Advances in the Management of Metastatic Her 2 Positive Breast Cancer

Advances in the Management of Metastatic Her 2 Positive Breast Cancer Sunil Verma MD, MSEd, FRCPC Medical Oncologist Research Lead, Division of Medical Oncology Chair, Breast Medical Oncology Sunnybrook Odette Cancer Centre Associate Professor, University of Toronto

The Her 2 Journey HER2 gene is cloned 2 HER2 protein found to be overexpressed in breast tumours 3 Anti-HER2 monoclonal mouse antibody developed 5 Trastuzumab clinical trials begin 1984 1985 1987 1989 1992 1993 1995 HER2/neu gene identified 1 HER2 overexpression associated with more aggressive phenotype 4 Anti-HER2 monoclonal mouse antibody humanised: trastuzumab 6 1. Ullrich A, et al. Nature 1984; 309:418 4253; 2. Ishii S, et al. Proc Natl Acad Sci USA 1985; 82:4920 4924 3. Sainsbury JR, et al. Lancet 1985; 1:364 366; 4. Di Fiore PP, et al. Science 1987; 237:178 182 5. Huzdiak RM, et al. Mol Cell Biol 1989; 9:1165 1172; 6. Carter P, et al. Proc Natl Acad Sci USA 1992; 89:4285 4289

Her 2 Story Poor Prognostic Marker

Outline First Line Treatment Second Line Treatment and Beyond Individualized Approach An Algorithm and Concluding Remarks

Outline First Line Treatment Second Line Treatment and Beyond Individualized Approach An Algorithm and Concluding Remarks

Overall survival (%) Trastuzumab prolongs overall survival in HER2-positive MBC 100 80 60 Chemotherapy (n = 234) Chemotherapy + trastuzumab (n = 235) RR = 0.80 (95% CI = 0.64,1.00) p = 0.046 40 20 Median OS: 20.3 months Median OS: 25.1 months 0 0 5 15 25 35 45 Time (months after enrolment) OS was a secondary endpoint in the study Chemotherapy = either doxorubicin or epirubicin + cyclophosphamide or paclitaxel OS, overall survival; RR, relative risk of death Adapted from Slamon DJ, et al. N Engl J Med 2001; 344:783 792.

First Line Treatment Approach (2001-2011) A number of effective options with chemo and anti-her2 Taxanes and Herceptin Vinorelbine and Herceptin Capecitabine and Anti-Her2 Doublet chemo with Her 2 generally not used Select group of patients may benefit from an anti-her2 and anti-estrogen approach

Recent Achievements in Her 2 positive MBC First Line MA.31 Taxane + H vs. Taxane + L Bolero -1 Paclitaxel + H vs. Paclitaxel + H +Everolimus CLEOPATRA Chemo + H vs. Chemo +H+P 8

Gelmon et. al ASCO 2012 9

Gelmon et. al ASCO 2012 10

San Antonio Breast Cancer Symposium December 9-13, 2014 BOLERO-1/TRIO 019: Study Design N = 719 Locally advanced or metastatic HER2+ breast cancer No prior therapy for advanced or metastatic disease (except endocrine therapy) Prior (neo)adjuvant TRAS and/or chemotherapy allowed 1 Measurable disease or presence of bone lesions (lytic or mixed) Endpoints Randomized 2:1 Stratification factors: Prior neo/adjuvant TRAS Visceral metastases Everolimus (10 mg PO daily) + Paclitaxel 2 + Trastuzumab 3 Placebo + Paclitaxel 2 + Trastuzumab 3 Therapy until disease progression or intolerable toxicity 4 Primary: PFS (investigator-assessed) Overall population and HR subpopulation Secondary: OS, ORR, CBR, Time to response, Safety, Duration of response 1 Discontinued > 12 mo before randomization; 2 Paclitaxel: 80 mg/m 2 weekly; 3 Trastuzumab: 4 mg/kg loading dose on day 1 at cycle 1 followed by 2 mg/kg weekly doses 4 Patients could discontinue any study treatment due to AEs; other study treatments continued until disease progression or intolerable toxicity ABC, advanced breast cancer; CBR, clnical benefit rate; ORR, overall response rate; OS, overall survival; PFS, progression free survival. This presentation is the intellectual property of the author/presenter. Contact them at shurvitz@mednet.ucla.edu for permission to reprint and/or distribute. 11

