1. Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer José Baselga, M.D., Ph.D., Javier Cortés, M.D., Sung-Bae Kim, M.D., Seock-Ah Im, M.D., Roberto Hegg, M.D.,Young-Hyuck Im, M.D., Laslo Roman, M.D., José Luiz Pedrini, M.D., Tadeusz Pienkowski, M.D.,Adam Knott, Ph.D., Emma Clark, M.Sc., Mark C. Benyunes, M.D., Graham Ross, F.F.P.M., Sandra M. Swain, M.D., for the CLEOPATRA Study Group N Engl J Med 2012;366:109-19. R2. Yujin Um / Prof. Sunkyung Beak Journal conference

2. BACKGROUND BACKGROUND 20% of all breast cancers gene amplification, Overexpression of HER2 (human epidermal growth factor receptor ) more aggressive phenotype a poor prognosis Treatment with Trastuzumab (anti-HER2 humanized monoclonal antibody) + chemotherapy improves progression-free and overall survival among patients with HER2- positive metastatic breast cancer N Engl J Med 2007;357:39-51. Figure 1. Signal Transduction by the HER Family and Potential Mechanisms of Action of Trastuzumab

3. BACKGROUND BACKGROUND Trastuzumab - binds to subdomain IV of the HER2 extracellular domain - antitumor effects by blocking HER2 cleavage stimulating antibody-dependent, cell-mediated cytotoxicity inhibiting ligand-independent, HER2- mediated mitogenic signaling.

4. BACKGROUND BACKGROUND HER2-positive metastatic breast cancer  disease progresses => the need for new targeted therapies for advanced disease.

5. BACKGROUND BACKGROUND Pertuzumab : Humanized monoclonal antibody : binds HER2 at a different epitope of the HER2 extracellular domain (subdomain II) : prevents HER2 from dimerizing with other ligand-activated HER receptors, most notably HER3 : stimulates antibody-dependent, cell-mediated cytotoxicity

6. BACKGROUND BACKGROUND pertuzumab and trastuzumab : bind to different HER2 epitopes : complementary mechanisms of action : given together => more comprehensive blockade of HER2 signaling => result in greater antitumor activity than either agent alone in HER2-positive tumor models pertuzumab–trastuzumab regimen : shown activity in patients with HER2-positive metastatic breast cancer in patients with early breast cancer

7. BACKGROUND BACKGROUND Clinical Evaluation of Pertuzumab and Trastuzumab study (CLEOPATRA) : assessed the efficacy and safety : as first-line treatment : for patients with HER2-positive metastatic breast cancer. pertuzumab + trastuzumab + docetaxel placebo + trastuzumab + docetaxel

8. METHODS METHODS Study Design randomized, double-blind, placebocontrolled, phase 3 trial HER2-positive metastatic breast cancer : not received chemotherapy or biologic therapy for their metastatic disease. primary end point - progression-free Survival : on the basis of the assessment of tumors at an independent review facility secondary end points : overall survival, progression-free survival

9. METHODS METHODS Patients Eligibility criteria 1) locally recurrent, unresectable, or metastatic HER2-positive breast cancer. 2) age of 18 years or older 3) left ventricular ejection fraction of 50% or more at Baseline 4) ECOG 0 or 1 HER2-positive status immunohistochemistrywith 3+ fluorescence in situ hybridization with an amplification ratio ≥2.0

10. METHODS METHODS Patients Exclusion criteria 1) therapy for metastatic breast cancer 2) central nervous system metastases 3) prior exposure to a cumulative dose of doxorubicin (> 360 mg per square meter of body-surface area ) 4) previous decline in the left ventricular ejection fraction to less than 50% during or after prior trastuzumab therapy 5) current uncontrolled medical conditions - limit a patient’s ability to undertake study therapy.

11. METHODS METHODS Procedures Trastuzumab loading dose8 mg per kilogram of body weight maintenance dose6 mg per kilogram every 3 weeks until disease proression, Docetaxel starting dose75 mg per square Meter Every 3 weeks maintenance doseincreased to 100 mg per square meter if the drug had toxic effectsreduce the dose by 25%, Pertuzumab fixed loading dose840 mg until disease progression420 mg every 3 weeks

12. RESULTS RESULTS Table 1. Baseline Characteristics of the Intention-to-Treat Population Study Population control grouppertuzumab group

13. RESULTS RESULTS Table 1. Baseline Characteristics of the Intention-to-Treat Population Study Population

14. RESULTS RESULTS Figure 1. Progression-free Survival, as Assessed at an Independent Review Facility. Progression-free Survival

15. RESULTS RESULTS Figure 1. Progression-free Survival, as Assessed at an Independent Review Facility. Progression-free Survival

16. RESULTS RESULTS Figure 2. Overall Survival. Key Secondary Efficacy End Points

17. RESULTS RESULTS Table 2. Overall Response, as Assessed at an Independent Review Facility Key Secondary Efficacy End Points

18. RESULTS RESULTS Table 2. Overall Response, as Assessed at an Independent Review Facility Side-Effect Profile and Cardiac Safety

19. CONCLUSIONS CONCLUSIONS The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects.