Present and Emerging Treatment Options in Her2/Neu Overexpressing Metastatic Breast Cancer

PRESENT AND EMERGING TREATMENT OPTIONS IN HER2/NEU OVEREXPRESSING METASTATIC BREAST CANCER

Rupert Bartsch1 and Christoph Zielinski2 1Clinical Division of Oncology, Department of Medicine I and 2Comprehensive Cancer Center, Medical University Vienna - General Hospital, Vienna, Austria BREAST CANCER IS A HETEROGENEOUS GROUP OF DISEASES

DFS

Cumulative incidence curves of first distant metastasis by breast cancer subtype

Luminal A Luminal B Luminal HER2+ HER2+ enriched Basal Nonbasal TN

Cumulative incidence of metastases of incidence Cumulative p<0.001

Time since diagnosis (years)

Kennecke H, et al. J Clin Oncol 2010;28:3271-3277. Reprinted with permission © 2010 American Society of Clinical Oncology. All rights reserved. OVERALL SURVIVAL FROM MBC IN DEPENDENCE ON MOLECULAR CHARACTERISTICS

 Analysis of outcome in 189 primary breast cancer cases

 HER2 amplification in 30%

 Significant correlation with DFS and OS

 Stronger prognosticator of outcome than the most relevant “conventional” markers such as nodal status and hormone-receptor

 3,726 patients

 Median observation: 14.8 years

 Median OS from diagnosis of MBC:

 Luminal A: 2.2 years

 HER2 positive: 0.7 years (remark: pre-Trastuzumab)

 Basal: 0.5 years (p<0.001)

Slamon D, et al. Science 1987;235:177-182; Kennecke H, et al. J Clin Oncol 2010;28:3271-3277. THE HER FAMILY OF RECEPTORS

TGF-α EGF Ligands Epiregulin No ligand- Betacellulin Heregulin (neuregulin-1) HB-EGF binding Epiregulin Amphiregulin activity* Heregulin HB-EGF Neuregulins-3, -4 Ligand- binding domain

Tyrosine kinase Erb-B1 Erb-B2 Erb-B3 domain HER1 neu HER3 HER2/ Erb-B4 EGFR HER4

*HER2 dimerizes with other members of the HER family.

Adapted from Roskoski R Jr. Biochem Biophys Res Commun 2004;319(1):1-11; Adapted from Rowinsky EK. Annu Rev Med.2004;55:433-457. HER2/NEU

Molecular pathways and clinical characteristics of breast cancer

 HER2 gene amplification is associated with increased tumour proliferation

 HER2 amplification is associated with high-grade disease, nodal metastases, tumour size, and inversely correlated with ER status

 HER2 activates ER in a low-oestrogen environment

 ER activates intracellular signalling potentiating HER2 activity and downregulates HER2 expression

 This negative loop is neutralised by HER2 overexpression

 Tumour proliferation linked to RAS/MAPK cascade

 Increased cell migration and lymph node involvement linked to Akt/PI3 kinase activity

Bartlett JMS, et al. J Clin Oncol 2007;25:4423. HER2-POSITIVE MBC

Evidence for targeted treatment

Current standards

 Chemotherapy plus trastuzumab

 Chemotherapy plus trastuzumab/pertuzumab

 T-DM1

 Trastuzumab/lapatinib

 Lapatinib/capecitabine

Specific treatment situations

 Trastuzumab or lapatinib plus aromatase-inhibitors

 Brain metastases

Novel approaches

 Second- and third-generation TKIs (neratinib, tucatinib)

 Immunotherapy with checkpoint inhibitors

 Optimised antibodies and ADCs TRASTUZUMAB IN HER2-POSITIVE MBC A unique story of success