Probability (%) San Antonio Breast Cancer Symposium December 9-13, 2014 BOLERO-1/TRIO 019: PFS Full Population (Investigator-assessment) 100% 80% Hazard Ratio = 0.89; 95% CI [0.73, 1.08] Log rank p value = 0.1166 Median PFS Everolimus: 14.95 months; 95% CI [14.55, 17.91] (n/n = 271/480) Placebo: 14.49 months; 95% CI [12.29, 17.08] (n/n = 154/239) 60% Censoring times 40% 20% 0% 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 Time (months) No. of patients still at risk Everolimus Placebo 480 416 365 324 289 260 217 178 151 130 122 107 94 80 72 63 58 48 42 35 26 21 17 13 10 5 3 3 0 239 221 199 166 144 123 106 91 80 69 53 47 43 38 36 36 31 24 17 15 12 9 7 6 4 3 1 1 0 - One-sided p-value is obtained from the log-rank test stratified by prior use of trastuzumab (Y/N) and Visceral metastasis (Y/N) from IWRS. This presentation is the intellectual property of the author/presenter. Contact them at shurvitz@mednet.ucla.edu for permission to reprint and/or distribute. 12

San Antonio Breast Cancer Symposium December 9-13, 2014 BOLERO-1/TRIO 019: Most Frequent Adverse Events (Safety set) [> 25% in everolimus arm] AE/Grade EVE + TRAS + PAC (N = 472) % PBO + TRAS + PAC (N = 238) % Any Grade 3 Grade 4 Any Grade 3 Grade 4 Non-hematologic Stomatitis 67 13 0 32 1 0 Diarrhea 57 9 0 47 4 0 Alopecia 47 <1 0 53 0 0 Rash 40 1 0 21 <1 0 Cough 40 <1 0 33 1 0 Pyrexia 39 2 0 27 1 0 Fatigue 35 5 0 36 3 0 Epistaxis 33 0 0 18 0 0 Peripheral edema 33 1 0 24 <1 0 Nausea 33 1 0 35 1 0 Peripheral neuropathy 29 4 0 24 5 0 Headache 28 1 0 29 1 0 Vomiting 26 1 0 23 3 0 Pneumonitis* 16 4 1 4 <1 0 Hematologic Neutropenia 38 21 4 25 11 4 Anemia 31 9 1 16 3 0 *AE of clinical importance EVE, Everolimus; HR, hormone receptor; PAC, Paclitaxel; PBO, Placebo; TRAS, Trastuzumab. This presentation is the intellectual property of the author/presenter. Contact them at shurvitz@mednet.ucla.edu for permission to reprint and/or distribute. 13

CLEOPATRA study design 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) HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; PD, progressive disease Swain et al. SABCS 2012 Poster P5-18-26. 14

Progression-free survival (%) Updated Kaplan-Meier curves of investigator-assessed PFS n at risk Ptz + T + D Pla + T + D 100 90 80 70 60 50 40 30 20 10 0 0 5 10 15 20 25 30 35 40 402 406 341 329 284 223 218 148 Ptz + T + D: median 18.7 months Pla + T + D: median 12.4 months 178 110 Time (months) 108 72 67 42 34 26 8 8 45 50 0 0 =6.3 months HR=0.69 95% CI 0.58 0.81 0 0 D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Swain et al. SABCS 2012 Poster P5-18-26. 15

Efficacy Analysis Milestones PFS primary analysis Δ 6.1 months HR 0.62 (p < 0.0001) Patients still on placebo offered crossover to pertuzumab May 2011 May 2012 July 2012 Feb 2014 OS 1 st interim analysis OS 2 nd interim analysis OS final analysis HR 0.64 (p = 0.005) HR 0.66 (p = 0.0008)* 16

OS (%) Final OS Analysis Median follow-up 50 months (range 0 70 months) n at risk Ptz + T + D Pla + T + D 100 90 80 70 60 50 40 30 20 10 0 HR 0.68 95% CI = 0.56, 0.84 p = 0.0002 0 10 20 30 40 50 60 70 402 406 371 350 318 289 Time (months) 268 230 40.8 months 226 179 Δ 15.7 months 104 91 Ptz + T + D Pla + T + D 56.5 months 28 23 1 0 ITT population. Stratified by geographic region and neo/adjuvant chemotherapy. CI, confidence interval; Pla, placebo; Ptz, pertuzumab. 17

Cleopatra Overall Survival Cross over patients (11%) excluded Swain et. al NEJM 2015

