1. New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC Image: Dr. Torsten Wittmann/Copyright©2010 Photo Researchers, Inc. All Rights Reserved This program is supported by an educational grant from

2. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer About These Slides  Our thanks to the presenters who gave permission to include their original data  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 Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options Disclaimer The materials published on the Clinical Care Options Web site reflect the views of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 New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Faculty Dennis J. Slamon, MD, PhD Professor and Chief Division of Hematology/Oncology Department of Internal Medicine David Geffen School of Medicine at UCLA Los Angeles, California Sara Hurvitz, MD Assistant Professor of Medicine Director, Breast Oncology Program Division of Hematology-Oncology Department of Internal Medicine David Geffen School of Medicine at UCLA Los Angeles, California

4. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Disclosure of Conflicts of Interest  Postgraduate Institute for Medicine (PIM) assesses conflict of interest with its instructors, planners, managers, and other individuals who are in a position to control the content of CME activities. All relevant conflicts of interest that are identified are thoroughly vetted by PIM for fair balance, scientific objectivity of studies utilized in this activity, and patient care recommendations. PIM is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.  The faculty and CCO staff reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity.

5. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Disclosures Dennis J. Slamon, MD, PhD, has disclosed that he has served on advisory boards for GlaxoSmithKline and Roche/Genentech. Sara Hurvitz, MD, has disclosed that she has received consulting fees from Abraxis, fees for non-CME services from Abraxis and Bristol-Myers Squibb, and contracted research from Roche/Genentech.

6. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Disclosures Jennifer Swanson; Edward King, MA; Andrew D. Bowser; Gordon Kelley; Jennifer M. Blanchette, PhD; and Jim Mortimer have no significant financial relationships to disclose. The following planners and managers, Jan Hixon, RN, BSN, MA; Trace Hutchison, PharmD; Julia Kimball, RN, BSN; Samantha Mattiucci, PharmD; Jan Schultz, RN, MSN, CCMEP; and Patricia Staples, MSN, NP-C, CCRN, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

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8. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Goal The goal of this activity is to provide participants with practical approaches on managing patients with HER2-positive metastatic breast cancer. Target Audience This program is intended for physicians and other healthcare providers who care for patients with breast cancer. Learning Objectives At the conclusion of this activity, participants should be able to:  Distinguish between the mechanisms of action and rationale for HER2-targeting approaches that have demonstrated efficacy in patients with HER2-positive breast cancer  Select treatment plans for patients with HER2-positive metastatic breast cancer based on available data on best management approaches  Formulate treatment approaches for women with breast cancer that progresses after treatment with HER2-targeted therapy  Discuss with patients agents in development for the treatment of HER2-positive metastatic breast cancer for which clinical trials may be available

9. Case 1

10. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Case 1: Woman With MBC and No Previous Trastuzumab  Presentation: 58-yr-old woman was found to have architectural distortion in the right breast, upper outer quadrant, on routine screening mammography –Core needle biopsy confirmed invasive ductal carcinoma, estimated by imaging to be a T1 lesion  Treatment: She underwent lumpectomy/SLNB that revealed a 0.9-cm intermediate-grade invasive ductal carcinoma that was ER+/PgR+/HER2+ by FISH, with a Ki-67 value of 30% –2 sentinel nodes were removed and found to be uninvolved by cancer

11. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Case 1: Woman With MBC and No Previous Trastuzumab  Follow-up: She received adjuvant radiation therapy followed by letrozole for 1 yr, at which time she was seen by her oncologist for new cough and mild shortness of breath –CT scan of the chest revealed a mild right pleural effusion and several nodules up to 1 cm in size in the right, middle, and lower lobes –Biopsy revealed adenocarcinoma that was ER+/PgR-/HER2 3+ by IHC, consistent with breast primary –No other metastases were detected by CT or bone scan  There are no clinical trials available at your center for which she is eligible. You review multiple treatment options with her and she tells you she would like to take the treatment that has the highest chance of leading to a response and to a prolonged survival, as she recently found out her daughter is pregnant with her first grandchild

12. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Case 1: Woman With MBC and No Previous Trastuzumab What treatment option would you recommend at this time? A.Trastuzumab plus chemotherapy B.Trastuzumab plus aromatase inhibitor C.Lapatinib plus capecitabine D.Single-agent aromatase inhibitor E.Trastuzumab single agent

13. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Case 1: Woman With MBC and No Previous Trastuzumab What treatment option would you recommend at this time? A.Trastuzumab plus chemotherapy (preferred choice) B.Trastuzumab plus aromatase inhibitor C.Lapatinib plus capecitabine D.Single-agent aromatase inhibitor E.Trastuzumab single agent

14. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Normal (1x) ~ 25,000-50,000 HER2 receptors Overexpressed HER2 (10-100x) up to ~ 2,000,000 HER2 receptors Excessive cellular division HER2 Overexpression in Breast Cancer Pegram MD, et al. Cancer Treat Res. 2000;103:57-75. Ross JS, et al. Am J Clin Pathol. 1999;112(suppl 1):S53-S71. Slamon DJ, et al. Science. 1987;235:177-182. HER2 is overexpressed in ~ 25% of breast cancers

15. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer HER2 Overexpression Shortens Survival HER2 oncogene amplification HER2 oncoprotein overexpression Shortened survival Median Survival From First Diagnosis HER2 overexpressing3 yrs HER2 normal6-7 yrs Slamon DJ, et al. Science. 1987;235:177-182. Slamon DJ, et al. Science. 1989;244:707-712.

