Breast Cancer: Background

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Program Agenda Demographics and Background Principles of HER2 Testing Metastatic and Progressive HER2+ Breast Cancer Early Stage HER2+ Breast Cancer Educational Outcomes Post-Assessment Question and Answer

Breast Cancer: Background Leading cause of cancer for women 2014 estimated new cases of invasive breast cancer is about 230,000 Second leading cause of cancer death in women Estimated 40,000 deaths in 2014 Biology is main driver of treatment Goal is to provide a more tailored individualized approach by targeting dysregulated pathways American Cancer Society. Key Statistics 2014. Atlanta: American Cancer Society; 2014.

HER Family of Receptors as Targets Trastuzumab added to chemotherapy: Standard of care for HER2-positive breast cancer In MBC, improvements in TTP, ORR, PFS, and OS Adjuvant trials demonstrated significant reductions in the risk of recurrence, of a magnitude seldom observed in oncology trials Archetype for targeted therapy development in breast cancer Herbst RS, et al. Int J Radiat Oncol Biol Phys. 2004;59:21; Roskoski R, et al. Biochem Biophys Res Commun. 2004;319:1; Rowinsky E, et al. Annu Rev Med. 2004;55:433; Hortobagyi GN. N Engl J Med. 2005;353:1734-1736.

HER2-Positive Breast Cancer Unanswered Questions Optimal use in the early disease setting? What about dual HER blockade? What do we do at progression? Are novel agents and combinations better?

HER2 Testing Polling Question A 48-year-old female presents with a T2, N1 (1+), M0 infiltrating ductal carcinoma of the right breast The malignancy is ER+, PR-, and HER2 2+ FISH testing is performed and the ratio is 1.9

What is the Next Best Course of Action? 1. Repeat FISH testing using another specimen and / or perform IHC test on same specimen 2. Treat patient with chemotherapy + trastuzumab 3. Treat patient with chemotherapy without trastuzumab

NCCN Principles of HER2 Testing IHC 0, 1+ HER2- Initial testing by IHC IHC 2+ Borderline result ISH testing IHC 3+ HER2+ FISH- HER2- IHC testing Initial testing by FISH Borderline result FISH retest HER2- Count additional cells Borderline result FISH+ HER2+ HER2+ Principles of HER2 testing. NCCN Guidelines Version 2.2014. Available at: www.nccn.org.

FDA vs CAP / ASCO Guidelines for HER2 Testing* FDA Result IHC Score FISH Positive 3+ Uniform, intense membrane staining of more than 10% of invasive tumor cells FISH HER2 / CEP 17 ratio 2.0 CAP / ASCO Result IHC Score FISH Positive 3+ Uniform, intense membrane staining of more than 10% of invasive tumor cells FISH HER2 / CEP 17 ratio 2.0 or FISH HER2 gene copy number 6.0 Equivocal 2+ FISH HER2 / CEP 17 ratio < 2.0 and FISH HER2 gene copy number 4 and < 6 Negative 0-1+ FISH HER2 / CEP 17 ratio < 2 and FISH HER2 gene copy number < 4.0 *These definitions depend on laboratory documentation of the following: proof of initial testing validation in which positive and negative HER2 categories are 95% concordant with alternative validated method or same validated method for HER2; ongoing internal QA procedures; participation in external proficiency testing; current accreditation by valid accrediting agency. Wolff A, et al. J Clin Oncol. 2013;31(31):3997-4013.

Controversy in Testing

Patient Case First-Line MBC Therapy A 53-year-old female presents with inflammatory breast cancer. Her breast biopsy reveals a poorly differentiated infiltrating ductal breast cancer The tumor is ER(-), PR(-), HER2 amplified (ratio 4.3) Metastatic workup reveals small volume metastases to both the lung and liver Labs reveal only minimal elevation of alkaline phosphatase

What Systemic Therapy Will You Initiate for Her Stage IV Breast Cancer? 1. Weekly paclitaxel 2. Weekly paclitaxel + trastuzumab 3. Weekly paclitaxel + trastuzumab + pertuzumab 4. Docetaxel + trastuzumab + pertuzumab 5. TCHP: docetaxel + carboplatin + trastuzumab + pertuzumab

Patient Case Progressive MBC 44-year-old female with metastatic HER2- positive breast cancer Diagnosed 12 months ago with breast cancer metastatic to the liver Liver biopsy demonstrated adenocarcinoma, ER / PR-negative, HER2-positive Treated with pertuzumab, trastuzumab, and docetaxel with initial partial response Progressive disease in liver after 12 months Performance status 0

How Would You Treat This Patient? 1. Trastuzumab-DM1 2. Lapatinib + capecitabine 3. Lapatinib + trastuzumab 4. Trastuzumab + vinorelbine 5. Trastuzumab / vinorelbine + everolimus

Targeted Therapies for HER2+ Breast Cancer: Trastuzumab, Lapatinib, Pertuzumab, and T-DM1 Available at: http://am.asco.org/her2-pathway-breast-cancer.

