Nuovo paradigma terapeutico nel trattamento del carcinoma mammario HER2+ metastatico: dagli studi alla pratica clinica Prima linea di trattamento

Nuovo paradigma terapeutico nel trattamento del carcinoma mammario HER2+ metastatico: dagli studi alla pratica clinica Prima linea di trattamento Prof. Sabino De Placido Dip. di Endocrinologia ed Oncologia Molecolare e Clinica Università Federico II --- Napoli, Italia

La terapia anti HER2 nel carcinoma mammario Come ha cambiato la storia naturale?

Overall Survival Probability Overall Survival by Trastuzumab Treatment Groups 1.0 0.8 HER2+ / Herceptin Negative No Trastuzumab Trastuzumab 0.6 0.4 HER2-0.2 HER2+ / No Herceptin 0.0 0 12 24 36 48 60 Months from Diagnosi

Trials of 1st-Line HER2+ MBC with Anti-HER2 Based Rx Author Trial Name Agent(s) No. of Pts RR (%) Median TTP (months) Median OS (months) Slamon et al H0684g Paclitaxel Paclitaxel + trastuzumab 96 92 17 41 3 6.9 18.4 22.1 Slamon et al H0648g Chemotherapy* Chemotherapy* + trastuzumab 234 235 32 50 4.6 7.4 20.3 25.1 Marty et al Docetaxel Docetaxel + trastuzumab 92 94 34 61 6.1 11.7 22.7 31.2 Perez et al N983252 Paclitaxel (q3w) + carboplatin + trastuzumab Paclitaxel (qw) + carboplatin + trastuzumab 43 48 68 81 9.9 13.8 27 38 Robert et al Paclitaxel + trastuzumab Paclitaxel + trastuzumab + carboplatin 94 92 36 52 7.1 10.7 32.2 35.7 Valero et al BCIRG 007 Docetaxel + trastuzumab Docetaxel + carboplatin + trastuzumab 131 132 72.7 72.5 11.07 10.35 37.1 37 Wardley et al CHAT Docetaxel. trastuzumab Docetaxel + capecitabine + trastuzumab 110 112 72.7 70.5 12.8 17.9 (2-yr: 66% 2 yr: 75%) Andersson et al HERNATA Docetaxel + trastuzumab Vinorelbine + trastuzumab 143 141 59 59 12.4 15.3 35.7 38.8 Guan Z et al EGF-104535 Paclitaxel Paclitaxel + lapatinib 222 222 50 69 6.5 9.7 20.5 27.8

Probabilità di sopravvivenza Probabilità di sopravvivenza Efficacia di Herceptin con Chemioterapia In pazienti HER2 positiva 3+ ad immunoistochimica 1.0 0.9 0.8 Herceptin + chemioterapia Chemioterapia 1.0 0.9 0.8 Herceptin + Paclitaxel Paclitaxel 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.0 20 29 0 10 20 30 40 50 0.1 0.0 18 25 0 10 20 30 40 50 Tempo (mesi) Tempo (mesi)

Estimated probability M77001: estimated survival 1.0 Herceptin + docetaxel Docetaxel alone 0.8 0.6 0.4 p=0.0002 18.3 27.7 0.2 0 0 3 6 9 12 15 18 21 24 27 30 Months Documented crossover = 44% 9.4 months

HERNATA Study

HERNATA study : results Time to Progression Overall Survival Andersson JCO 2010

HERNATA study: results Time to Treatment Failure Andersson JCO 2010

HERNATA study : safety profile Andersson JCO 2010

Probability First Line Single Agent Herceptin Time To Progression 1 Responders 0,8 0,6 Non Responders 0,4 0,2 0 10 20 30 40 months

Mechanisms of resistance to HER2 directed therapy Loss of trastuzumab binding -(e.g. downregulation of HER expression) Activation of alternative growth factor - (e.g. IGF-1R) Activation of downstream signaling pathways -(e.g. PI3-Kinase)

HER2:HER3 dimers have the strongest mitogenic signalling Homodimers Heterodimers HER2:HER2 HER1:HER1 HER3:HER3 HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4 HER2:HER3 HER2:HER4 HER3:HER4 + + + + + + + + Signalling activity Tzahar, et al. Mol Cell Biol 1996