16. HER2-Targeted Agents

17. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Burstein HJ, et al. N Engl J Med. 2005;353:1652-1654. Trastuzumab: Mechanism of Action Copyright © 2005 Massachusetts Medical Society. All rights reserved.

18. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Single-Agent Trastuzumab in First-line Treatment of HER2+ MBC PatientsResponse Rate, %Median Time to Progression, Mos HER2+ by IHC (N = 111) 263.5 HER2+ by FISH (n = 79) 344.9 Vogel CL, et al. J Clin Oncol. 2002; 20:719-726.

19. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Trastuzumab Combinations as First-line Therapy for MBC: Pivotal Phase III Trial Patients with HER2+ (IHC 2+/3+) MBC, no previous chemotherapy, measurable disease, KPS ≥ 60% (N = 469) No previous adjuvant AC Paclitaxel (n = 96) Trastuzumab + Paclitaxel (n = 92) AC (n = 138) Trastuzumab + AC (n = 143) Previous adjuvant AC Slamon DJ, et al. N Engl J Med. 2001;344:783-792.

20. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Trastuzumab in MBC: The Pivotal Trial TreatmentObjective Response Rate, % Median TTP, MosMedian OS, Mos Chemo324.620.3 Chemo + Trastuzumab 507.425.1 Slamon DJ, et al. N Engl J Med. 2001;344:783-792. P <.001 for all 3 comparisons.

21. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Trastuzumab in Recommended First-line Combinations for HER2+ MBC  HER2+ disease without previous trastuzumab: trastuzumab plus –Paclitaxel ± carboplatin –Docetaxel –Vinorelbine –Capecitabine  HER2+ disease with previous trastuzumab: trastuzumab plus –Other first-line agents –Capecitabine –Lapatinib (without cytotoxic therapy) NCCN. Clinical practice guidelines in oncology: breast cancer. v2.2011.

22. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Addition of Carboplatin to Docetaxel/ Trastuzumab Does Not Improve Efficacy  BCIRG 007 phase III study (N = 263 patients with HER2-amplified MBC)  No significant differences seen in responses, survival, or TTP –Differences in docetaxel dose between 2 groups Valero V, et al. J Clin Oncol. 2011;29:149-156. OutcomeDocetaxel/Carboplatin/ Trastuzumab (n = 132) Docetaxel/Trastuzumab (n = 131) ORR, % 72  PR 5554  CR 1718 Median TTP, mos 10.3511.07 Median OS, mos 37.437.1

23. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Trastuzumab in Triple-Combination Regimens: Response Rates ORR (%) H + Carbo + T H + V + T H + E90 + C H + E60 + C H + Carbo + T H + V + X H + G + P H + G + Carbo H + G + P H + E + T H + Carbo + P every 3 wks H + Carbo + P every wk H + TLC D-99 + P H + Carbo + T H + Cisplatin + T H + Carbo + P H + X + T Forbes et al, 2006 (N = 130) Wardley et al, 2006 (N = 111) Robert et al, 2006 (N = 92) Pegram et al, 2004 (N = 62) Pegram et al, 2004 (N = 59) Yardley et al, 2002 (N = 61) Cortes et al, 2004 (N = 54) Perez et al, 2005 (N = 48) Perez et al, 2005 (N = 43) Venturini et al, 2006 (N = 45) Miller et al, 2002 (N = 45) Yardley et al, 2006 (N = 41) Fountzilas et al, 2004 (N = 40) Chan et al, 2007 (N = 34) Dirix et al, 2006 (N = 34) Untch et al, 2004 (N = 26) Untch et al, 2004 (N = 25) Yardley et al, 2004 (N = 24) 0102030405060708090100

24. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Hormonal Therapy in HER2+ MBC RegimenORR, %PFS, Mos Trastuzumab (N = 79) [1] 263.5-3.8 Anastrozole + trastuzumab (N = 103) [2] 204.8 Anastrozole (N = 104) [2] 72.4 Lapatinib + letrozole (N = 642) [3] 288.2 Letrozole (N = 644) [3] 153.0 Lapatinib (N = 138) [4] 24NA 1. Vogel C, et al. J Clin Oncol. 2002;20:719-726. 2. Mackey JR, et al. SABCS 2006. Abstract 3. 3. Johnston S, et al. J Clin Oncol. 2009;27:5538-5546. 4. Gomez HL, et al. J Clin Oncol. 2008;26:2999-3005.

25. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Lapatinib Blocks Signaling Through Multiple Receptor Combinations Downstream signaling cascade 1 + 1 2 + 2 1 + 2  Blocks signaling through ErbB1 and ErbB2 homodimers and heterodimers  Might also prevent signaling through heterodimers between these receptors and other ErbB family members  Potentially blocks multiple ErbB signaling pathways Lapatinib is indicated in MBC only for patients with progression after trastuzumab, anthracycline, and taxane treatment

26. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer  Patients (N = 138) randomized to 2 schedules of lapatinib monotherapy  Median time to response (all patients): 7.9 wks; median duration of response (all patients): 28.4 wks  Safety: only grade 1/2 asymptomatic cardiac adverse events (4 patients) Lapatinib as First-line Treatment for HER2- Amplified LABC or MBC EndpointLapatinib 1500 mg/day (n = 69) Lapatinib 500 mg BID (n = 69) All Patients (N = 138) Response rate, n (%)15 (22)18 (26)33 (24) Clinical benefit rate, n (%)20 (29)23 (33)43 (31) 6-mo PFS, %414543 Gomez HL, et al. J Clin Oncol. 2008;26:2999-3005.

27. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Recap Case 1: Woman With MBC and No Previous Trastuzumab What treatment option would you recommend as first-line therapy for the 58-year-old woman with MBC? A.Trastuzumab plus chemotherapy (preferred choice) B.Trastuzumab plus aromatase inhibitor C.Lapatinib plus capecitabine D.Single-agent aromatase inhibitor E.Trastuzumab single agent

28. Case 2

29. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Case 2: Woman With HER2+ MBC and Progression Following Trastuzumab  Background: 39-yr-old woman diagnosed with stage IIA, breast cancer in 2004 –2.6-cm tumor –ER+/PgR-/HER2+  Treatment: TAC for 6 cycles plus radiation therapy and tamoxifen  Follow-up: 1 yr after end of chemotherapy, she is found to have bone and lymph node metastases –Lymph node biopsy reveals the tumor is negative for hormone receptors (ER/PgR) and continues to overexpress HER2  Treatment: she receives 6 cycles of TCH and achieves CR –She continues on maintenance single-agent trastuzumab without progression for almost 2 yrs

30. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Case 2: Woman With HER2+ MBC and Progression Following Trastuzumab Scans reveal new liver metastases, and vinorelbine is added to trastuzumab. She has another CR that lasts 9 mos, at which time scans reveal progressive disease in the liver and bones. What treatment option would you recommend at this time? A.Switch to lapatinib/capecitabine B.Switch to lapatinib/trastuzumab C.Switch to trastuzumab and new chemotherapy D.Start chemotherapy without HER2-targeted therapy E.Switch to lapatinib alone

31. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Case 2: Woman With HER2+ MBC and Progression Following Trastuzumab Scans reveal new liver metastases, and vinorelbine is added to trastuzumab. She has another CR that lasts 9 mos, at which time scans reveal progressive disease in the liver and bones. What treatment option would you recommend at this time? A.Switch to lapatinib/capecitabine (preferred choice) B.Switch to lapatinib/trastuzumab (reasonable) C.Switch to trastuzumab and new chemotherapy D.Start chemotherapy without HER2-targeted therapy E.Switch to lapatinib alone

32. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer 12 Downstream signaling pathways Cell proliferation Cell survival 211 2 Trastuzumab T Lapatinib LLLLLL Erb receptors Mechanism of Action of Lapatinib Compared to Trastuzumab

33. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Patients with HER2+ progressive MBC or stage IIIB/IIIC LABC with T4 lesion and unlimited previous therapies*  Primary endpoint: TTP  Secondary endpoints: OS, PFS, ORR  Primary endpoint: TTP  Secondary endpoints: OS, PFS, ORR Lapatinib 1250 mg/day PO + Capecitabine 2000 mg/m 2 /day on Days 1-14 every 21 days Lapatinib 1250 mg/day PO + Capecitabine 2000 mg/m 2 /day on Days 1-14 every 21 days Capecitabine 2500 mg/m 2 /day on Days 1-14 every 21 days Capecitabine 2500 mg/m 2 /day on Days 1-14 every 21 days *No previous capecitabine and must have included trastuzumab (MBC) or anthracycline/taxane (MBC or adjuvant). Geyer C, et al. N Engl J Med. 2006;355:2733-2743. EGF100151 Phase III Study: Lapatinib + Capecitabine in Advanced Breast Cancer

34. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Lapatinib + Capecitabine in HER2+ MBC: TTP Cameron D, et al. Oncologist. 2010;15:924-934. TTP With 1 Previous Trastuzumab RegimenTTP With > 1 Previous Trastuzumab Regimen Capecitabine Lapatinib + capecitabine Cumulative Progression Free (%) 100 80 60 40 20 0 0 406080 Wks 100 80 60 40 20 0 0 406080 Wks Cumulative Progression Free (%) Capecitabine Lapatinib + capecitabine Reproduced with permission of The Oncologist, from Lapatinib plus capecitabine in women with HER-2–positive advanced breast cancer: Final survival analysis of a phase III randomized trial, Cameron D, et al., Vol 15, 2010; permission conveyed through Copyright Clearance Center, Inc.

35. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer ResultCapecitabine (n = 201) Capecitabine + Lapatinib (n = 207 † ) HRP Value Median TTP, wks [1] 18.631.30.50<.001 OS, wks [1] 56.671.40.79.077 ORR, % [2] 13.923.7--.017 Brain mets as site of first progression,* n (%) [2] 13 (6)4 (2)--.045 † n=198 in 2008 study. *Exploratory analysis. 1. Cameron D, et al. Oncologist. 2010;15:924-934 2. Cameron D, et al. Breast Cancer Res Treat. 2008;112:533-543. Lapatinib + Capecitabine in HER2+ MBC: Efficacy

36. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Combining Lapatinib and Trastuzumab Increases Antitumor Activity Scaltriti M, et al. Oncogene. 2009;28:803-814. Konecny GE, et al. Cancer Res. 2006;66:1630- 1639. Xia W, et al. Oncogene. 2004;23:646-653. Tumor Volume (mm 3 ) 1600 1400 1200 1000 800 600 400 200 0 1316192123 Days After Injection *P <.05; † P <.01 vs control; ‡ P <.05 vs trastuzumab; § P <.01 vs both lapatinib and trastuzumab. Control Trastuzumab Lapatinib Trastuzumab + lapatinib * * †‡ † † § Reprinted by permission from Macmillan Publishers Ltd: Oncogene; Scaltriti, et al. 28:803-814, copyright 2009.  Treatment with lapatinib plus trastuzumab resulted in complete tumor remission in mouse model –Effect was durable: no tumor relapse observed at 8 mos after treatment  Lapatinib induced accumulation of inactive HER2 at plasma membrane –Trastuzumab-mediated cytotoxicity was higher with the addition of lapatinib in MCF7/HER2 cells  In vivo activity was consistent with in vitro data demonstrating the combination as synergistic

37. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Blackwell KL, et al. J Clin Oncol. 2010;28:1124-1130. Staging occurred at 4, 8, 12, 16 weeks, and then every 8 weeks Steady state of single-agent lapatinib occurs at approximately 7 days Crossover allowed to lapatinib + trastuzumab if progression after at least 4 weeks on therapy 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 weekly (n = 148)  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 EGF104900 Phase III Study: Dual HER2 Blockade in MBC

38. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Lapatinib ± Trastuzumab in MBC: Efficacy OutcomeLapatinib, % (95% CI) (n = 145) Lapatinib/ Trastuzumab, % (95% CI) (n = 146) OR (95% CI) P Value ORR*6.9 (3.4-12.3) 10.3 (5.9-16.4) 1.5 (0.6-3.9).46 Clinical benefit rate † 12.4 (7.5-18.9) 24.7 (17.9-32.5) 2.2 (1.2-4.5).01 *Confirmed CR + PR. † Confirmed CR + PR + stable disease ≥ 6 mos. Blackwell KL, et al. J Clin Oncol. 2010;28:1124-1130.

39. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Lapatinib ± Trastuzumab in MBC: PFS OutcomeLapatinib (n = 145) Lapatinib/ Trastuzumab (n = 146) HR (95% CI) P Value 6-mos PFS, %1328 0.73 (0.57-0.93).008 Progressed or died, n128127 -- Median PFS, wks8.112.0-- Blackwell KL, et al. J Clin Oncol. 2010;28:1124-1130.

40. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer EGF104900: OS With Lapatinib ± Trastuzumab in MBC (ITT Population) OS Outcome L (n = 145) L + T (n = 146) Died, n (%)113 (78)105 (72) Median, mos9.514 HR (95% CI)0.74 (0.57-0.97) Log-rank P value.026 6 Month OS 80% 70% 12 Month OS 56% 41% Blackwell KL, et al. SABCS 2009. Abstract 61. Alive without Progression (Cumulative %) Patients at Risk, n 148 L L + T 121 102 88 65 64 47 43 28 25 13 0 20 40 60 80 100 051015202535 Mos From Randomization 1 30 L L + T

41. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Adverse Event (All Grades), %Lapatinib + Trastuzumab (n = 149) Lapatinib (n = 146) P Value Nausea28 NS Fatigue2119NS Diarrhea*6048.03 Rash2229NS *7% grade 3/4 events on each treatment arm. Cardiac Events † Lapatinib + Trastuzumab (n = 149) Lapatinib (n = 146) Total no. patients with events ‡  Symptomatic 8383 3232 Therapy related83 Deaths1§1§ 0 † Defined by ≥ 20% LVEF drop relative to baseline and below institution’s lower limits of normal. ‡ 2 patients had > 1 occurrence. § Cause of death: pulmonary thromboembolism. Blackwell KL, et al. J Clin Oncol. 2010;28:1124-1130. Lapatinib ± Trastuzumab in Heavily Pretreated MBC: Selected Adverse Events

42. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Trastuzumab Beyond Progression in HER2+ MBC: BIG 03-05 Phase III Trial Patients with progressive MBC or LABC, HER2 overexpression, previous trastuzumab within 6 wks, and LVEF ≥ 50 (N = 156*)  Primary endpoint: TTP  Secondary endpoints: OS, ORR, safety  Primary endpoint: TTP  Secondary endpoints: OS, ORR, safety Trastuzumab 6 mg/kg every 3 wks + Capecitabine 2500 mg/m 2 /day on Days 1-14 every 21 days (n = 78) Trastuzumab 6 mg/kg every 3 wks + Capecitabine 2500 mg/m 2 /day on Days 1-14 every 21 days (n = 78) Capecitabine 2500 mg/m 2 /day on Days 1-14 every 21 days (n = 78) Capecitabine 2500 mg/m 2 /day on Days 1-14 every 21 days (n = 78) *Study closed at 156 patients due to slow accrual following FDA approval of lapatinib for this indication. von Minckwitz G, et al. J Clin Oncol. 2009;27:1999-2009.

43. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer BIG 03-05: Trastuzumab Beyond Progression in HER2+ MBC Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. von Minckwitz G, et al. J Clin Oncol. 2009;27:1999-2009. PFS 1.0 0.8 0.6 0.4 0.2 0 Probability of PFS 010203040 Mos X XH Censored Log-rank P =.0338 Pts at Risk, n X XH 74 77 40 55 15 29 8 12 54543 212111 OS 1.0 0.8 0.6 0.4 0.2 0 Probability of OS 010203040 Mos X XH Censored Log-rank P =.2570 Pts at Risk, n X XH 74 77 66 68 50 59 33 47 21 27 10 15 3636 3131 2121

44. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Trastuzumab Beyond Progression in HER2+ MBC: Effect of Previous Treatment OutcomeCapecitabineCapecitabine + Trastuzumab HRP Value Median TTP, mos5.68.20.69.034 Median OS, mos20.425.50.76.26 ORR, %27.048.1--.012 CBR,* %54.175.3--.0068 *CBR: CR + PR + SD > 24 wks. Previous treatments (N = 156)  First-line taxane + trastuzumab (n = 111)  Trastuzumab alone or with other first-line chemotherapy (n = 42)  Taxane + trastuzumab as adjuvant therapy (n = 3) von Minckwitz G, et al. J Clin Oncol. 2009;27:1999-2009.

45. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Recap Case 2: Woman With HER2+ MBC and Progression Following Trastuzumab What treatment option would you recommend for the 39- year-old woman who has progressed following trastuzumab? A.Switch to lapatinib/capecitabine (preferred choice) B.Switch to lapatinib/trastuzumab (reasonable) C.Switch to trastuzumab and new chemotherapy D.Start chemotherapy without HER2-targeted therapy E.Switch to lapatinib alone

46. Case 3

47. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/Lapatinib  Presentation: 56-yr-old woman was diagnosed with stage III ER+/ PgR-/HER2+ breast cancer –Treatment: doxorubicin/cyclophosphamide and docetaxel/trastuzumab  Follow-up: 3 yrs after completing maintenance trastuzumab, she was diagnosed with bone and lung metastases –Treatment: docetaxel/trastuzumab  Follow-up: after achieving PR that lasted for 9 mos, she developed liver metastases –Treatment: lapatinib/capecitabine  Follow-up: she achieved SD for 6 mos, after which she developed lung and lymph node metastases

48. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/Lapatinib What treatment options do you feel are appropriate to consider for this patient at this time? A.Lapatinib/trastuzumab B.Enrollment in a trial evaluating a new agent for HER2+ breast cancer C.Trastuzumab plus bevacizumab D.Lapatinib/trastuzumab/chemotherapy E.Trastuzumab plus chemotherapy

49. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/Lapatinib What treatment options do you feel are appropriate to consider for this patient at this time? A.Lapatinib/trastuzumab (reasonable) B.Enrollment in a trial evaluating a new agent for HER2+ breast cancer (preferred choice) C.Trastuzumab plus bevacizumab D.Lapatinib/trastuzumab/chemotherapy E.Trastuzumab plus chemotherapy (reasonable)

50. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Highly potent cytotoxic agent Cytotoxic agent: DM1 Monoclonal antibody: Trastuzumab Target expression: HER2 Systemically stable Linker: SMCC T-DM1 Average drug:antibody ratio ≅ 3.5:1 Trastuzumab-DM1: Novel Antibody-Drug Conjugate Trastuzumab MCC DM1

51. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer T-DM1 Safety in MBC: Every-3-Wk and Weekly Schedules (Phase I Studies)  Safety profile was similar between every-3-wk and weekly schedules  MTD: determined for each schedule tested –Every-3-wk schedule: 3.6 mg/kg –Weekly schedule: 2.4 mg/kg  Efficacy: similar between every-3-wk and weekly schedules –15 patients treated at every-3-wk MTD (3.6 mg/kg) –Median PFS: 10.4 mos –Clinical benefit rate with every-3-wk schedule: (ORR + SD at 6 mos): 73% –Measurable disease: 9 patients; confirmed response rate in these patients was 44% Krop IE, et al. J Clin Oncol. 2010;28:2698-2704. Holden SN, et al. ASCO 2008. Abstract 1029.

52. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer T-DM1: Phase II Results in Previously Treated HER2+ MBC  Treatment: single-agent T-DM1 3.6 mg/kg every 3 wks 1. Burris HA, et al. J Clin Oncol. 2011;29:398-405. 2. Krop I, et al. SABCS 2009. Abstract 5090. OutcomeTDM4258 [1] (N = 112) TDM4374 [2] (N = 110) ORR, % 25.932.7 CBR, % 34.844.5 Median PFS, mos 5.37.3  Confirmed HER2+ 8.2-- Grade 3/4 AEs, %  Thrombocytopenia8.05.4  Fatigue4.52.7  Hypokalemia 8.9--

53. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Phase II Study of First-line T-DM1 vs Trastuzumab/Docetaxel in HER2+ MBC  No statistically significant differences between study groups  Primary endpoint: PFS  Secondary endpoints: ORR, CBR, OS, QoL, symptom control  Patients in trastuzumab/docetaxel arm allowed to cross over to T-DM1 on progression PD Perez EA, et al. ESMO 2010. Abstract LBA3. Stratified by region (US vs ROW), previous adjuvant trastuzumab, disease-free interval (≤ 24 mos vs > 24 mos) T-DM1 3.6 mg/kg q3w (n = 67) Trastuzumab 8 mg/kg dose → 6 mg/kg q3w followed by Docetaxel 75 or 100 mg/m 2 (n = 70) Patients with HER2+ MBC or recurrent LABC and no previous chemo for metastatic disease (N = 137)

54. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer First-line T-DM1 vs Trastuzumab/ Docetaxel in HER2+ MBC: Prior Treatment Previous Treatment, n (%)Trastuzumab + Docetaxel (n = 70) T-DM1 (n = 67) Trastuzumab  Yes  No 18 (25.7) 52 (74.3) 13 (19.4) 54 (80.6) Taxane  Yes  No 28 (40.0) 42 (60.0) 22 (32.8) 45 (67.2) Trastuzumab and/or taxane  Yes  No 31 (44.3) 39 (55.7) 24 (35.8) 43 (64.2) Perez EA, et al. ESMO 2010. Abstract LBA3.

55. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer First-line T-DM1 vs Trastuzumab/ Docetaxel in HER2+ MBC: Adverse Events Adverse Event, n (%)Trastuzumab + Docetaxel (n = 68) T-DM1 (n = 67) Any AE68 (100)63 (94.0) Grade ≥ 3 AE51 (75.0)25 (37.3) Serious AE*15 (22.1)13 (19.4) Most common AEs (any grade) on trastuzumab + docetaxel arm  Alopecia  Neutropenia  Diarrhea 45 (66.2) 39 (57.4) 31 (45.6) 1 (1.5) 5 (7.5) 7 (10.4) Most common AEs (any grade) on T-DM1 arm  Nausea  Fatigue  Pyrexia 27 (39.7) 29 (46.2) 14 (20.6) 32 (47.8) 31 (46.3) 24 (35.8) Perez EA, et al. ESMO 2010. Abstract LBA3. *Resulting in death, life threatening situation, in-patient hospitalization, prolongation of existing hospitalization, persistent or significant disability/incapacity, or birth defects.

56. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer First-line T-DM1 vs Trastuzumab/ Docetaxel in HER2+ MBC: Grade ≥ 3 AEs Grade ≥ 3 AEs, n (%)NCI CTCAE Grade Trastuzumab + Docetaxel (n = 68) T-DM1 (n = 67) Neutropenia 3434 6 (8.8) 30 (44.1) (0) Leukopenia 3434 12 (17.6) 5 (7.4) (0) Febrile neutropenia 3434 6 (8.8) 1 (1.5) (0) Pneumonia 3434 1 (1.5) 0 (0) 3 (4.5) 0 (0) Hypercalcemia 3434 (0) 1 (1.5) Thrombocytopenia31 (1.5)5 (7.5) Perez EA, et al. ESMO 2010. Abstract LBA3.

57. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Objective Response Rate, n/N (%; range) Trastuzumab + Docetaxel T-DM1 Overall population29/70 (41.4; 30.2-53.8)32/67 (47.8; 35.4- 60.3) Previous trastuzumab and/or taxane therapy 11/31 (35.5; 20.0-53.4)13/24 (54.2; 33.9-74.5) No previous trastuzumab and/or taxane therapy 18/39 (46.2; 30.1-61.7)19/43 (44.2; 29.5-60.1) Perez EA, et al. ESMO 2010. Abstract LBA3. First-line T-DM1 vs Trastuzumab/Docetaxel in HER2+ MBC: Efficacy Summary

58. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Phase III MARIANNE Study: T-DM1 ± Pertuzumab in HER2+ MBC  Primary endpoints: PFS as assessed by IRF, AEs –Superiority design with a noninferiority analyses –Interim futility analysis: option to drop experimental arm  Secondary endpoints: OS, TTF by IRF, ORR, CBR, DOR ClinicalTrials.gov. NCT01120184. PD Trastuzumab + Taxane (n = 364) T-DM1 + Pertuzumab (n = 364) T-DM1 + Placebo (n = 364) Patients with HER2+, previously untreated MBC (N = 1092)

59. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer EMILIA (TDM4370g) Phase III Study: T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC Patients with HER2+ locally advanced or metastatic breast cancer following treatment with a taxane and trastuzumab (N = 980) T-DM1 q3w (n = 490) Lapatinib + Capecitabine q3w (n = 490)  Primary endpoint: PFS by IRF, OS, safety  Secondary endpoints: QoL (FACT B), DOR, PFS by investigator assessment PD or unacceptable toxicity ClinicalTrials.gov. NCT00829166.

60. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Pertuzumab and Trastuzumab Bind to Distinct Extracellular HER2 Epitopes Hubbard SR. Cancer Cell. 2005;7:287-288. Pertuzumab-HER2 ComplexTrastuzumab-HER2 Complex Pertuzumab Dimerization domain Trastuzumab III II I  Inhibits HER2 dimerization with other HER family receptors (particularly HER3)  Activates ADCC  Inhibits multiple HER-mediated signaling pathways  Activates ADCC  Inhibits HER-mediated signaling pathways  Prevents HER2 domain cleavage III II I IV

61. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Phase II Trial of Pertuzumab + Trastuzumab in HER2+ MBC: Efficacy Responses were durable:  Median duration of response: 5.8 mos  Median PFS (all patients): 5.5 mos Baselga J, et al. J Clin Oncol. 2010;28:1138-1144. 60 50 30 20 10 0 Patients (%) All Patients (N = 66) 40 SD PR CR

62. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer CLEOPATRA Phase III Trial: Trastuzumab + Docetaxel ± Pertuzumab in HER2+ MBC  Primary endpoint: PFS (IRF evaluation)  Secondary endpoints: OS, incidence of CHF and LVEF events, safety Patients with HER2+ MBC and no previous treatment for metastatic disease (N = 808) Docetaxel 75 mg/m 2 + Trastuzumab 8 mg/kg → 6 mg/kg + Placebo q3w Docetaxel 75 mg/m 2 + Trastuzumab 8 mg/kg → 6 mg/kg + Pertuzumab 840 mg → 420 mg q3w ClinicalTrials.gov. NCT00567190.