Chemotherapy Plus Trastuzumab in Metastatic Disease Slamon et al n = 469 Treatment Arms AC or T* vs AC or T H Time to Disease Progression (mos) 4.6 7.4 P value Marty et al n = 186 Docetaxel vs Docetaxel H P value < 0.001 6.1 11.7 0.0001 Response Rate 32% 50% < 0.001 34% 61% 0.0002 Median Overall Survival (mos) 20 25 0.046 23 31 0.0325 *T = paclitaxel; H = trastuzumab. Hudis CA. N Engl J Med. 2007;357:36-51; Slamon DJ, et al. N Engl J Med. 2001;344:783-792; Marty M, et al. J Clin Oncol. 2005;23:4265-4267.

Phase III Trial Comparing Paclitaxel + Lapatinib or Trastuzumab as First-Line Therapy for HER2+ MBC NCIC CTG MA.31 HER+ MBC No prior anthracycline / taxane-based chemotherapy in the metastatic setting (N = 600) R A N D O M I Z A T I O N Lapatinib 1250 mg PO daily + Taxane* x 24 weeks Lapatinib 1500 mg PO daily until PD Trastuzumab + Taxane* x 24 weeks Trastuzumab 6 mg/kg IV q3wk until PD Primary Endpoint: PFS *Paclitaxel 80 mg/m 2 IV qwk (3/4) or docetaxel 75 mg/m 2 IV q2wk; 6 mg/kg IV 13 wk or 2 mg/kg qwk. Gelmon K, et al. J Clin Oncol. 2012;(suppl). Abstract LBA671.

Percentage Planned Interim Analysis Nov 2011 100 80 60 Progression-Free Survival Intent to T reat Analysis Median PFS T T AX/ T = 1 1.4 months Median PFS LT AX/ T = 8.8 months HR = 1.33 (95% CI = 1.06-1.67), P = 0.01 40 20 0 T T AX/ T LT AX/ L 0 5 10 15 20 25 30 35 40 # T T AX/ T 318 223 110 44 21 8 1 0 0 # LT AX/ L 318 218 85 35 13 2 0 0 0 T ime (months) Serious Adverse Events Lapatinib / Taxane Lapatinib n = 318 Trastuzumab / Taxane Trastuzumab n = 318 Diarrhea 32 5 Febrile Neutropenia 17 7 Gelmon K, et al. J Clin Oncol. 2012;(suppl). Abstract LBA671.

Phase III CLEOPATRA Study Design First-Line Pertuzumab for MBC HER2+ MBC (N = 800) 90% of enrolled patients trastuzumab naïve R A N D O M I Z A T I O N Docetaxel 75 mg/m 2* q3wk + Trastuzumab 8 mg/kg, 6 mg/kg q3wk + PLACEBO Docetaxel 75 mg/m 2 q3wk +Trastuzumab 8 mg/kg, 6 mg/kg q3wk + Pertuzumab 840 mg cycle 1, 420 mg q3wk Primary endpoint: PFS *Docetaxel can be increased to 100 mg/m 2 q3wk if tolerable. Baselga J, et al. N Engl J Med. 2012;366(2):109-119. Swain S, et al. Lancet Oncol. 2013;14(6):461-471.

Baselga J, et al. N Engl J Med. 2012;366(2):109-119. CLEOPATRA: PFS Independent Assessment

Overall Survival (%) CLEOPATRA: OS 1 year 100 90 80 94% 89% 2 years 81% 3 years 70 60 50 40 69% 66% 50% HR = 0.66 95% CI 0.52-0.84 P = 0.0008 30 N o. a t Ri sk Ptz + T + D Pta + T + D 2 0 10 0 Ptz + T + D: 113 events; median not reached Pta + T + D: 154 events; median 37.6 months 0 5 10 15 20 25 30 35 40 45 50 55 402 387 371 342 317 230 143 84 33 9 0 0 406 383 350 324 285 198 128 67 22 4 0 0 Time (m on t h s) Swain S, et al. Lancet Oncol. 2013;14(6):461-471.

Grade 3 Events CLEOPATRA: Safety Profile Placebo + Trastuzumab + Docetaxel (n = 397) Pertuzumab + Trastuzumab + Docetaxel (n = 407) Neutropenia 46% 49% Febrile neutropenia 8% 14% *Febrile neutropenia in Asian patients 11.7% 25.6% Leukopenia 15% 12% Mucosal Inflammation 20% 28% Diarrhea 5% 9% Peripheral neuropathy 2% 3% Anemia 4% 3% Asthenia 2% 3% Fatigue 3% 2% Granulocytopenia 2% 2% LVSD 8% 4% Symptomatic LVSD 1% 2% Decline 10 pts from baseline & to < 50% 7% 4% Dyspnea 2% 1% Baselga J, et al. N Engl J Med. 2012;366(2):109-119. Swain S, et al. Lancet Oncol. 2013;14(6):461-471. Swain S, et al. Oncologist. 2013;18(3):327-264. LVSD = Left ventricular systolic dysfunction *Swain S, et al. SABCS 2013; P4-12-10.

T-DM1: Mechanism of Action HER2 T-DM1 Emtansine release Inhibition of microtubule polymerization Lysosome P P P Internalization Nucleus Adapted from LoRusso PM, et al. Clin Cancer Res. 2011;17:6437-6447.