Potential new approaches to target HER2-positive breast cancer

San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Pertuzumab and trastuzumab have complementary mechanisms of action HER2 Pertuzumab Trastuzumab HER1/3/4 Subdomain IV Dimerization domain Trastuzumab: Inhibits ligand-independent HER2 signaling Activates ADCC Prevents HER2 ECD shedding ADCC, antibody-dependent cell-mediated cytotoxicity; ECD, extracellular domain Pertuzumab: Inhibits ligand-dependent HER2 dimerization and signaling Activates ADCC Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 17

Pertuzumab binds to the dimerisation domain of HER2, prevents HER2 forming dimer pairs and may flag cells for destruction by the immune system HER2 HER3 RAS Raf GSK3 MEK mtor Cyclin D1 BAD NF B MAPK p27 apoptosis cell cycle control survival angiogenesis proliferation

Study design San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 n=406 Placebo + trastuzumab PD Patients with HER2-positive MBC centrally confirmed (N = 808) 1:1 Docetaxel* 6 cycles recommended Pertuzumab + trastuzumab PD n=402 Docetaxel* 6 cycles recommended Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not) Study dosing q3w: Pertuzumab/Placebo: Trastuzumab: Docetaxel: 840 mg loading dose, 420 mg maintenance 8 mg/kg loading dose, 6 mg/kg maintenance 75 mg/m 2, escalating to 100 mg/m 2 if tolerated * <6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion MBC, metastatic breast cancer; PD, progressive disease Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 19

Study endpoints San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Primary endpoint Independently assessed progression-free survival (PFS) Secondary endpoints PFS by investigator assessment Objective response rate Overall survival Safety Duration of response Evaluation of biomarkers and correlation with clinical outcomes Time to symptom progression Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 20

San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Prior therapy for breast cancer Prior (neo)adjuvant chemotherapy, n (%) Yes No Placebo + trastuzumab + docetaxel (n = 406) 192 (47.3) 214 (52.7) Pertuzumab + trastuzumab + docetaxel (n = 402) 184 (45.8) 218 (54.2) Components of (neo)adjuvant therapy*, n (%) Anthracycline Hormones Taxane Trastuzumab 164 (40.4) 97 (23.9) 94 (23.2) 41 (10.1) 150 (37.3) 106 (26.4) 91 (22.6) 47 (11.7) * Numbers add up to more than 100% because patients could have received more than one therapy Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 21

San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Efficacy results Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute.

Progression-free survival (%) San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Primary endpoint: Independently assessed PFS n = 433 PFS events 100 90 80 70 60 50 40 30 20 10 0 n at risk Ptz + T + D Pla + T + D 0 5 10 15 20 25 30 35 40 402 345 267 139 83 32 10 0 0 406 311 209 93 42 17 7 0 0 D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Ptz + T + D: median 18.5 months Pla + T + D: median 12.4 months Time (months) = 6.1 months HR = 0.62 95% CI 0.51 0.75 p<0.0001 Stratified by prior treatment status and region Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 23

Progression-free survival (%) San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Independently and investigator-assessed PFS 100 90 80 70 60 50 40 30 20 10 0 Pertuzumab + T + D Placebo + T + D Pertuzumab + T + D Placebo + T + D 0 5 10 15 20 25 30 35 40 D, docetaxel; PFS, progression-free survival; T, trastuzumab Independently assessed Investigator-assessed Independent assessment Investigator assessment HR = 0.62 95% CI, 0.51 0.75; p<0.0001 HR = 0.65 95% CI, 0.54 0.78; p<0.0001 Time (months) Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 24

San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Independently assessed PFS in predefined subgroups Favors pertuzumab Favors placebo n HR 95% CI Prior (neo)adjuvant chemotherapy Region Age group Race All No Yes Europe North America South America Asia <65 years 65 years <75 years 75 years White Black Asian Other 808 0.63 0.52 0.76 432 0.63 0.49 0.82 376 0.61 0.46 0.81 306 0.72 0.53 0.97 135 0.51 0.31 0.84 114 0.46 0.27 0.78 253 0.68 0.48 0.95 681 0.65 0.53 0.80 127 0.52 0.31 0.86 789 0.64 0.53 0.78 19 0.55 0.12 2.54 480 0.62 0.49 0.80 30 0.64 0.23 1.79 261 0.68 0.49 0.95 37 0.39 0.13 1.18 Disease type ER/PgR status HER2 status Visceral disease Non-visceral disease Positive Negative Unknown IHC 3+ FISH-positive 630 0.55 0.45 0.68 178 0.96 0.61 1.52 388 0.72 0.55 0.95 408 0.55 0.42 0.72 12 721 0.60 0.49 0.74 767 0.64 0.53 0.78 0 0.2 0.4 0.6 1 2 Unstratified analyses ER, estrogen receptor; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; PgR, progesterone receptor; PFS, progression-free survival Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 25

San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Independently assessed PFS by prior trastuzumab therapy in patients with (neo)adjuvant therapy Prior (neo)adjuvant trastuzumab treatment (n = 88) No prior (neo)adjuvant trastuzumab treatment (n = 288) Placebo + trastuzumab + docetaxel Median PFS, months Pertuzumab + trastuzumab + docetaxel Median PFS, months 10.4 16.9 12.6 21.6 Hazard ratio (CI) 0.62 (0.35 1.07) 0.60 (0.43 0.83) PFS, progression-free survival Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 26

San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Independently reviewed objective response In patients with measurable disease at baseline Objective response rate, n (%) Complete response rate, n (%) Partial response rate, n (%) Placebo + trastuzumab + docetaxel (n = 336) 233 (69.3) 14 (4.2) 219 (65.2) Pertuzumab + trastuzumab + docetaxel (n = 343) 275 (80.2) 19 (5.5) 256 (74.6) p = 0.0011* Stable disease, n (%) 70 (20.8) 50 (14.6) Progressive disease, n (%) 28 (8.3) 13 (3.8) Unable to assess or no assessment, n (%) * The statistical test result is deemed exploratory 5 (1.5) 5 (1.5) Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 27

Overall survival (%) San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Overall survival: Predefined interim analysis Median follow-up: 19.3 months, n = 165 OS events 100 90 80 70 60 50 HR = 0.64* 95% CI 0.47 0.88 p = 0.0053* 40 30 20 10 Ptz + T + D: 69 events Pla + T + D: 96 events 0 0 5 10 15 20 25 30 35 40 45 n at risk Time (months) Pertuzumab + T + D 402 387 367 251 161 87 31 4 0 0 Placebo + T + D 406 383 347 228 143 67 24 2 0 0 * The interim OS analysis did not cross the pre-specified O Brien-Fleming stopping boundary (HR 0.603; p 0.0012) D, docetaxel; OS, overall survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 28

San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Safety results Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute.

Cardiac tolerability San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Placebo + trastuzumab + docetaxel (n = 397) Pertuzumab + trastuzumab + docetaxel (n = 407) Investigator-assessed symptomatic LVSD* Independently adjudicated symptomatic LVSD* Fall in LVEF to <50% and by 10 percentage points from baseline 1.8% 1.0% 1.0% 1.0% 6.6% 3.8% * LVSD was defined as NYHA class III/IV LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 30

San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Summary and conclusions CLEOPATRA met its primary endpoint and demonstrated a statistically significant and clinically meaningful improvement in PFS (HR = 0.62) in patients with HER2-positive MBC Median PFS increased by 6.1 months from 12.4 to 18.5 months The PFS improvement was consistent across subgroups and supported by the secondary endpoints of ORR and OS (immature) The combination of pertuzumab and trastuzumab plus docetaxel increased rates of diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin These adverse events were primarily grades 1 2, manageable, and occurred during docetaxel therapy There was no increase in cardiac adverse events or LVSD This new regimen may be practice-changing in HER2-positive first-line MBC Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 31

M77001 & Cleopatra Docetaxel Docetaxel + Tras Docetaxel + Tras Docetaxel + Tras + Pert CR 2% 7% 4% 5.5% PR 32% 54% 65% 75% PD 15% 12% 8% 4% Median TTP (mos) Median OS (mos) 5.7 11 12 18.5 22 30.5 38 >40

This new regimen may be practicechanging in HER2-positive first-line MBC Docetaxel + Trastuzumab or Paclitaxel + Trastuzumab Old Standard of Care Docetaxel + Trastuzumab + Pertuzumab New Standard of Care

Optimal Therapy in Metastatic Breast- Cancer Do all patients need chemotherapy?