63. mTOR Inhibitors

64. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Widakowich C, et al. Anticancer Agents Med Chem. 2008;8:488-496. Miller TW, et al. Clin Cancer Res. 2009;15:7266-7276. mTOR AKT AMPK TSC1 TSC2 PTEN LKB1 PI3K RHEB IGF-1R EGFR/HER2 Increased signaling through IGF-1R Constitutive PI3K/AKT activation Elevated AKT or pAKT Absent or low PTEN Truncated HER2 Nutrients mTOR inhibitor Growth & proliferation Angiogenesis Cell metabolism  Downstream inhibition with mTOR inhibitor counters these resistance mechanisms  Synergy of mTOR inhibition and trastuzumab in vitro and in vivo mTOR Inhibition May Overcome Trastuzumab Resistance

65. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Andre F, et al. J Clin Oncol. 2010;28:5110-5115.  Women with HER2- overexpressing MBC and progression after trastuzumab, WHO PS 0-1 –Previous exposure to lapatinib allowed –Unrestricted number of previous antineoplastic therapy lines (N = 33) Endpoints: safety, tumor response, cardiac toxicity Everolimus: 5 mg → 2.5 or 10 mg/day, or 30 mg → 20, 50, or 70 mg/wk Trastuzumab: 4 mg/kg → 2 mg/kg/wk Paclitaxel: 80 mg/m 2 on Days 1, 8, 15, every 4 wks Everolimus, Trastuzumab, and Paclitaxel in HER2+ MBC (J2101 Phase I Study)

66. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Characteristic, %Patients (N = 33) Visceral disease73 Trastuzumab resistant97 Taxane pretreated  Taxane resistant 94 39 Resistant to lapatinib48 Pretreated with anthracyclines73 Prior endocrine treatment70 Andre F, et al. J Clin Oncol. 2010;28:5110-5115. Everolimus, Trastuzumab, and Paclitaxel in HER2+ MBC: Baseline Characteristics

67. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Response/Outcome, n (%) Everolimus Dose 5 mg/day (n = 5) 10 mg/day (n = 13) 30 mg/wk (n = 9) All (N = 27) Objective response5 (100)4 (31)3 (33)12 (44) CR1 (20)1 (8)0 (0)2 (7) PR4 (80)3 (23)3 (33)10 (37) Clinical benefit rate (CR + PR + SD ≥ 24 wks) 5 (100)8 (61)7 (78)20 (74) Worse patient characteristics in 10-mg arm vs 5-mg arm  More visceral disease (82% vs 50%)  Median number of previous treatments (3 vs 2 [range: 1-6 vs 0-4])  More patients ongoing (7 vs 1) Andre F, et al. J Clin Oncol. 2010;28:5110-5115. Everolimus, Trastuzumab, and Paclitaxel in HER2+ MBC (J2101): Antitumor Activity

68. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Everolimus, Trastuzumab, and Paclitaxel in HER2+ MBC (J2101): PFS RegimenMedian PFS, Wks95% CI Daily33.023.7-NA Weekly40.730.0-NA Overall34.029.1-40.7 Andre F, et al. J Clin Oncol. 2010;28:5110-5115.

69. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer BOLERO-1 Phase III Study: Paclitaxel + Trastuzumab  Everolimus in HER2+ MBC Patients with HER2- overexpressing, unresectable locally advanced or metastatic breast cancer, no previous trastuzumab or chemotherapy within 12 mos for advanced disease (N = 717) Everolimus 10 mg/day PO + Paclitaxel 80 mg/m 2 on Days 1, 8, 15 + Trastuzumab 4 mg → 2 mg/kg on Days 1, 8, 15, 22 Paclitaxel 80 mg/m 2 on Days 1, 8, 15 + Trastuzumab 4 mg → 2 mg/kg on Days 1, 8, 15, 22 + Placebo PO daily  Primary endpoint: PFS  Secondary endpoints: OS, ORR, CBR, safety, PK, biomarkers Stratification by previous adjuvant or neoadjuvant trastuzumab and presence of visceral metastases ClinicalTrials.gov. NCT00876395. 2:1 28-day cycle

70. Targeting Angiogenesis

71. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Angiogenesis in MCF-7 Spheroids: Day 14 MCF-7 Neo: 3.5 x mag.  Mature vasculature  No vessel buds  Development stopped MCF-7 Neo: 3.5 x mag.  Mature vasculature  No vessel buds  Development stopped MCF-7 HER-2/neu: 10 x mag.  High number mature vessels  Vessel buds in center of tumor  Vasculature still growing MCF-7 HER-2/neu: 10 x mag.  High number mature vessels  Vessel buds in center of tumor  Vasculature still growing

72. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Pegram MD, et al. Breast Cancer Res Treat. 2004;88(suppl 1):S124. Phase I/II Trial of Trastuzumab + Bevacizumab in Relapsed/MBC  Investigator-initiated, investigator held IND  First report of 2 humanized MAbs in human subjects  Primary endpoints: PK and safety Phase I Cohort 1 (n = 3) Trastuzumab qw + Bevacizumab 3 mg/kg on Day 7, then q2w Cohort 2 (n = 3) Trastuzumab qw + Bevacizumab 5 mg/kg on Day 7, then q2w Cohort 3 (n = 3) Trastuzumab qw + Bevacizumab 10 mg/kg on Day 7, then q2w* *RP2D HER2+ (FISH+) (N = 9)

73. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer PK/Toxicity/Efficacy Data in 9 Patients  No change in PK of either antibody when used as combination  No untoward toxicity induced by combination –1 patient with mild increased blood pressure –1 patient with decreased LVEF  Response –1 CR –4 PRs –2 SDs > 11 mos –2 PDs Pegram MD, et al. Breast Cancer Res Treat. 2004;88(suppl 1):S124.

74. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Trastuzumab 4 mg/kg  2 mg/kg qw + Bevacizumab q14d Trastuzumab 4 mg/kg  2 mg/kg qw + Bevacizumab q14d Trastuzumab 4 mg/kg  2 mg/kg qw + Bevacizumab dose escalation (n = 24) 3 mg/kg  5 mg/kg  10 mg/kg IV on Day 7, then q14d Trastuzumab 4 mg/kg  2 mg/kg qw + Bevacizumab dose escalation (n = 24) 3 mg/kg  5 mg/kg  10 mg/kg IV on Day 7, then q14d Phase I/II Trial of Trastuzumab and Bevacizumab in Relapsed/MBC (TORI B03) Inclusion Criteria:  LABC or MBC  HER2+ by FISH  ECOG 0-1  > 18 yrs of age  LVEF WNL Hypothesis: Upregulation of VEGF in HER2+ MBC contributes to the aggressive phenotype of HER2+ MBC. The “angiogenic switch” modulated by trastuzumab can be exploited in the clinic by combined blockade of these 2 “linked” pathways Study endpoints 1.Clinical safety 2.Pharmacokinetics 3.Efficacy Pegram MD, et al. SABCS 2006. Abstract 301.

75. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Phase II Trial of Trastuzumab and Bevacizumab in Relapsed/MBC (TORI B03)  No change in PK of either antibody when used as combination in phase I; currently being tested in phase II  Toxicity –1 patient with grade IV decreased LVEF and CHF –1 patient with gastric perforation  Response: ORR 48% –2 CR –22 PRs (many with continued response → ? CR) –15 SDs (out to minimum of 24 wks) –5 PDs  Median TTP: 7.1 mos (95% CI: 5.5-12.9)  Median OS: 43.8 mos (95% CI: 40.6-not reached)  Clinical benefit: 86% Hurvitz, S, et al. SABS 2009. Poster 6094.

76. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer  Locally recurrent or MBC, HER2+  No previous chemotherapy for MBC  RT for metastatic bone pain relief only (N = 407)  Primary endpoint: PFS  Secondary outcomes: OS, OR, DR, TTF, QoL, safety/tolerability Trastuzumab 8 mg/kg IV loading dose, 6 mg/kg IV q3w + Docetaxel 100 mg/m 2 IV q3w Trastuzumab 8 mg/kg IV loading dose, 6 mg/kg IV q3w + Bevacizumab 15 mg/kg IV q3w + Docetaxel 100 mg/m 2 IV q3w ClinicalTrials.gov. NCT00391092. AVEREL Phase III Study: Trastuzumab ± Bevacizumab in 1st-line HER2+ MBC

77. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer 6 x docetaxel and carboplatin 1 yr of trastuzumab TCHB (Group 1B) 1 yr of bevacizumab RT 6 x docetaxel and carboplatin 1 yr of trastuzumab TCH (Group 1A) RT BETH Phase III Study: Chemotherapy + Trastuzumab ± Bevacizumab  Primary endpoint: IDFS  Secondary endpoints: DFS, OS, RFI, DRFI, toxicity HER2+, N+ or high-risk N- Stratified by Ns and HRS (N ~ 3500) ClinicalTrials.gov. NCT00625898.

78. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer P P P P Cell growth, proliferation, survival, metastasis, angiogenesis Akt/PKB mTOR S6K1 PI3-K Lapatinib phase III Gefitinib phase II Everolimus phase III EGFR HER2 4E-BP1 elF-4E Protein synthesis Neratinib phase III Pertuzumab phase III Trastuzumab T-DM1 phase III P P P P PTEN VEGFR Sunitinib phase II Bevacizumab phase III VEGF Targeted Agents for HER2+ Breast Cancer

79. clinicaloptions.com/oncology New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Recap Case 3: Woman With HER2+ MBC, Relapse Following Trastuzumab/Lapatinib What treatment options do you feel are appropriate to consider for this 56-year-old woman who has relapsed? A.Lapatinib/trastuzumab (reasonable) B.Enrollment in a trial evaluating a new agent for HER2+ breast cancer (preferred choice) C.Trastuzumab plus bevacizumab D.Lapatinib/trastuzumab/chemotherapy E.Trastuzumab plus chemotherapy (reasonable)

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