Breast cancer therapies following discontinuation of study treatment in patients who had withdrawn from study treatment n (%) Placebo + trastuzumab + docetaxel (n=338) Pertuzumab + trastuzumab + docetaxel (n=298) Any 260 (76.9) 225 (75.5) In patients receiving subsequent breast cancer treatment n=260 n=225 Any HER2-targeted treatment 178 (68.5) 160 (71.1) Trastuzumab 104 (40.0) 106 (47.1) Lapatinib 114 (43.8) 93 (41.3) Trastuzumab emtansine 26 (10.0) 21 (9.3) Capecitabine 140 (53.8) 113 (50.2) Vinorelbine 70 (26.9) 51 (22.7) Cyclophosphamide 43 (16.5) 30 (13.3) Doxorubicin 46 (17.7) 29 (12.9) Paclitaxel 32 (12.3) 21 (9.3) Docetaxel 11 (4.2) 13 (5.8) Swain et al. SABCS 2012 Poster P5-18-26. 20

Adverse events (all grades) with 25% incidence or 5% difference between arms n (%) Placebo + trastuzumab + docetaxel (n=396) Pertuzumab + trastuzumab + docetaxel (n=408) Diarrhea 191 (48.2) 278 (68.1) Alopecia 240 (60.6) 248 (60.8) Neutropenia 197 (49.7) 216 (52.9) Nausea 168 (42.4) 179 (43.9) Fatigue 148 (37.4) 155 (38.0) Rash 95 (24.0) 149 (36.5) Decreased appetite 105 (26.5) 121 (29.7) Mucosal inflammation 79 (19.9) 112 (27.5) Asthenia 121 (30.6) 110 (27.0) Vomiting 97 (24.5) 104 (25.5) Peripheral edema 122 (30.8) 101 (24.8) Pruritus 40 (10.1) 68 (16.7) Constipation 101 (25.5) 63 (15.4) Febrile neutropenia 30 (7.6) 56 (13.7) Dry skin 23 (5.8) 44 (10.8) Highlighted are adverse events with 5% higher incidence Swain et al. SABCS 2012 Poster P5-18-26. 21

Cardiac adverse events n (%) Data cutoff date May 2011 (n=397) Placebo + trastuzumab + docetaxel May 2012 (n=396) Pertuzumab + trastuzumab + docetaxel May 2011 (n=407) May 2012 (n=408) LVSD (all grades) 33 (8.3) 34 (8.6) 18 (4.4) 22 (5.4) Symptomatic LVSD 7 (1.8) 7 (1.8) 4 (1.0) 5 (1.2) LVEF decline to <50% and by 10% points from baseline* 25/379 (6.6) 28/378 (7.4) 15/393 (3.8) 18/394 (4.6) LVEF recovery to 50%* 18/25 (72.0) 25/28 (89.3) 13/15 (86.7) 16/18 (88.9) * In patients with post-baseline assessment LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction Swain et al. SABCS 2012 Poster P5-18-26. 22

T-DM1 Mechanism of Action KADCYLA is a HER2-targeted antibody and microtubule inhibitor conjugate consisting of HERCEPTIN, a humanized anti-her2 IgG1 monoclonal antibody DM1, a cytotoxic microtubule inhibitor derived from maytansine on average, KADCYLA has 3.5 DM1 molecules per antibody MCC, a stable thioether linker, covalently linking HERCEPTIN to DM1 Antibody (HERCEPTIN) Stable linker Cytotoxic agent (DM1) Emtansine DM: derivative of maytansine MCC: 4-[N-maleimidomethyl] cyclohexane-1- carboxylate KADCYLA Product Monograph. Hoffmann-La Roche Limited. September 11, 2013. Swanton C, Johnston SR, editors. Handbook of Metastatic Breast Cancer, 2 nd ed. Informa Healthcare, New York, 2012.

T-DM1 Retains Activity of Herceptinf In vitro studies in human breast cancer cells that overexpress HER2 have shown that, like HERCEPTIN, KADCYLA Binds subdomain IV of the HER2 extracellular domain Inhibits HER2 signaling Mediates antibody-dependent cell-mediated cytotoxicity (ADCC) Inhibits shedding of the HER2 extracellular domain KADCYLA Product Monograph. Hoffmann-La Roche Limited. September 11, 2013.

T-DM1 Intracellular Delivery of DM1 HER2 KADCYLA DM1 release* Internalization Lysosomal degradation Inhibition of tubulin polymerizatio n KADCYLA has the additional MOA of DM1. Upon binding to HER2, KADCYLA undergoes Receptor-mediated internalization Subsequent lysosomal degradation Intracellular release of DM1-containing cytotoxic catabolites DM1 binding to tubulin, disrupting microtubule networks in the cell, resulting in cell cycle arrest and apoptotic cell death *The primary DM1-containing cytotoxic catabolite released is lysine-mcc-dm1. KADCYLA Product Monograph. Hoffmann-La Roche Limited. September 11, 2013. LoRousso PM, et al. Clin Cancer Res 2011.