TANDEM : Anastrazole +/- Trastuzumab in HER2+/ER+ MBC

EGF30008: Lapatinib plus Letrozole in first line HER2/HR+ MBC Johnston S. et al, JCO

Tumor Volumes (mm3) Effect of HER Family Inhibitors on Tam-Stimulated Growth 800 600 400 E2 Tam Tam+P Complete Responses Tam+P 5/18 Tam+P+T 12/18 Tam+P+T+G 18/20 200 0 Tam+P+T Tam+P+T+G 1 21 42 63 84 105 126 147 168 189 209 Days Arpino, JNCI 2007

PERTAIN: Phase II trial of pertuzumab in combination with trastuzumab plus an aromatase inhibitor in first line HER2+/HR+MBC

PERTAIN: recruitment status

Data Driven Practice 1. Most active therapy appears to be a combination of chemothrapy + anti-her2 therapy 2. Most active anti-her2 therapy appears to be a combination of a combination of agents (Trastuzumab + Pertuzumab) 3. Sensitivity to anti-her2 therapies remains despite progression after an anti-her2 agent Similarities to endocrine agents

The Future.

Trastuzumab emtansine (T-DM1): the first-inclass HER2-targeted antibody-drug conjugate Target expression: HER2 Monoclonal antibody: trastuzumab Cytotoxic agent: DM1 Highly potent chemotherapy (maytansine derivative) Linker Systemically stable Breaks down in target cancer cell T-DM1 42

Study Design TDM4450g: ongoing Phase II study of T-DM1 vs trastuzumab + docetaxel in first-line HER2-positive MBC HER2-positive, recurrent locally advanced breast cancer or MBC (N=137) 1:1 Trastuzumab 8 mg/kg loading dose; 6 mg/kg q3w IV + Docetaxel 75 or 100 mg/m 2 q3w (n=70) T-DM1 3.6 mg/kg q3w IV (n=67) PD a PD a Crossover to T-DM1 (optional) Randomized, phase II, international, open-label study b Stratification factors: World region, prior adjuvant trastuzumab therapy, disease-free interval Primary end points: PFS by investigator assessment, and safety Data analyses were based on clinical data cut of Nov 15, 2010 prior to T-DM1 crossover Key secondary end points: OS, ORR, DOR, CBR, and QOL a Patients were treated until PD or unacceptable toxicity. b This was a hypothesis generating study; the final PFS analysis was to take place after 72 events had occurred. 43

Proportion progression-free Progression-Free Survival by Investigator Randomized Patients 1.0 0.8 Trastuzumab + docetaxel (n=70) T-DM1 (n=67) Median PFS, mos 9.2 14.2 Hazard ratio 0.594 95% CI 0.364 0.968 Log-rank P value 0.0353 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 Time (months) Number of patients at risk T+D 70 66 63 53 43 27 12 4 2 2 0 T-DM1 67 60 51 46 42 35 22 15 6 3 0 Hazard ratio and log-rank P value were from stratified analysis. 44

Proportion progression-free Duration of Response by Investigator Patients with Measurable Disease at Baseline with an Objective Response 1.0 0.8 Trastuzumab + docetaxel (n=40) T-DM1 (n=43) Median DOR, mos 95% CI 9.5 6.6 10.6 NR a 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 18 Duration of objective response (months) Number of patients at risk T+D 40 40 38 32 19 8 2 1 1 0 T-DM1 43 41 38 33 27 19 12 6 3 0 Kaplan-Meier estimates are shown. a NR, not reached; longer follow-up is needed to estimate the duration of response in the T-DM1 arm. 45

Incidence of Hematologic Adverse Events: 30% (All Grade) and/or 5% (Grade 3) of Patients a AE Trastuzumab + docetaxel (n=66) c All grade, n (%) Grade 3 b, n (%) T-DM1 (n=69) c,d Trastuzumab + docetaxel (n=66) c T-DM1 (n=69) c,d Neutropenia e 42 (63.6) 12 (17.4) 40 (60.6) 4 (5.8) Febrile neutropenia 9 (13.6) 0 9 (13.6) 0 Thrombocytopenia e 4 (6.1) 21 (30.4) 2 (3.0) f 6 (8.7) f Leukopenia e 18 (27.3) 6 (8.7) 17 (25.8) 0 Green represents those AEs with 20% difference between treatment arms. a In either treatment arm. b No adverse events listed were grade 5. c Two patients mistakenly received a dose of T-DM1 and were thus included in the T-DM1 arm for safety analyses. d Includes 3 patients who received at least 1 dose of trastuzumab alone or trastuzumab plus docetaxel. e Neutropenia includes events classified as MedDRA preferred terms neutropenia or neutrophil count decreased; thrombocytopenia includes events classified as MedDRA preferred terms thrombocytopenia, platelet count decreased or heparin-induced thrombocytopenia; leukopenia includes events classified as MedDRA preferred terms leukopenia or white blood cell count decreased. f All of these events were grade 3. 46

Incidence of Nonhematologic Adverse Events: 30% (All Grade) and/or 5% (Grade 3) of Patients a AE Trastuzumab + docetaxel (n=66) c Green represents those AEs with 20% difference between treatment arms. All grade, n (%) Grade 3 b, n (%) T-DM1 (n=69) c,d Trastuzumab + docetaxel (n=66) c T-DM1 (n=69) c,d Alopecia 44 (66.7) 3 (4.3) e e Fatigue 30 (45.5) 34 (49.3) 3 (4.5) 3 (4.3) Nausea 29 (43.9) 33 (47.8) 0 2 (2.9) Diarrhea 30 (45.5) 11 (15.9) 2 (3.0) 0 Peripheral edema 29 (43.9) 7 (10.1) 3 (4.5) 0 Increased AST 4 (6.1) 27 (39.1) 0 6 (8.7) Pyrexia 15 (22.7) 27 (39.1) 1 (1.5) 0 Headache 12 (18.2) 25 (36.2) 0 0 Back pain 20 (30.3) 18 (26.1) 3 (4.5) 1 (1.4) Increased ALT 4 (6.1) 16 (23.2) 0 6 (8.7) Pneumonia 1 (1.5) 6 (8.7) 0 4 (5.8) a In either treatment arm. b No adverse events listed were grade 5. c Two patients mistakenly received a dose of T-DM1 and were thus included in the T-DM1 arm for safety analyses. d Includes 3 patients who received at least 1 dose of trastuzumab alone or trastuzumab plus docetaxel. e National Cancer Institute Common Terminology Criteria for Adverse Events v.3 only categorizes alopecia as grade 1 or grade 2; there is no grade 3 for this AE. 47

Cardiac Safety Cardiac function was assessed locally and centrally based on cardiac ECHO/MUGA Prior anthracycline in the adjuvant setting was 44.8% and 48.6% in the T-DM1 and trastuzumab + docetaxel arms, respectively Asymptomatic LV dysfunction Local assessment LVEF assessment Trastuzumab + docetaxel T-DM1 Patients assessed 65 67 Patients with post-baseline LVEF 40% 2 a 0 Central assessment Patients assessed 60 65 Patients with post-baseline LVEF 40% 1 b 0 There were no clinically significant cardiac events reported a Both patients had prior anthracycline therapy in the adjuvant setting; 1 patient received prior trastuzumab therapy in the adjuvant setting. b This patient did not receive prior treatment with an anthracycline. 48

Summary and Conclusions This is the first randomized study to evaluate an antibody-drug conjugate for HER2- positive MBC First-line treatment of HER2-positive MBC with T-DM1, compared with trastuzumab + docetaxel was associated with: A significant improvement in PFS (14.2 vs 9.2 mos; HR=0.594; P value=0.0353) Similar ORR but more durable responses (64.2%, median duration not reached vs. 58.0%, median duration 9.5 months) A lower rate of grade 3 AEs (46.4% vs 89.4%) These results validate the hypothesis that the unique properties of T-DM1 may lead to an improved therapeutic index Improved PFS with T-DM1 may result from improved tolerability/duration of treatment/response and intrinsic potency of HER2-targeted DM1 T-DM1 is being evaluated in phase III randomized clinical trials for HER2-positive MBC 49

MARIANNE: HER2-positive progressive or recurrent locally advanced BC or previously untreated MBC (n=1092) Primary efficacy objective: T-DM1 + pertuzumab (n=364) Trastuzumab + taxane (n=364) T-DM1 + placebo (n=364) PFS assessed by an independent review facility Primary safety objective: To compare the safety of T-DM1 + pertuzumab or T-DM1 + placebo vs trastuzumab + taxane BC = br east cancer ; MBC = met ast at i c br east cancer ; PFS = pr ogr essi on- f r ee sur vi val 50