Phase III Trial: Trastuzumab-DM1 vs Capecitabine + Lapatinib (EMILIA) Study Design Patients with HER2+ locally advanced or MBC previously tx with a taxane and trastuzumab (N = 980) R A N D O M I Z A T I O N Verma S, et al. N Engl J Med. 2012;367:1783-9128. Trastuzumab-DM1 3.6 mg/kg q3wk Lapatinib + Capecitabine Continue until disease progression or unacceptable toxicity occurs Continue until disease progression or unacceptable toxicity occurs Co-Primary Endpoints: OS and PFS 61% of patients in each group had 0-1 prior chemo regimens for locally advanced or metastatic disease. 39% had > 1 prior regimen.

Proportion Progression-Free EMILIA: Progression-Free Survival Independent Review Unstratified HR = 0.66 (P < 0.0001) Verma S, et al. N Engl J Med. 2012;367:1783-9129.

Overall Survival (%) EMILIA: Overall Survival 100 80 60 40 20 M ed i an N o. 85. 2 % ( 95% CI, 82.0-88.5) o f M on t h s Lapa t i n i b C ape c i t ab i n e 25. 1 T - D M 1 30. 9 64. 7 % ( 95 % C I, 59. 3-70.2) 78. 4 % ( 95 % C I, 74. 6-82.3) T - D M 1 51. 8 % ( 95 % C I, 45. 9-57.7) Lapa t i n i b Capecitabine N o. o f E v en t s 182 149 S t r a t i f i ed ha z a r d r a t i o, 0. 6 8 ( 95 % C I, 0. 5 5-0.85) P < 0. 00 1 E ff i c a cy s t opp i ng bounda r y, P = 0. 0037 N o. a t Ri sk Lapa t i n i b c ape c i t ab i n e T - D M 1 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 M on t h s 496 471 453 435 403 368 297 240 204 159 133 110 495 485 474 457 439 418 349 293 242 197 164 136 111 8 6 6 3 8 6 4 5 6 2 2 7 3 8 32 34 36 17 28 7 13 4 5 Verma S, et al. N Engl J Med. 2012;367:1783-9130.

EMILIA: Safety Profile Capecitabine + Lapatinib (n = 488) T-DM1 (n = 490) Adverse Event All Grades Grade 3 All Grades Grade 3 Diarrhea 80% 21% 23% 2% Hand-Foot Syndrome 58% 16% 1% 0% Vomiting 29% 5% 19% 1% Hypokalemia 9% 4% 9% 2% Fatigue 28% 4% 35% 2% Nausea 45% 3% 39% 1% Mucosal Inflammation 19% 2% 7% < 1% Increased AST 9% 1% 22% 4% Increased ALT 9% 1% 17% 3% Thrombocytopenia 3% < 1% 28% 13% Verma S, et al. N Engl J Med. 2012;367:1783-9131.

TDM-4450 Phase II First-Line Study Design Patients with HER2+ locally advanced or MBC (N = 137) Trastuzumab-DM1 3.6 mg/kg q3wk Trastuzumab 6 mg/kg q3wk + Docetaxel 75 or 100 mg/m 2 q3wk Continue until disease progression or unacceptable toxicity occurs Continue until disease progression or unacceptable toxicity occurs crossover to T-DM1 Primary Endpoint: PFS Hurvitz SA, et al. J Clin Oncol. 2013;31(9):1157-1163.

Progression-Free Survival (proportion) TDM-4450 Progression-Free Survival 1.0 0.8 Median PFS n months HR 95% CI Log-rank P H T 70 9.2 T -DM1 67 14.2 0.59 0.36 to 0.97 0.035 0.6 0.4 0.2 No. at risk H T T -DM1 0 2 4 6 8 10 12 14 16 18 20 Time (months) 70 66 63 53 43 27 12 4 2 2 0 67 60 51 46 42 35 22 15 6 3 0 Hurvitz SA, et al. J Clin Oncol. 2013;31(9):1157-1163. HT = trastuzumab + docetaxel

TDM-4450: Select Adverse Events Trastuzumab + Docetaxel (n = 66) T-DM1 (n = 69) All Grades Grade 3-4 All Grades Grade 3-4 Neutropenia 65% 62% 16% 5.8% Thrombocytopenia 6% 3% 28% 7% Leucopenia 26% 24% 10% 0% Febrile Neutropenia 14% 14% 0% 0% Alopecia 67% 0% 4% 0% Fatigue 46% 5% 49% 0% Diarrhea 46% 3% 16% 0% Peripheral Edema 44% 6% 10% 0% Increased AST 6% 0% 44% 9% Headache 18% 0% 41% 0% Arthralgias 30% 2% 23% 0% Pneumonia 2% 0% 9% 6% Hurvitz SA, et al. J Clin Oncol. 2013;31(9):1157-1163.

T-DM1 vs Physician s Choice in Patients Who Have Received at Least 2 Prior Regimens of HER2-Targeted Therapy (TH3RESA) Metastatic or unresectable locally advanced HER2+ BC Prior trastuzumab, taxane and lapatinib R A N D O M I Z A T I O N T-DM1 3.6 mg/kg IV every 21 days Physician s choice: chemo, hormone therapy, biologic, HER2-targeted Primary Endpoints: PFS, OS Available at: http://clinicaltrials.gov/nct014191971.

Proportion Progression-Free TH3RESA Progression-Free Survival 1.0 0.8 0.6 Median (months) Number of events TPC* (n = 198) 3.3 129 T rastuzumab emtansine* (n = 404) 6.2 219 Stratified HR = 0.528 (95% CI: 0.422-0.661) P < 0.0001 0.4 0.2 0.0 0 2 4 6 8 10 12 14 T ime (months) CI = confidence interval; HR = hazard ratio; TPC = treatment of physician s choice *Median follow-up: TPC = 6.5 months; trastuzumab emtansine = 7.2 months. Wildiers H, et al. ESMO 2013. LBA 15.

Proportion Surviving TH3RESA Overall Survival 1.0 0.8 0.6 0.4 0.2 0.0 Median (months) Number of events TPC* (n = 198) 14.9 44 T rastuzumab emtansine* (n = 404) NE 61 Stratified HR = 0.552 (95% CI: 0.369-0.826) P < 0.0034 E f ficacy stopping boundary: HR < 0.363 or P < 0.0000013 0 2 4 6 8 10 12 14 14 T ime (months) CI = confidence interval; HR = hazard ratio; NE = not established; TPC = treatment of physician *Observed 21% of target events. Wildiers H, et al. ESMO 2013. LBA 15.

Phase III MARIANNE Study Design HER2+ Progressive or recurrent locally advanced or chemotherapynaïve MBC (N = 1092) R A N D O M I Z A T I O N TRASTUZUMAB q3wk + DOCETAXEL q3wk OR PACLITAXEL qwk T-DM1 + PERTUZUMAB q3wk T-DM1 + PLACEBO q3wk Primary endpoint: PFS Available at: www.clinicaltrials.gov/nct 01120184.

PI3K / AKT / mtor Pathway GF mutation of PIK3CA R e s i st ance t o t r a st u z um a b? IRS1 loss of PTEN SOS SCH GRB2 GD P GT P GD P GT P PI3K Ras Raf P1P2 P1P3 PDK1 LKB1 PTEN AMPK AK T FOXO GSK3 IKK BAD p A K T = s u r r og a t e o f an ac t i v a t ed p a t h w ay 4EBP1 eif4e MAPK MEK ERK RSK TSC2 RHEB m T OR S6K eif4b S6 P r oli f e r a t ion S u r v i v al Lu CH. Clin Cancer Res. 2007;13:5883-5888.

Morrow PK, et al. J Clin Oncol. 2011;29(23):3126-3123. Hurvitz SA, et al. Breast Cancer Res Treat. 2013;141:437-446. Phase I / II Everolimus Experience Everolimus 10 mg qday and Trastuzumab 6 mg/kg q3wk Best Response N (%) N = 47 Complete response (CR) Partial response (PR) 7 (15%) Stable disease 24 weeks (SD) - 9 (19%) Overall response rate 7 (15%) Clinical benefit rate 16 (34%) Median PFS Most frequent grade 3 / 4 adverse events (> 10%) 4.1 months Lymphopenia, hyperglycemia, mucositis Everolimus 10 mg qday, Paclitaxel 80 mg/m 2 days 1, 8, and 15 q4wk + Trastuzumab 2 mg/kg qwk Best Response N (%) N = 48 Complete response (CR) Partial response (PR) 9 (19%) Stable disease (SD) 30 (62%) Overall response rate 9 (19%) Clinical benefit rate 19 (40%) Progressive disease 9 (19%) Most frequent grade 3 / 4 adverse events (> 10%) - Neutropenia, lymphopenia, stomatitis

Phase III Trial of Everolimus in Combination With Trastuzumab and Paclitaxel as Frontline Therapy for HER2+ MBC (BOLERO-1) HER+ MBC No prior anthracycline / taxane-based chemotherapy in the metastatic setting (N = 719) R A N D O M I Z A T I O N Everolimus 10 mg PO + Paclitaxel 80 mg/m 2 qwk d 1, 8, 15 + Trastuzumab 2 mg/kg d 1, 8, 15, 22 Placebo + Paclitaxel 80 mg/m 2 qwk d 1, 8, 15 + Trastuzumab 2 mg/kg d 1, 8, 15, 22 Primary Endpoint: PFS Available at: www.clinicaltrials.gov/nct 00876395.

Phase III Trial of Daily Everolimus in Combination With Trastuzumab and Vinorelbine in Pretreated HER2+ MBC (BOLERO-3) HER+ MBC Prior trastuzumab and taxane-based chemotherapy (No more than 3 prior lines of tx for MBC) (N = 569) R A N D O M I Z A T I O N > 40% had > 2 prior regimens Everolimus 5 mg PO + Vinorelbine 25 mg/m 2 weekly + Trastuzumab 2 mg/kg weekly (n = 284) Placebo + Vinorelbine 25 mg/m 2 weekly + Trastuzumab 2 mg/kg weekly (n = 285) Primary Endpoint: PFS Andre F, et al. Lancet Oncology. 2014;15(6):580-591.

BOLERO-3: Primary Endpoint Progression-Free Survival by Local Assessment 100 Hazard ratio = 0.78; 95% CI 0.65-0.95 P value = 0.0067 80 Median PFS Everolimus: 7.00 months; 95% CI 6.74-8.18 Placebo: 5.78 months; 95% CI 5.49-6.90 60 40 20 Censoring times Everolimus (n/n = 196 / 284) Placebo (n/n = 219 / 285) 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Time, weeks 90 96 102 Number of Patients Still at Risk Everolimus 284 259 233 200 161 126 98 78 54 40 35 26 18 14 14 9 5 4 Placebo 285 253 202 177 138 109 85 64 49 38 26 23 19 16 12 10 7 4 Andre F, et al. Lancet Oncology. 2014;15(6):580-591.

BOLERO-3: 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 Andre F, et al. Lancet Oncology. 2014;15(6):580-591. 0.25 0.5 1 2 4 Favors EVE Favors PBO 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)

BOLERO-3: Safety Profile Everolimus Arm (n = 280) Placebo Arm (n = 282) All Grades Grade 3-4 All Grades Grade 3-4 Stomatitis 63% 13% 28% 1% Pyrexia 39% 3% 23% 1% Decreased Appetite 33% 1% 17% 1% Fatigue 43% 12% 42% 4% Diarrhea 38% 4% 31% 1% Nausea 35% 3% 37% 1% Constipation 30% < 1% 31% < 1% Rash 25% 0% 18% 1% Noninfectious Pneumonitis 6% < 1% 3% 1% Hyperlipidemia 2% 0% 1% 0% Hyperglycemia 9% 6% 5% 3% Andre F, et al. Lancet Oncology. 2014;15(6):580-591.

HER2 Beyond Progression Author Agents N TTP PFS OS Von Minckwitz et al Capecitabine + trastuzumab vs capecitabine 156 8.2 months vs 5.6 months, P = 0.03 NR 25.5 months vs 20.4 months, P = 0.257 Geyer et al Capecitabine + lapatinib vs capecitabine 324 8.4 months vs 4.4 months, P < 0.001 8.4 months vs 4.1 months, P < 0.001 19 months vs 16 months, P = 0.206 Blackwell et al Lapatinib + trastuzumab vs lapatinib 296 NR 12 weeks vs 8.1 weeks, P = 0.008 14 months vs 9.5 months, P = 0.026 Blackwell K, et al. J Clin Oncol. 2010;28(7):1124-1130; Blackwell K, et al. J Clin Oncol. June 11, 2012. Epub; Geyer CE, et al. N Engl J Med. 2006;355:2733-2743; Cameron D, et al. Oncologist. 2010;15(9):924-934; Von Minckwitz G, et al. J Clin Oncol. 2009;27(12):1999-2006.

Patient Case Frontline Therapy A 42-year-old female presents with new right breast mass Examination demonstrates a 3 cm mass in the right breast with a palpable right axillary lymph node Mammogram: suspicious mass right breast Ultrasound: 2.8 cm mass right breast with suspicious right axillary node

Patient Case Continued Biopsy: IDC, ER-35%, PR-negative, HER2 3+, Ki67 82% Lymph node aspirate: positive for malignant cells Systemic staging demonstrates 4 cm right breast mass, right axillary nodes, but no distant disease

How Would You Approach This Patient? 1. Pertuzumab + trastuzumab + docetaxel x 4 cycles pre-operatively with FEC x 3 cycles post-operatively 2. Pertuzumab, trastuzumab, carboplatin, and docetaxel for 6 cycles pre-operatively 3. Surgery followed by adjuvant trastuzumab-based chemotherapy

Event-Free Survival Probability Event-Free Survival Probability Event-Free Survival Probability pcr Correlates With Better EFS in Subsets of BC, Including HER2+ BC: a FDA Led Meta-Analysis (N = 11,955 / 1,989 HER2+) HER2+ HER2+ HR+ HER2+ HR- 1.0 1.0 1.0 0.8 0.8 0.8 0.6 0.6 0.6 0.4 HR = 0.39, P < 0.001 0.4 HR = 0.58, P = 0.001 0.4 HR = 0.25, P < 0.001 0.2 0.0 pcr (n = 586) no pcr (n = 1403) 0.2 0.0 pcr (n = 247) no pcr (n = 839) 0.2 0.0 pcr (n = 325) no pcr (n = 510) 0 20 40 60 80 100 120 0 20 40 60 80 100 120 0 20 40 60 80 100 120 Months Since Randomization Months Since Randomization Months Since Randomization Cortazar P, et al. Lancet. 2014. Epub ahead of print.

Phase III NeoALTTO Study Design 6 weeks 12 weeks 9 weeks 34 weeks B A S E L I N E Lapatinib Trastuzumab Lapatinib + trastuzumab Lapatinib + paclitaxel Trastuzumab + paclitaxel Lapatinib + trastuzumab + paclitaxel S U R G E R Y F E C x 3 Lapatinib Trastuzumab Lapatinib + trastuzumab tumor biopsy blood sample PET / CT scan Week 2 tumor biopsy blood sample PET / CT Week 8 PET / CT scan 1. Blood for translational studies 2. Blood for CTC analysis centers only 3. In selected sites only CTC analysis to be also performed at start and completion of adjuvant therapy (W1 and Month 12 FU) Tumor biopsy blood sample Radiotherapy (if indicated) Blood sample Blood sample Baselga J, et al. Lancet. 2012;379(9816):633-640.

NeoALTTO Primary Outcome Measure: pcr* 100% 80% 60% 40% 20% 0% pcr HR+ Subset 25% 30% Lapatinib n = 154 pcr 51% Trastuzumab n = 149 Lapatinib n = 154 Trastuzumab n = 149 Lapatinib + Trastuzumab n = 152 Lapatinib + Trastuzumab n = 152 P Value 16% 23% 42% 0.03 pcr 34% 37% 61% 0.005 HR- Subset *Pathologic complete response (pcr) rate defined as the absence of invasive cancer in the breast at the time of surgery. Baselga J, et al. Lancet. 2012;379(9816):633-640.

Overall Survival NeoALTTO: Does pcr Translate Into Improved EFS and OS? Found correlation between pcr and EFS and OS 3-year EFS was 86% for those who achieved pcr, 72% for those who did not (P = 0.0003) OS was 94% for those who achieved pcr, 87% for those who did not (P = 0.005) Most notable in HRnegative disease Not powered to detect difference in survival between study arms 100% 80% 60% 40% 20% 0% pcr no pcr pcr status No. patients No. deaths 3 yr OS rate Hazard ratio P value pcr no pcr 137 262 9 42 95% 87% 0.35 (0.15, 0.70) 0.005 0 1 2 3 4 Y ears Since Landmark Date (30 wks after randomization) Piccart-Gebhart M, et al. Presented at the 2013 San Antonio Breast Cancer Symposium. Abstract S1-01.

NeoALTTO Safety Outcomes Number of Patients With Grade 3 Adverse Events Lapatinib (n = 154) Trastuzumab (n = 149) Lapatinib + Trastuzumab (n = 152) Diarrhea 23% 2% 21% Hepatic 13% 1% 9% Neutropenia 16% 3% 9% Skin Disorders 7% 3% 7% No major cardiac dysfunction noted One death in the lapatinib + trastuzumab arm immediately after end of treatment Baselga J, et al. Lancet. 2012;379(9816):633-640.

Phase III Adjuvant Lapatinib and / or Trastuzumab Treatment Optimization (ALTTO) Surgery At least 4 cycles of (neo) adjuvant chemotherapy Design 1 no concurrent taxane Design 2 concurrent taxane (12 weeks) R A N D O M I Z A T I O N Trastuzumab Lapatinib Trastuzumab Break Lapatinib 12 weeks 6 weeks 34 weeks Lapatinib + Trastuzumab Available at: http://www.cancer.gov/search/clinical_trials/.gov..

Pct of Patients Alive and Disease Free ALLTO: Disease-Free Survival 100% 80% 60% 40% 20% 0% Lap+ T ras T ras->lap T ras Lap+ T ras T ras->lap T ras MFU = 4.5 yrs Arm Lap+ T ras T ras->lap T ras No. Patients No. Events 4 yr DFS rate 2093 254 2091 284 2097 301 88% 87% 86% 0 1 2 3 4 5 Y ears Since Randomization Hazard Ratio c.f. T ras* 0.84 (0.70, 1.02) 0.96 (0.80, 1.15) *97.5% CI P value 0.048 0.610 2093 1938 1832 1672 1256 474 2091 1957 1822 1684 1261 476 2097 1959 1838 1658 1246 448 P value < 0.025 required for statistical significance. Piccart-Gebhart M, et al. Presented at the 2014 ASCO Annual Meeting.

Pct of Patients Alive and Disease Free ALLTO: DFS by Chemotherapy Timing 100% Sequential (Design 1) Sequential (Design 2 & 2B) 80% 60% 40% 20% 0% Lap+ T ras T ras->lap T ras Lap+ T ras T ras->lap T ras MFU = 4.9 yrs Arm No. No. Lap+ T ras Patients Events 1155 168 T ras->lap 1143 184 T ras 1147 207 4 yr DFS rate 86% 85% 83% 0 1 2 3 4 5 Y ears Since Randomization Hazard Ratio c.f. T ras* 0.80 (0.65, 0.98) 0.90 (0.74, 1.10) *95% CI P value 0.034 0.317 1155 1057 995 935 875 399 1143 1147 1060 1060 985 990 941 913 891 846 409 382 Lap+ T ras T ras->lap T ras MFU = 3.9 yrs Arm No. Patients Lap+ T ras T ras->lap T ras No. Events 938 86 948 100 950 94 4 yr DFS rate 90% 89% 90% 0 1 2 3 4 5 Y ears Since Randomization Hazard Ratio c.f. T ras* 0.94 (0.70, 1.26) 1.08 (0.81, 1.43) *95% CI P value 0.680 0.593 938 881 837 737 381 75 948 950 897 899 837 848 743 745 370 400 67 66 Interaction T ests P = 0.41 L+ T P T Piccart-Gebhart M, et al. Presented at the 2014 ASCO Annual Meeting.

ALLTO: Overall Survival 100% Percentage of Patients Alive 80% 60% 40% 20% 0% Lap+ T ras T ras->lap T ras Lap+ T ras T ras->lap T ras MFU = 4.5 yrs Arm Lap+ T ras T ras->lap T ras No. Patients No. Deaths 4 yr OS rate 2093 106 2091 119 2097 135 95% 95% 94% Hazard Ratio c.f. T ras* 0.80 (0.62, 1.03) 0.91 (0.71, 1.16) *95% CI P value 0.078 0.433 0 1 2 3 4 5 Y ears Since Randomization 2093 1979 1930 1795 1362 533 2091 2005 1933 1805 1368 521 2097 2023 1949 1804 1373 508 Piccart-Gebhart M, et al. Presented at the 2014 ASCO Annual Meeting.

% of Cardiac Events % of AEs by T reatment Arm ALLTO: Adverse Events 100 Diarrhea Hepatobiliary Rash or Erythema 80 75 60 50 55 49 40 20 0 20 (15) (5) (1) 23 24 (3) (3) 16 (1) (5) (4) 20 (1) AEs L+ T L T P < 0.001 for incidence for all arms when compared to T 10 8 Any Cardiac Event CARDIAC SAFETY Primary Cardiac Event 6 4 2 0 3.7 4.5 2.4 0.97 0.25 0.86 L+ T T -> L T alone L+ T T -> L T alone Note: Primary CE: cardiac death or severe CHF NYHA Class III-IV; Secondary CE: asymptomatic (NYHA I) or mildly symptomatic (NYHA II) significant confirmed drop in LVEF. A significant LVEF drop is defined as an absolute decrease of > 10 points below the baseline LVEF and to < 50%. Piccart-Gebhart M, et al. Presented at the 2014 ASCO Annual Meeting.

Phase II NeoSphere Study Design Docetaxel q3wk x 4 FEC q3wk x 3 + Trastuzumab q3wk cycles 5-17 FEC = 5-fluorouracil, epirubicin, and cyclophosphamide. Gianni L, et al. Lancet Oncol. 2012;13(1):25-32.

NeoSphere Primary Outcome Measure: pcr* 100% 80% 60% P = 0.014 P = 0.019 P = 0.003 TH n = 107 THP n = 107 40% HP n = 107 TP n = 96 20% 0% 29% 46% pcr 17% 24% *Pathologic complete response (pcr) rate defined as the absence of invasive cancer in the breast at the time of surgery. T = docetaxel; H = trastuzumab, P = pertuzumab. Gianni L, et al. Lancet Oncol. 2012;13(1):25-32.

NeoSphere Safety Outcomes Most Common Grade 3 Adverse Events TH (n = 107) THP (n = 107) HP (n = 108) TP (n = 94) Neutropenia 57% 44.9 1% 55.3 Febrile Neutropenia 8% 8% - 7% Leukopenia 12% 5% - 7% Diarrhea 4% 6% - 4% Asthenia - 2% - 2% Granulocytopenia 1% 1% - 2% Rash 2% 2% - 1% Menstruation Irregularity 1% 1% - 4% Drug Hypersensitivity - 1% 2% - ALT Increase 3% - - 1% One case of CHF developed in the trastuzumab + pertuzumab (HP) arm. Gianni L, et al. Lancet Oncol. 2012;13(1):25-32.

Phase II TBCRC 006 66 patients with HER2+ tumors > 3 cm or > 2 cm with palpable nodes Bx 0 Lapatinib 1000 mg po daily Trastuzumab 2 mg/kg qwk 2 8 12 Plus letrozole or goserelin (pre-menopausal patients) if ER+ Rimawi MF, et al. J Clin Oncol. 2013;31(14):1726-1731. S U R G E R Y 100% 80% 60% 40% 20% 0% 28.0% All Patients 21.0% Increased pcr in the absence of cytotoxic chemotherapy pcr Breast 40.0% ER + ER - Addition of estrogen blockade in ER+ patients led to increased efficacy when compared to NeoSphere (ER+ pcr 6%)

Chemotherapy + Dual Targeted Therapy Evidence of Benefit pcr Breast NeoALTTO (N = 455) NSABP B-41 (N = 529) NeoSphere (N = 417) TBCRC 006 (N = 66 ) Phase III III II II Chemo + T 30% 53% 22% - Chemo + L 25% 53% - - Chemo + TL 51% 62% - - Dual Targeted Therapy Alone 17% (Trastuzumab + Pertuzumab) 28% (Trastuzumab + Lapatinib) T = trastuzumab; L = lapatinib. All show an increased pcr rate in ER- tumors Baselga J, et al. Lancet. 2012;379(9816):633-640; Robidoux A, et al. J Clin Oncol. 2012;30(suppl). Abstract LBA506; Gianni L, et al. Lancet Oncol. 2012;13(1):25-32; Chang JCN, et al. J Clin Oncol. 2011;29(suppl). Abstract 505.

On the Horizon

Phase III Trial of Pertuzumab + Chemotherapy + Trastuzumab as Adjuvant Therapy (APHINITY) Nonmetastatic node-positive HER2+ BC S U R G E R Y R A N D O M I Z A T I O N Placebo + Trastuzumab 6-8 cycles of AC- or non-ac-based chemo Pertuzumab + Trastuzumab 6-8 cycles of AC- or non AC-based chemo Primary endpoint: invasive diseasefree survival (IDFS) 52 weeks Available at: http://clinicaltrials.gov/nct01358877.

NSABP B-52 Study Design HR+ HER2+ operable or locally advanced breast cancer Docetaxel, Carboplatin, Trastuzumab, and Pertuzumab x 6 courses Docetaxel, carboplatin, trastuzumab, and pertuzumab plus goserelin and aromatase inhibitor for pre-menopausal and aromatase inhibitor for postmenopausal women S U R G E R Y R A D I A T I O N Trastuzumab every 21 days x 1 year Trastuzumab every 21 days x 1 year Available at: http://clinicaltrials.gov/nct02003209. Primary outcome: rate of pcr in breast and lymph nodes

Phase II Study of T-DM1 vs Paclitaxel + Trastuzumab for Stage I HER2+ Breast Cancer (ATEMPT) Stage I confirmed invasive carcinoma of the breast Confirmed HER2+ S U R G E R Y R A N D O M I Z A T I O N T-DM1 Q3wk x 17 weeks Paclitaxel + Trastuzumab Qwk x 12 Trastuzumab q3wk x 13 weeks Primary endpoint: diseasefree survival (DFS) Available at: http://clinicaltrials.gov/nct01853748.

Clinical Implications Combined HER2 targeting with 2 different mechanisms of action improves pcr The combination of monoclonal antibodies targeting HER2 without chemotherapy results in substantial pcr rate We need to explore this group to determine which patients may not need chemotherapy Will the increase in pcr translate into improvements in efficacy?

Opportunities for Novel Agents of the Next Decade Learning how to optimize anti-her2 therapy in all stages of breast cancer Continued HER2 therapy benefits HER2-positive patients post-disease progression but which agents and which combinations will provide the most efficacy and least toxicity? Will it be possible to treat patients with individualized targeted regimens alone and omit cytotoxic therapy?

HER2 Testing Polling Question A 48-year-old female presents with a T2, N1 (1+), M0 infiltrating ductal carcinoma of the right breast The malignancy is ER+, PR-, and HER2 2+ FISH testing is performed and the ratio is 1.9

What Do You Now Believe is the Next Best Course of Action? 1. Repeat FISH testing using another specimen and / or perform IHC test on same specimen 2. Treat patient with chemotherapy + trastuzumab 3. Treat patient with chemotherapy without trastuzumab

Patient Case First-Line MBC Therapy A 53-year-old female presents with inflammatory breast cancer. Her breast biopsy reveals a poorly differentiated infiltrating ductal breast cancer The tumor is ER(-), PR(-), HER2 amplified (ratio 4.3) Metastatic workup reveals small volume metastases to both the lung and liver Labs reveal only minimal elevation of alkaline phosphatase

What Systemic Therapy Will You Now Initiate for Her Stage IV Breast Cancer? 1. Weekly paclitaxel 2. Weekly paclitaxel + trastuzumab 3. Weekly paclitaxel + trastuzumab + pertuzumab 4. Docetaxel + trastuzumab + pertuzumab 5. TCHP: docetaxel + carboplatin + trastuzumab + pertuzumab

Patient Case Progressive MBC 44-year-old female with metastatic HER2- positive breast cancer Diagnosed 12 months ago with breast cancer metastatic to the liver Liver biopsy demonstrated adenocarcinoma, ER / PR-negative, HER2-positive Treated with pertuzumab, trastuzumab, and docetaxel with initial partial response Progressive disease in liver after 12 months Performance status 0

After Participating in This Education Program, How Would You Treat This Patient? 1. Trastuzumab-DM1 2. Lapatinib + capecitabine 3. Lapatinib + trastuzumab 4. Trastuzumab + vinorelbine 5. Trastuzumab / vinorelbine + everolimus

Patient Case Frontline Therapy A 42-year-old female presents with new right breast mass Examination demonstrates a 3 cm mass in the right breast with a palpable right axillary lymph node Mammogram: suspicious mass right breast Ultrasound: 2.8 cm mass right breast with suspicious right axillary node

Patient Case Continued Biopsy: IDC, ER-35%, PR-negative, HER2 3+, Ki67 82% Lymph node aspirate: positive for malignant cells Systemic staging demonstrates 4 cm right breast mass, right axillary nodes, but no distant disease

How Would You Approach This Patient Now? 1. Pertuzumab + trastuzumab + docetaxel x 4 cycles pre-operatively with FEC x 3 cycles post-operatively 2. Pertuzumab, trastuzumab, carboplatin, and docetaxel for 6 cycles pre-operatively 3. Surgery followed by adjuvant trastuzumab-based chemotherapy