PHASE II STUDY T-DM1 vs. Docetaxel and Trastuzumab 1:1 HER2-positive, recurrent locally advanced breast cancer or MBC (N=137) 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)

Objective Response by Investigator Patients With Measurable Disease at Baseline Trastuzumab + docetaxel (n=69) a T-DM1 (n=67) Patients with an objective response, b n (%) 40 (58.0) 43 (64.2) 95% CI 45.5 69.2 51.8 74.8 Objective responses, n (%) Complete response 3 (4.3) 7 (10.4) Partial response 37 (53.6) 36 (53.7) Stable disease 23 (33.3) 13 (19.4) Progressive disease 4 (5.8) 8 (11.9) Unable to evaluate or missing 2 (2.9) 3 (4.5) Patients with clinical benefit, c n (%) 56 (81.2) 50 (74.6) 95% CI 70.7 89.1 63.2 84.2 a One patient was not included in the efficacy analysis due to study site withdrawal. b Defined as complete or partial response based on RECIST 1.0 determined on 2 consecutive tumor assessments at least 4 weeks apart. c Defined as objective response any time during the study or maintained stable disease for at least 6 months from randomization. Hurvitz, et al., JCO, 2013 Hurvitz SA, et al. Abstract 5.001. ESMO 2011.

Proportion progression-free Progression-Free Survival by Investigator Randomized Patients 1.0 Median PFS, mos Hazard ratio 95% CI Log-rank P value 0.8 Trastuzumab + docetaxel (n=70) T-DM1 (n=67) 9.2 14.2 0.59 0.36 0.97 0.035 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 Number of patients at risk Time (months) 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. This presentation contains non-licensed product information and may be subject to local affiliate compliance and / or legal approval before onward internal distribution. This information is for internal use only and must not be distributed externally Hurvitz, et al., JCO, 2013

MARIANNE: A clinical trial of pertuzumab and T-DM1 in first-line metastatic breast cancer Pertuzumab + T-DM1 HER2-positive, progressive or recurrent, locally advanced or untreated MBC (N = 1092) R Placebo + T-DM1 Trastuzumab + taxane (docetaxel or paclitaxel) T-DM1 ± pertuzumab: blinded, placebo-controlled Trastuzumab + taxane: open-label 2010 2011 2012 2013 First patient in July 2010 Last patient in Q2 2012 Figure adapted from: http://clinicaltrials.gov/ct2/show/nct01120184; Roche. Data on file

MARIANNE Statistical Analysis

Summary First Line The standard of care should consist of pertuzumab and trastuzumab along with docetaxel (? other taxane alternative) 31

Future Questions First Line Can we combine Pertuzumab and Herceptin with other partners Other taxanes (PERUSE) Other chemotherapies - Vino/Cape (VELVET/PHREXA) Other biologics T-DM1 (MARIANNE negative) Developing effective drugs that can target brain metastases Duration of targeted therapy for those responding Duration of chemotherapy when receiving dual targeted therapy Combination of endocrine therapy with dual targeted anti-her 2 tx for ER+/Her 2 +ve pts 32

Outline First Line Treatment Second Line Treatment and Beyond Individualized Approach An Algorithm and Concluding Remarks

Second Line (2006-2010) There is continued benefit of trastuzumab beyond progression Capecitabine and Trastuzumab There is benefit of Lapatinib in combination with Capecitabine upon progression on Trastuzumab

Recent Achievements in Her 2 positive MBC Second Line and Beyond EGF 104900 L+ H vs L alone EMILIA T-DM1 vs Cape + L Bolero-3 Vinorelbine + H + Everolimus vs. Vinorelbine + H 35

Trastuzumab and Lapatinib Overall Survival

EMILIA Study Design HER2-positive LABC or MBC (N=980) Prior taxane and trastuzumab Progression on metastatic treatment or within 6 months of adjuvant treatment 1:1 T-DM1 3.6 mg/kg q3w IV Capecitabine 1000 mg/m 2 PO bid, days 1 14, q3w + Lapatinib 1250 mg/day PO qd PD PD Verma et al NEJM 2012

EMILIA: Progression Free Survival Verma et al NEJM 2012

EMILIA: Overall Survival Verma et al NEJM 2012

EMILIA Adverse Events Verma et al NEJM 2012 40

TH3RESA Study Schema HER2-positive (central) advanced BC a (N=600) 2 T-DM1 3.6 mg/kg q3w IV (n=400) PD 2 prior HER2-directed therapies for advanced BC Prior treatment with trastuzumab, lapatinib, and a taxane 1 Treatment of physician s choice (TPC) b (n=200) PD T-DM1 c (optional crossover) Stratification factors: World region, number of prior regimens for advanced BC, d presence of visceral disease Co-primary endpoints: PFS by investigator and OS Key secondary endpoints: ORR by investigator and safety a Advanced BC includes MBC and unresectable locally advanced/recurrent BC. b TPC could have been single-agent chemotherapy, hormonal therapy, or HER2-directed therapy, or a combination of a HER2-directed therapy with a chemotherapy, hormonal therapy, or other HER2-directed therapy. c First patient in: Sep 2011. Study amended Sep 2012 (following EMILIA 2nd interim OS results) to allow patients in the TPC arm to receive T-DM1 after documented PD. d Excluding single-agent hormonal therapy. BC, breast cancer; IV, intravenous; ORR, objective response rate; PD, progressive disease; q3w, every 3 weeks. Wildiers H, et al. ECC 2013; Abstract 15LBA.

Proportion progression-free PFS by Investigator Assessment 1.0 0.8 0.6 TPC (n=198) T-DM1 (n=404) Median (months) 3.3 6.2 No. of events 129 219 Stratified HR=0.528 (95% CI, 0.422, 0.661) P<0.0001 0.4 0.2 0.0 0 2 4 6 8 Time (months) 10 12 14 No. at risk: TPC 198 120 62 28 13 6 1 0 T-DM1 404 334 241 114 66 27 12 0 Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months. Unstratified HR=0.521 (P<0.0001). Wildiers H, et al. ECC 2013; Abstract 15LBA.

Proportion surviving First Interim OS Analysis 1.0 Observed 21% of targeted events 0.8 0.6 No. at risk: TPC 198 T-DM1 0.4 0.2 0.0 0 2 4 6 8 10 12 14 Time (months) 404 169 381 125 316 80 207 TPC (n=198) 51 127 T-DM1 (n=404) Median (months) 14.9 NE No. of events 44 61 Stratified HR=0.552 (95% CI, 0.369, 0.826); P=0.0034 Efficacy stopping boundary HR<0.363 or P<0.0000013 30 65 9 30 3 7 16 0 0 44 patients in the TPC arm received crossover T-DM1 treatment after documented progression. Unstratified HR=0.57 (P=0.004). Wildiers H, et al. ECC 2013; Abstract 15LBA.

O Regan R, et al. ASCO 2013; Abstract 505. Not for distribution. O Regan ASCO 2013 44

O Regan R, et al. ASCO 2013; Abstract 505. Not for distribution. O Regan ASCO 2013 45

Summary Second Line and Beyond T-DM1 offers significant clinical benefit and superior toxicity profile and is effective for second line Her 2 + treatment Patients progressing on T-DM1 still may derive a benefit from ongoing systemic tx with chemo with anti-her 2 approaches The role of Lapatinib has evolved and now is generally considered in third or later lines of treatment. One may consider earlier use if: Progressive brain metastases despite radiation Lack of response to first/second line of herceptin based regimen? Biomarkers p95 still needs to be validated 46

Future Questions Is there a benefit of Pertuzumab or T-DM1 (along with other partners) beyond progression? What is the effect on tumor biology once patients progress on Pertuzumab/T-DM1? What are potential targeted agents that may help overcome resistance? What will be the role of PI3K inhibitors in second line + treatment? Who are the ideal patients for dual targeted treatment alone? The Next Generation of anti-her 2 Drugs. 47

PHEREXA: A clinical trial of pertuzumab in second-line metastatic breast cancer Arm A: Pertuzumab + trastuzumab + capecitabine HER2-positive MBC (N = 450) R Arm B: Trastuzumab + capecitabine 2013 2014 Last patient in Q3 Figure adapted from: Muñoz-Mateu M, et al. ASCO 2011 (Abstract TPS118: poster presentation); Roche. Data on file.

MM-302 is a HER2-targeted antibody-drug conjugated liposomal formulation anti-her2 scfv Targets liposome to HER2-overexpressing cells Promotes internalization Binds to different epitope than trastuzumab Does not inhibit HER2 signaling No uptake of F5 containing liposomes into cardiomyocytes Liposome Extended half-life Stably encapsulates doxorubicin Passive accumulation in tissues possessing leaky vasculature Size precludes delivery to cardiac tissue Lipid Membrane PEG 75-110 nm Doxorubicin Crystals Effective cytotoxic agent in Br Ca DNA intercalator, TOP2A inhibitor, free radical generator

T cell dependent bispecific antibody (TDB) platform Hole: acd3 Knob: atumor antigen Full length TDB + = T366S L368A Y407V T366W Produced using modular knobs into holes technology Effector functions removed (E. coli production / N297A) Minimal immunogenic potential PK is similar to conventional IgG1 Ridgeway...Carter. 1996 Prot. Engineering Atwell...Carter. 1997 J. Mol Biol.

Outline First Line Treatment Second Line Treatment and Beyond Individualized Approach An Algorithm and Concluding Remarks

Personalized Factors to Consider Hormone Receptor Status Prior Adjuvant Trastuzumab CNS Metastases Biomarkers

CLEOPATRA PFS in predefined subgroups 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 Favors pertuzumab Favors placebo Hormone Receptor Status n HR 95% CI 808 0.69 0.58 0.81 432 0.67 0.54 0.85 376 0.70 0.55 0.90 306 0.70 0.53 0.91 135 0.60 0.40 0.91 114 0.54 0.34 0.85 253 0.81 0.60 1.10 681 0.72 0.60 0.87 127 0.49 0.31 0.76 789 0.69 0.59 0.82 19 0.62 0.16 2.40 480 0.65 0.52 0.80 30 0.50 0.16 1.54 261 0.81 0.60 1.10 37 0.47 0.20 1.10 Disease type ER/PgR status HER2 status Visceral disease Non-visceral disease Positive Negative IHC 3+ FISH-positive 630 0.63 0.53 0.76 178 0.89 0.61 1.31 388 0.76 0.60 0.97 408 0.62 0.49 0.78 721 0.66 0.55 0.79 767 0.70 0.59 0.83 0 1 2 3 ER, estrogen receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; PFS, progression-free survival; PgR, progesterone receptor Swain et al. SABCS 2012 Poster P5-18-26. 54

Cleopatra PFS Subgroup Analysis

Cleopatra OS Subgroup Analysis

EMILIA Overall Survival Subgroup Analyses Cap + Lap T-DM1 Baseline Total Median Median HR characteristic n (mos) (mos) (95% CI) All patients 991 25.1 30.9 0.70 (0.56, 0.87) Age group <65 years 853 24.6 30.9 0.66 (0.52, 0.83) 65 74 years 113 27.1 NR 0.74 (0.37, 1.47) 75 years 25 NR 11.1 3.45 (0.94, 12.65) ER and PR status ER+ and/or PR+ 545 25.3 31.9 0.62 (0.46, 0.85) ER and PR 426 23.7 27.1 0.75 (0.54, 1.03) Line of therapy a First-line 118 27.9 NR 0.61 (0.32, 1.16) Second-line 361 NR 27.1 0.88 (0.61, 1.27) Third- and later-line 512 23.3 33.9 0.62 (0.46, 0.84) T-DM1 Better Cap + Lap Better Hazard ratio 0.2 0.5 1 2 5 a Defined as any systemic therapy including endocrine and chemotherapy. NR, not reached. From confirmatory OS analysis; data cut-off July 31, 2012. Verma et al. ESMO 2012; Oral Abstract #LBA12 Hormone Receptor Status

Hormone Receptor Status BOLERO-3: PFS Subgroup Analyses by Local Assessment Subgroup N All 569 Age < 65 years 472 65 97 Region Europe 223 North America 123 Asia 166 Latin America 36 Other 21 Prior lapatinib* Yes 161 No 408 Prior adj/neo trastuzumab** Yes 251 No 318 Baseline ECOG PS 0 382 1 or 2 186 Hormonal status ER /PgR 250 ER + /PgR + 317 Visceral involvement Yes 439 No 130 Hazard Ratio [95% CI] 0.78 [0.65-0.95] 0.77 [0.62-0.95] 0.93 [0.56-1.57] 0.72 [0.53-0.99] 0.86 [0.55-1.32] 0.83 [0.59-1.18] 0.61 [0.27-1.38] 1.28 [0.48-3.45] 0.79 [0.56-1.11] 0.78 [0.62-0.99] 0.65 [0.48-0.87] 0.92 [0.71-1.18] 0.79 [0.63-1.00] 0.75 [0.53-1.05] 0.65 [0.48-0.87] 0.93 [0.72-1.20] 0.89 [0.72-1.10] 0.48 [0.30-0.76] Abbreviations: CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status. Favors EVE Favors PBO 58 O Regan R, et al. ASCO 2013; Abstract 505. Not for distribution.

Probability (%) San Antonio Breast Cancer Symposium December 9-13, 2014 BOLERO-1/TRIO 019: PFS HR Subpopulation (Investigator Assessment) 100% Hazard Ratio = 0.66; 95% CI [0.48, 0.91] Log rank p value = 0.0049 80% 60% Median PFS Everolimus: 20.27 months; 95% CI [14.95,24.08] (n/n = 97/208) Placebo: 13.08 months; 95% CI [10.05,16.56] (n/n = 66/103) Censoring times 40% 20% 0% 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 Time (months) No. of patients still at risk Everolimus 208 183 166 151 138 125 100 84 73 64 62 55 49 40 35 32 30 24 21 19 15 11 10 7 5 2 1 1 0 Placebo 103 96 83 68 58 49 43 34 32 28 24 21 20 19 19 19 17 13 7 6 5 4 2 1 1 0 0 0 0 - One-sided p-value is obtained from the log-rank test stratified by prior use of trastuzumab (Y/N) and Visceral metastasis (Y/N) from IWRS. Sensitivity analysis without censoring patients at the start of new antineoplastic therapy: Median PFS and 95% CIs HR=0.66 [0.48, 0.9], p = 0.0043 20.27 mo (14.82, 24.08) for everolimus [n = 102] 12.88 mo (10.94, 16.56) for placebo [n = 68] This presentation is the intellectual property of the author/presenter. Contact them at shurvitz@mednet.ucla.edu for permission to reprint and/or distribute. 59

Prior Trastuzumab CLEOPATRA: Independently assessed PFS by prior trastuzumab therapy in patients with (neo)adjuvant therapy HT Median PFS, months PHT Median PFS, months Hazard ratio (CI) Prior (neo)adjuvant trastuzumab treatment (n = 88) 10.4 16.9 0.62 (0.35, 1.07) No prior (neo)adjuvant trastuzumab treatment (n = 288) 12.6 21.6 0.60 (0.43, 0.83) CI, confidence interval; PFS, progression-free survival Adapted from Baselga J, et al. N Engl J Med 2012; 366:109 119.

Cleopatra OS Subgroup Analysis

EMILIA: Progression-Free Survival Subgroup Analyses Baseline characteristic All pts Total n 991 Cap + Lap Median, mos 6.4 T-DM1 Median, mos HR (95% CI) 9.6 0.66 (0.56, 0.78) Prior Trastuzumab T-DM1 better Cap + Lap better Age <65 yrs 65 yrs 853 138 6.0 8.1 9.8 7.0 0.62 (0.52, 0.74) 1.06 (0.68, 1.66) ER and PR status ER+ and/or PR+ ER and PR 545 426 7.1 5.6 9.0 10.3 0.72 (0.58, 0.91) 0.56 (0.44, 0.72) Line of therapy a First Second Third 118 361 512 5.7 6.8 6.5 10.8 9.6 9.0 0.51 (0.30, 0.85) 0.69 (0.53, 0.91) 0.69 (0.55, 0.86) Data cut-off Jan 14, 2012 HRs were from unstratified analysis. a Defined as any systemic therapy, including endocrine or chemotherapy. Hazard ratio 0.2 0.5 1 2 5 Verma et al. N Eng J Med 2012 (incl. supplementary appendix) Blackwell et al. ASCO 2012; Abst #LBA1

Prior Trastuzumab EMILIA: Overall Survival Subgroup Analyses Cap + Lap T-DM1 Baseline Total Median Median HR characteristic n (mos) (mos) (95% CI) All patients 991 25.1 30.9 0.70 (0.56, 0.87) T-DM1 Better Cap + Lap Better Age group <65 years 853 24.6 30.9 0.66 (0.52, 0.83) 65 74 years 113 27.1 NR 0.74 (0.37, 1.47) 75 years 25 NR 11.1 3.45 (0.94, 12.65) ER and PR status ER+ and/or PR+ 545 25.3 31.9 0.62 (0.46, 0.85) ER and PR 426 23.7 27.1 0.75 (0.54, 1.03) Line of therapy a First-line 118 27.9 NR 0.61 (0.32, 1.16) Second-line 361 NR 27.1 0.88 (0.61, 1.27) Third- and later-line 512 23.3 33.9 0.62 (0.46, 0.84) Hazard ratio 0.2 0.5 1 2 5 a Defined as any systemic therapy including endocrine and chemotherapy. NR, not reached. From confirmatory OS analysis; data cut-off July 31, 2012. Verma et al. ESMO 2012; Oral Abstract #LBA12

CNS Metastases EMILIA CNS metastases at baseline and Progression 64

EMILIA: Outcomes of patients with CNS mets at Baseline A. PFS Independent Assessment B. PFS Investigator Assessment D. Overall Survival Krop et. al Annals of Oncology 2014 65

66

BIOMARKERS 67

Alterations in PI3K Pathway Signaling Components Are Frequent in HER2+ Breast Cancer 20% 10% 68 BGT226A2101 CONFIDENTIAL INFORMATION, NOT TO BE DISTRIBUTED

PI3K Pathway activation status Predicts Response to Trastuzumab Bernard R et al Cancer Cell. 2007 Oct;12(4):395-402

pcr and PIK3CA Status by Treatment Arm in NEO-ALTTO For each treatment arm, the pcr rate was lower in tumors with a PIK3CA mutation The difference was statistically significant in the combination arm p=0.012 N= Baselga AACR 2013 124 112 119 70

PIK3CA Mutation Associated With Poorer Prognosis on Both Arms of Cleopatra Study Baselga et al, SABCS 2012

Proportion progression-free EMILIA Biomarker Analysis: PFS by PIK3CA Mutation Status and Treatment Arm 1.0 0.8 0.6 PIK3CA mutation status Lap + Cap n Median (months) n T-DM1 Median (months) Hazard ratio a 95% CI Mutated 39 4.3 40 10.9 0.45 0.25 0.82 Wild type 87 6.4 93 9.8 0.74 0.50 1.10 0.4 No. at risk: 0.2 0.0 Lap + Cap (PIK3CA mutated) Lap + Cap (PIK3CA wild type) T-DM1 (PIK3CA mutated) T-DM1 (PIK3CA wild type) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Time (months) Lap + Cap (Mutated) 39 28 22 9 5 3 2 1 0 0 0 0 0 0 0 Lap + Cap (Wild type) 87 69 55 31 21 16 13 10 7 4 4 3 2 1 0 T-DM1 (Mutated) 40 31 26 18 15 12 8 6 6 5 2 2 1 0 0 T-DM1 (Wild type) 93 82 66 42 36 24 19 15 12 9 6 3 2 1 0 a Hazard ratios are based on unstratified analyses. Baselga et al, SABCS 2013

Proportion surviving EMILIA Biomarker Analysis: OS by PIK3CA Mutation Status and Treatment Arm 1.0 0.8 Lap + Cap T-DM1 PIK3CA mutation status n Median (months) n Median (months) Hazard ratio a 95% CI Mutated 39 17.3 40 NE 0.26 0.12 0.57 Wild type 87 27.8 93 NE 0.68 0.40 1.15 0.6 0.4 No. at risk: Lap + Cap (Mutated) Lap + Cap (Wild type) T-DM1 (Mutated) T-DM1 (Wild type) 0.2 0.0 a Hazard ratios are based on unstratified analyses NE, not estimable. Lap + Cap (PIK3CA mutated) Lap + Cap (PIK3CA wild type) T-DM1 (PIK3CA mutated) T-DM1 (PIK3CA wild type) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) 39 34 32 31 28 27 22 17 14 10 8 6 4 3 2 0 0 0 0 87 83 77 74 68 66 57 44 38 32 28 26 20 14 11 6 4 3 2 40 40 40 40 38 37 36 34 27 25 21 14 12 7 4 4 3 2 2 93 91 89 86 82 78 69 52 44 37 30 27 21 17 12 7 5 3 2

Outline First Line Treatment Second Line Treatment and Beyond Individualized Approach An Algorithm and Concluding Remarks

HISTORY 30 YEARS IN THE MAKING

Milestones in the Management of HER2-positive MBC Overall Survival First Line Second Line + Abbreviations: Ana, anastrozole; Cape, capecitabine; CT, chemotherapy; Doc, docetaxel; Lap, lapatinib; Let, letrozole; OS, overall survival; Pac, paclitaxel; Pert, pertuzumab; T-DM1, trastuzumab emtansine; Tras, trastuzumab. Verma et. al The Oncologist 2013

An Algorithm to Manage Her 2 positive MBC Verma et. al The Oncologist 2013

An Algorithm to Manage Her 2 positive MBC Can we consider Pertuzumab for DFI 6m- 1year? Can we consider another taxane with P + H? Is there still activity of Trastuzumab/Lapatini b post T-DM1? Verma et. al The Oncologist 2013

Beyond Breast Cancer Development of Targeted Therapy 2000 2005 2010 2015 2020

Conclusion Raising the Bar The outcome of patients with Her 2 positive breast cancer has significantly improved in the past two decades Novel targeted drugs are improving survival and reducing toxicity for patients with advanced breast cancer The future looks quite bright as we can now envision a total targeted approach for some of these patients..and an overall survival in excess of five years for some of our patients!