24. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer www.clinicaloptions.com/Oncology/Treatment Updates/MBC Insight 2013/tool/mbc_tool

25. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Endocrine Resistance in ER-Positive Breast Cancer  Approximately 50% of hormone receptor–positive breast cancers are de novo resistant to endocrine therapy  Almost all patients with advanced disease will develop acquired resistance to endocrine therapies  The mechanisms of de novo and acquired resistance are likely similar but are not completely understood  For the case patient, a node biopsy would be warranted to establish diagnosis and reconfirm markers

26. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Everolimus 10 mg/day + Exemestane 25 mg/day (n = 485) Everolimus 10 mg/day + Exemestane 25 mg/day (n = 485) Placebo + Exemestane 25 mg/day (n = 239) Placebo + Exemestane 25 mg/day (n = 239) BOLERO-2: Exemestane ± Everolimus in Nonsteroidal AI–Refractory Advanced BC  Refractory to therapy: – Recurrence during or within 12 mos of end of adjuvant treatment – Progression during or within 1 mo after end of treatment for advanced disease  Stratification: –Sensitivity to previous hormonal therapy –Presence of visceral disease  No crossover allowed  Primary endpoint: PFS – Secondary endpoints: OS, ORR, CBR, safety, QoL, bone markers Baselga J, et al. N Engl J Med. 2012;366:520-529. Postmenopausal women with HR-positive, HER2-negative advanced breast cancer refractory to letrozole or anastrozole (N = 724) Postmenopausal women with HR-positive, HER2-negative advanced breast cancer refractory to letrozole or anastrozole (N = 724)

27. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer EVE + EXE PBO + EXE 48543636630425722118515812491665035242213108210 23919013296675039302115108531110000 Patients at Risk, n 0 20 40 60 80 100 06121824303642485460667278849096102108114120 Censoring Times EVE + EXE (n/N = 310/485) PBO + EXE (n/N = 200/239) Median PFS, Mos EVE + EXE: 7.82 PBO + EXE: 3.19 HR: 0.45 (95% CI: 0.38- 0.54; Log-rank P <.0001) Patients (%) Week BOLERO-2: PFS at 18-Mo Follow-up Piccart-Gebhart M, et al. ASCO 2012. Abstract 559.

28. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer BOLERO-2: Adverse Events at 18-Mo Follow-up Adverse Event, % Everolimus + Exemestane (n = 482) Placebo + Exemestane (n = 238) Grade All34 34 Total10044991235 Stomatitis598012< 10 Rash3910700 Fatigue374< 12710 Diarrhea342< 119< 10 Nausea31< 1 2910 Appetite decreased31101310 Noninfectious pneumonitis 1630000 Hyperglycemia145< 12 0 Piccart-Gebhart M, et al. ASCO 2012. Abstract 559.

29. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Baselga J, et al. N Engl J Med. 2012;366:520-529. BOLERO-2: Efficacy Analysis VariableEverolimus and Exemestane (n = 485) Placebo and Exemestane (n = 239) P ValueHR (95% CI) Local assessment PFS  Events, n (%)202 (42)157 (66)<.0010.43 (0.35-0.54)  Duration, mos Median6.92.8 95% CI6.4-8.12.8-4.1 Best overall response, %  CR0.40.0  PR9.10.4  SD70.158.6  PD9.931.4  Unknown or too early10.59.6 Objective response, % (95% CI)9.5 (7.0-12.4)0.4 (0.0-2.3)<.001

30. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Phase II Study of Letrozole ± Palbociclib (PD-0332991) in ER+, HER2- MBC Palbociclib 125 mg QD + Letrozole 2.5 mg QD Letrozole 2.5 mg QD Postmenopausal women with ER-positive, HER2-negative advanced breast cancer (N = 66) Stratified by disease site (visceral, bone only, or other); disease-free interval (> 12 vs ≤ 12 mos from end of adjuvant to recurrence or de novo advanced disease) Palbociclib 125 mg QD + Letrozole 2.5 mg QD Letrozole 2.5 mg QD Postmenopausal women with ER-positive, HER2-negative advanced breast cancer, CCND1 amp, and/or p16 loss (N = 99) Part 1Part 2 All patients continued assigned treatment until disease progression, withdrawal of consent, or unacceptable toxicity with follow-up tumor assessment every 2 mos. Finn RS, et al. SABCS 2012. Abstract S1-S6. Stratified by disease site (visceral, bone only, or other); disease-free interval (> 12 vs ≤ 12 mos from end of adjuvant to recurrence or de novo advanced disease)

31. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Letrozole ± Palbociclib in ER+, HER2- MBC: PFS Finn RS, et al. SABCS 2012. Abstract S1-6. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Probability of PFS 2802468121416182022242610 Mos Patients at Risk, n Palb + LET LET 84 81 1111 75 57 60 33 53 29 43 22 35 17 25 11 18 6 15 5 14 4 9393 5353 3131 Palb + LET (n = 84) LET (n = 81) Events, n (%)21 (25)40 (49) Median PFS, mos (95% CI)26.1 (12.7-26.1) 7.5 (5.6-12.6) HR (95% CI)0.37 (0.21-0.63) P value<.001

32. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Letrozole ± Palbociclib in ER+, HER2- MBC: Grade 3/4 AEs Finn RS, et al. SABCS 2012. Abstract S1-6. Grade 3/4 AE, %Palbociclib + LET (n = 83) LET (n = 77) Neutropenia511 Leukopenia140 Fatigue21 Anemia41 Nausea21 Hot flush00 Alopecia00 Arthralgia01 Diarrhea40

33. HER2-Positive Metastatic Breast Cancer

34. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer HER2+ MBC: Key Treatment Options  Trastuzumab  Pertuzumab  Ado-trastuzumab emtansine (T-DM1)  Everolimus  Lapatinib

35. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer HER2+ MBC, Case 1: Presentation and Staging  A 56-yr-old woman presents to your clinic with palpable mass –Married with 2 grown children, working full time as lawyer –No previous medical history –Active lifestyle  Mammogram revealed 3-cm abnormality that correlated with palpable abnormality  Ultrasound-guided biopsy of breast and axilla revealed ER- negative, PgR-negative, HER2-amplified (FISH ratio: 8.2) breast cancer  Staging studies revealed multiple pulmonary nodules but no other sites of metastasis  CT-guided lung biopsy revealed ER-negative, PgR-negative, HER2 FISH–amplified carcinoma

36. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer www.clinicaloptions.com/Oncology/Treatment Updates/MBC Insight 2013/tool/mbc_tool

37. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Phase III CLEOPATRA Study: Trastuzumab and Docetaxel ± Pertuzumab in HER2+ MBC  Primary endpoint: PFS (independently assessed)  Secondary endpoints: PFS (investigator assessment), ORR, OS, Safety Women with previously untreated, HER2-positive locally recurrent/metastatic breast cancer (N = 808) Trastuzumab 6 mg/kg q3w* + Docetaxel 75-100 mg/m 2 q3w † + Pertuzumab 420 mg q3w ‡ (n = 402) Trastuzumab 6 mg/kg q3w* + Docetaxel 75-100 mg/m 2 q3w † + Placebo q3w (n = 406) Treatment until disease progression or unacceptable toxicity Stratified by geographic region and previous (neo)adjuvant chemotherapy *Trastuzumab 8-mg/kg loading dose. † Minimum of 6 docetaxel cycles recommended; < 6 cycles permitted for unacceptable toxicity or PD. ‡ Pertuzumab 840-mg loading dose. Baselga J, et al. N Engl J Med. 2012;366:109-119.

38. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Baselga J, et al. N Engl J Med. 2012;366:109-119. Trastuzumab and Docetaxel ± Pertuzumab in HER2+ MBC (CLEOPATRA): PFS PFS independently assessed. 100 90 80 70 60 50 40 30 20 10 0 PFS (%) Months 4005101520253035 HR: 0.62 (95% CI: 0.51-0.75; P <.001) Pertuzumab (median: 18.5 mos) Control (median: 12.4 mos)

39. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Trastuzumab and Docetaxel ± Pertuzumab in HER2+ MBC (CLEOPATRA): OS  Second interim analysis of OS (median follow-up: 30 mos) –Significant, confirmatory, crosses stopping boundary Swain SM, et al. Lancet Oncol. 2013;14:461-471. OSPmabPlaceboHR (95% CI) P Value 3-yr estimated OS, % 66500.66 (0.52-0.84).0008 Median OS, mosNot reached 37.6-- Pertuzumab, trastuzumab, docetaxel Placebo, trastuzumab, docetaxel 100 90 80 70 60 50 40 30 20 10 0 OS (%) Mos 5505102025303540455015

40. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Select Adverse Events (Grade ≥ 3), %Pertuzumab (n = 407) Placebo (n = 397) Neutropenia48.945.8 Febrile neutropenia13.87.6 Leukopenia12.314.6 Diarrhea7.95.0 Peripheral neuropathy2.71.8 Left ventricular systolic dysfunction1.22.8 Baselga J, et al. N Engl J Med. 2012;366:109-119. Trastuzumab and Docetaxel ± Pertuzumab in HER2+ MBC (CLEOPATRA): Safety

41. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer APHINITY: CT and Trastuzumab ± Pertuzumab in HER2+ BC Chemotherapy (6-8 cycles)* Trastuzumab (1 yr) Pertuzumab 840 mg in cycle 1, then 420 mg q3w Chemotherapy (6-8 cycles)* Trastuzumab (1 yr) Placebo Patients with resected HER2+ primary breast cancer (planned N = 4800) 10-yr follow-up Randomization within 7 wks of surgery *Anthracycline or nonanthracycline. Radiotherapy and/or endocrine therapy may be started after completion of adjuvant chemotherapy. ClinicalTrials.gov. NCT01358877. Primary endpoint: invasive DFS Secondary endpoints: invasive DFS, including second non-breast cancer, DFS, OS, RFI, distant RFI, safety, QoL

42. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer NCCN: First-line Treatment of HER2+ MBC With No Previous Trastuzumab Exposure  Preferred regimens –Docetaxel + trastuzumab + pertuzumab (category 1) –Paclitaxel + trastuzumab + pertuzumab  Other regimens –Chemotherapy + trastuzumab NCCN. Clinical practice guidelines in oncology: breast cancer. v.3.2013.

43. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer HER2+ MBC, Case 2: Presentation and Initial Treatment  A 76-yr-old woman presented in early 2006 with T3N1 breast cancer –ER- and PgR-positive, HER2 IHC 3+, FISH amplified (ratio: 5.3)  Lumpectomy and ALND revealed 4-cm grade 3 IDC with 5 of 15 positive axillary lymph nodes  Initial treatment –AC followed by 12 wks of paclitaxel/trastuzumab and completion of 52 wks of trastuzumab –Postlumpectomy radiation –Started letrozole (completed March 2011)  In September 2013, she presented with right hip pain. Staging studies revealed multiple bony metastasis and pleural thickening of the right lung. CT- guided bone biopsy revealed ER-positive, PgR-positive, HER2 FISH– amplified carcinoma

44. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer www.clinicaloptions.com/Oncology/Treatment Updates/MBC Insight 2013/tool/mbc_tool

45. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer HER2+ MBC, Case 3: Presentation and Initial Treatment  A 46-yr-old woman presented with a locally advanced breast cancer, including a 5-cm mass, positive axillary LNs (by exam and imaging), and skin changes on the breast  Biopsy confirmed an infiltrating ductal breast carcinoma with an inflammatory component and lymphovascular invasion. It is ER negative, PgR negative, and HER2 positive (by FISH)  She received neoadjuvant TCH x 6 and had an excellent response clinically. A mastectomy and LN dissection revealed a near-complete pathologic remission and 2/16 LNs involved microscopically. Radiation therapy was completed, and she finished 12 mos of trastuzumab  2 years later, her liver function tests are slightly elevated, and a CT scan shows 3 scattered hepatic nodules. A biopsy confirms recurrent breast cancer, which is ER negative, PgR negative, and HER2+

46. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer HER2+ MBC, Case 3: First-line Treatment  She begins weekly paclitaxel with trastuzumab and does well, achieving a CR (by imaging). After 6 mos of chemotherapy, she begins maintenance trastuzumab  Repeat CT scans at 3 mos show 2 new liver lesions and 2 pulmonary nodules; also positive on PET scan

47. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer www.clinicaloptions.com/Oncology/Treatment Updates/MBC Insight 2013/tool/mbc_tool

48. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Phase III EMILIA Study: T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC  Primary endpoint: PFS by IRF, OS, safety  Secondary endpoints: QoL (FACT B), DOR, PFS by investigator assessment Patients with HER2+ locally advanced or metastatic breast cancer following treatment with a taxane and trastuzumab (N = 980) T-DM1 3.6 mg/kg IV q3w (n = 490) Capecitabine 1000 mg/m 2 PO BID, Days 1-14, q3w Lapatinib 1250 mg/day PO (n = 490) Stratified by world region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease Disease progression Verma S, et al. N Engl J Med. 2012;367:1783-1791.

49. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer EMILIA Study of T-DM1 vs Lapatinib/ Capecitabine in HER2+ MBC: PFS (IRC) Verma S, et al. N Engl J Med. 2012;367:1783-1791. PFS (%) Stratified HR: 0.65 (95% CI: 0.55-0.77; P <.001) T-DM1 Lapatinib/capecitabine Mos 100 80 60 40 20 0 Lapatinib/capecitabine T-DM1 Median Mos, n 6.4 9.6 Events, n 304 265 300246812141618202224262810

50. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer EMILIA Study of T-DM1 vs Lapatinib/ Capecitabine in HER2+ MBC: OS Verma S, et al. N Engl J Med. 2012;367:1783-1791. Mos 64.7% (95% CI: 59.3-70.2) Lapatinib/capecitabine T-DM1 Stratified HR: 0.68 (95% CI: 0.55-0.85; P <.001) Efficacy stopping boundary, P =.0037 or HR: 0.73 OS (%) 85.2% (95% CI: 82.0-88.5) 78.4% (95% CI: 74.6-82.3) 51.8% (95% CI: 45.9-57.7) Lapatinib/capecitabine Median Mos, n 25.1 30.9 Events, n 182 149 100 80 60 40 20 0 0 4 8 12 16 20 24 28 32 36

51. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Phase III BOLERO-3: Trastuzumab and Vinorelbine ± Everolimus in HER2+ BC  Multicenter, randomized, double-blind study  Patients were stratified by previous lapatinib use (≥ 6 wks of treatment)  Granulocyte colony–stimulating factor support allowed following febrile neutropenia *After a loading dose of 4 mg/kg on Day 1, Cycle 1; 1 cycle = 21 days. ClinicalTrials.gov. NCT01007942. Anticipated recruitment (N = 572)  Women ≥ 18 yrs old  HER2+ advanced BC  Progression during trastuzumab treatment Primary Endpoint  PFS Secondary Endpoints  OS  ORR  Clinical benefit rate  Toxicity Everolimus 5 mg/day + Vinorelbine 25 mg/m 2 IV on Days 1, 8, 15 + Trastuzumab 2 mg/kg IV* on Days 1, 8, 15 Placebo daily + Vinorelbine 25 mg/m 2 IV on Days 1, 8, 15 + Trastuzumab 2 mg/kg IV* on Days 1, 8, 15

52. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Trastuzumab/Vinorelbine ± Everolimus in HER2+ BC (BOLERO-3): PFS 100 80 60 40 20 0 Wks PFS (%) 06121824303642485460667278849096102108114120126132138144150156162168174 Median PFS Everolimus: 7.00 mos Placebo: 5.78 mos HR: 0.78 (95% CI: 0.65-0.95; log-rank P =.0067) Everolimus (n/N = 196/284) Placebo (n/N = 219/285) Censoring Times O’Regan R, et al. ASCO 2013. Abstract 505.

53. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer  Primary endpoint: PFS  Secondary endpoints: OS, ORR, clinical benefit  Patients with progression after ≥ 4 wks of lapatinib monotherapy allowed to cross over to receive trastuzumab Blackwell KL, et al. J Clin Oncol. 2010;28:1124-1130. Patients with HER2+ (FISH/IHC3+) MBC and progression on anthracycline, taxane, and trastuzumab Lapatinib 1500 mg/day PO (n = 148) Lapatinib 1000 mg/day PO + Trastuzumab 4 mg/kg → 2 mg/kg IV wkly (n = 148) Pivotal EGF104900 Phase III Study: Dual HER2 Blockade in MBC

54. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer EGF104900 Phase III Study of Dual HER2 Blockade in MBC: OS L + T (n = 146) L (n = 145) Median OS, mos14.09.5 HR (95% CI)0.74 (0.57-0.97) Stratified log-rank P value.026 52% of patients in the L arm crossed over to L + T 35 20 40 60 80 0 100 5 10 15 20 25 30 0 Mos From Randomization OS (%) 12-mo OS 6-mo OS 41% 70% 80% 56% Pts at risk, n L 1000/T L 1500 120 100 87 64 63 46 42 28 25 13 1 146 145 Blackwell KL, et al. J Clin Oncol. 2012;30:2585-2592.

55. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer HER2-Positive MBC: Conclusions  Multiple effective and approved options in HER2+ MBC –Trastuzumab –Pertuzumab –T-DM1 –Lapatinib  Preferred first-line regimens include dual HER2 inhibition with pertuzumab and trastuzumab  Other HER2 inhibitors continue to have a role outside the first-line setting

56. Choice of Chemotherapy

57. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Choice of Chemotherapy, Case 1: Presentation and Initial Treatment  A 58-yr-old woman presented in 2006 with a 3-cm grade 3 IDC that was ER+, PR-, and HER2- with 4 positive lymph nodes  She received mastectomy and postmastectomy radiation + TAC chemotherapy followed by letrozole  In 2010, she developed bone metastases (biopsy proven with the same biological profile) and was started on a bisphosphonate and exemestane  After 6 mos, she is restaged and now has 3 pulmonary nodules, each ~ 1 cm  She is switched to a fulvestrant and is stable for 3 mos. She has now developed 5 pulmonary nodules and 3 liver lesions. Weight is stable, and LFTs are normal  She is given megestrol acetate, but repeat scan shows progression of disease. She remains asymptomatic

58. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer MBC: Sequential vs Combination Cytotoxic Therapy Many patients with TNBC treated with adjuvant anthracycline, taxane, and cyclophosphamide  PFS ≤ 4 mos with chemotherapy for metastatic disease [1]  First-line gemcitabine and paclitaxel, [2] capecitabine and docetaxel [3] each showed improved TTP, RR, and OS vs single-agent taxane –In patients who received single-agent docetaxel, poststudy treatment with capecitabine improved survival vs other poststudy treatments [4]  However, other trials have shown that combination cytotoxic therapy is no better vs single-agent or single-agent sequential therapy and is associated with more toxicity [5] 1. Kassam F, et al. Clin Breast Cancer. 2009;9:29-33. 2. Albain KS, et al. J Clin Oncol. 2008;26:3950-3957. 3. O’Shaughnessy J, et al. J Clin Oncol. 2002;20:2812-2823. 4. Miles D, et al. Clin Breast Cancer. 2004;5:273-278. 5. Sledge GW, et al. J Clin Oncol. 2003;21:588-592.

59. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer NCCN Guideline–Recommended Chemotherapy Regimens for MBC  Single agents (preferred) –Anthracyclines (doxorubicin, pegylated liposomal doxorubicin) –Antimetabolites (capecitabine, gemcitabine) –Microtubule inhibitors (eribulin, vinorelbine) –Taxanes (paclitaxel)  Panel: little compelling evidence that combination chemotherapy is superior to sequential single agents for patients where immediate response is not necessary (ie, visceral crises)  Chemotherapy combinations –AC (doxorubicin/ cyclophosphamide) –EC (epirubicin/cyclophosphamide –GT (gemcitabine/paclitaxel) –Paclitaxel/bevacizumab –CMF (cyclophosphamide/ methotrexate/fluorouracil) –FAC (fluorouracil/epirubicin/ cyclophosphamide) –FEC (fluorouracil/doxorubicin/ cyclophosphamide) NCCN. Clinical practice guidelines in oncology: breast cancer. v.3.2013.

60. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Choice of Chemotherapy, Case 2: Presentation and Initial Treatment  A 63-year-old woman presented in 2009 with a 4-cm, grade 3 IDC that was ER-, PgR-, and HER2- with 6 positive lymph nodes  She was treated with mastectomy, postmastectomy radiation, and TAC chemotherapy  3 yrs later, she developed metastatic disease with lung and liver involvement (biopsy proven with no change in profile)  She is treated with paclitaxel and bevacizumab and does well for 8 mos  She progresses, but with a good performance status and normal LFTs

61. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer www.clinicaloptions.com/Oncology/Treatment Updates/MBC Insight 2013/tool/mbc_tool

62. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Study 301: Eribulin vs Capecitabine in Previously Treated LABC or MBC  Global, open-label, randomized phase III trial Kaufman PA, et al. SABCS 2012. Abstract S6-6. Eribulin Mesylate 1.4 mg/m 2 on Days 1 and 8 of a 21-day cycle (n = 554) Capecitabine 1250 mg/m 2 on Days 1-14 of a 21-day cycle (n = 548) Locally advanced or MBC (N = 1102) Stratified by geographical region, HER2 status

63. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Eribulin vs Capecitabine in Previously Treated LABC or MBC (Study 301): PFS  PFS similar with eribulin compared with capecitabine Survival OutcomeEribulin (n = 554) Capecitabine (n = 548) HR (95% CI) P Value Median PFS, mos  Independent review4.14.2 1.079 (0.932-1.250).305  Investigator review4.24.1 0.977 (0.857-1.114).736 Kaufman PA, et al. SABCS 2012. Abstract S6-6.

64. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Eribulin vs Capecitabine in Previously Treated LABC or MBC (Study 301): OS Kaufman PA, et al. SABCS 2012. Abstract S6-6. Survival Outcome Eribulin (n = 554) Capecitabine (n = 548) HR (95% CI) P Value Median OS, mos15.914.50.879 (0.770-1.003).056 OS, %  1 yr64.458.0.035  2 yrs32.829.8.324  3 yrs17.814.5.175 Median OS by receptor status, %  HER2 positive14.317.10.965 (0.688-1.355)  HER2 negative15.913.50.838 (0.715-0.983)  ER positive18.216.80.897 (0.737-1.093)  ER negative14.410.50.779 (0.635-0.955)  Triple negative14.49.40.702 (0.545-0.906)  Not triple negative17.516.60.927 (0.795-1.081)

65. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Eribulin vs Capecitabine in Previously Treated LABC or MBC (Study 301): AEs  Key differences in toxicity profiles –Higher grade 3/4 neutropenia and leukopenia for eribulin –Much higher incidence (all grades) of hand-foot syndrome for cape  Rates of other adverse events (eg, anemia, fatigue, asthenia, decreased appetite) similar in the 2 study populations Kaufman PA, et al. SABCS 2012. Abstract S6-6.

66. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Choice of Chemotherapy, Case 3: Presentation and Initial Treatment  A 52-yr-old woman presented in 2010 with a 2-cm grade 3 IDC that was ER-, PgR-, and HER2- with 1 positive lymph node (BRCA-)  She was treated with lumpectomy and radiotherapy, then given dose-dense chemotherapy  She developed dyspnea and a 10-lb weight loss  Mildly elevated liver function tests  CT scan reveals right pleural effusion, multiple lung nodules, and liver lesions  Thoracentesis reveals malignant cells consistent with breast cancer

67. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer www.clinicaloptions.com/Oncology/Treatment Updates/MBC Insight 2013/tool/mbc_tool

68. clinicaloptions.com/oncology Treatment and Management Approaches in Metastatic Breast Cancer Conclusion  Sequential single-agent chemotherapy preferable vs combination chemotherapy for most patients without visceral crisis  Choice of chemotherapy based on chronic disease model –Goal: increase disease control; decrease treatment-related toxicity

69. Go Online for More Breast Cancer Education! Interactive Decision Support Tool: enter your patient’s details and see what treatment 5 breast cancer experts would recommend ClinicalQuiz™: Metastatic Breast Cancer Edition Interactive Case Challenge clinicaloptions.com\oncology