Phase III trial, 469 patients, MBC, HER2-pos, first-line1

 AC +/- trastuzumab or paclitaxel +/- trastuzumab

 PFS: 7.4 versus 4.6 months; p<0.001

 OS: 25.1 versus 20.3 months; p=0.046

Phase II trial, 186 patients, MBC, first-line2

 Docetaxel +/- trastuzumab

 PFS: 11.7 versus 6.1 months; p=0.0001

 OS: 31.2 versus 22.7 months; p=0.0325

1. From N Engl J Med, Slamon DJ, et al. Use of Chemotherapy plus a Monoclonal Antibody against HER2 for Metastatic Breast Cancer That Overexpresses HER22001;344:783–92. Copyright © 2001 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society 2. Marty M, et al. J Clin Oncol, 23(19), 2005: 4265–74. Reprinted with permission. © 2005 American Society of Clinical Oncology. All rights reserved. OS IN DEPENDENCE FROM TRASTUZUMAB-TREATMENT AND HER2-STATUS

Comparative pharmacokinetics of trastuzumab subcutaneous formulation administered using a proprietary single-use injection device, or manually using a syringe

 Bioequivalence for the co-primary PK endpoints, AUC0–21 days and Cmax, between Herceptin SC administered using the SID and hand-held manual syringe was demonstrated

 Overall secondary PK parameters were also comparable between the two methods of administration

 SID: no failures, consistently high performance; tolerability did not differ from administration from the hand-held syringe

 Herceptin SID may have even greater potential to improve patient convenience

Wynne C, et al. ESMO 2012;abstr 2219. HANNAH

Randomised open-label Phase III non-inferiority study to compare the PK, efficacy and safety of trastuzumab SC and IV in HER2-positive EBC Herceptin SC

HER2-positive R Follow-up: EBC (N=596) 1:1 24 month for EFS, OS Herceptin IV Surgery

Trastuzumab SC 1 year (18 cycles) Herceptin Fixed dose of 600 mg (5 mL over 5 minutes) Safety, tumour response pCR Safety, EFS, OS Trastuzumab IV PK 8 mg/kg loading dose; 6 mg/kg maintenance Primary endpoint dose Show non-inferiority of SC vs. IV based on co-primary endpoints Docetaxel 2 75 mg/m  PK: observed Trastuzumab Ctrough pre-dose Cycle 8 (pre-surgery)

FEC  Efficacy: pathological complete response (pCR) in the breast 500/75/500 mg/m2 Reprinted from Lancet Oncology, 2012; 13(9), Ismael G, et al., Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I–III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial, 869-878, © Copyright 2012, with permission from Elsevier. HANNAH SUB-ANALYSIS

Pathological complete response to trastuzumab subcutaneous fixed-dose formulation in the HannaH study

 Subgroup analysis of patient demographics and tumour characteristics and

influence of body weight (BW) and serum trough (Ctrough) concentration of trastuzumab:

 Numerically higher pCR rate point estimate in Herceptin SC vs. IV in the majority of subgroups

 The 600 mg fixed dose of Herceptin SC is efficacious irrespective of body weight

 Additional analyses and MLR showed neither body weight nor serum Ctrough of Herceptin affected efficacy in either treatment arm

Melichar B, et al. ESMO 2012 Poster discussion: abstr 2546(254PD). TRASTUZUMAB: ESCAPE-MECHANISMS

 High EGFR expression (Smith I, et al. 1993)

 Overexpression of insulin- like growth factor receptor I (IGF-RI) with amplification of the PI-3K pathway (Nahta R, et al. 2005)

 Somatic mutations of the HER2/neu gene (Shigematsu H, et al. 2006)

Siena S, et al. J Natl Cancer Inst 2009;101(19):1308-1324. By permission of Oxford University Press. HALLMARKS OF THE HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 (HER2) -HER3 ACTIVATION AND SIGNALLING PATHWAY

Makhija S, et al. J Clin Oncol 2010;28(7):1215-1223. Reprinted with permission © 2010 American Society of Clinical Oncology. All rights reserved. PERTUZUMAB AND TRASTUZUMAB BIND TO DIFFERENT REGIONS ON HER2 Synergistic activity

Reprinted from Cancer Cell, 2004;5 (4), Badache A and Hynes NE, A new therapeutic antibody masks ErbB2 to its partners, 299-301, © 2004, with permission from Elsevier. TRASTUZUMAB PLUS PERTUZUMAB IN HER2-POSITIVE MBC The CLEOPATRA trial

Phase III trial, 808 pat., MBC, HER2-pos., first-line Docetaxel (D) + trastuzumab (T) +/- pertuzumab (P)

Pertuzumab: Anti-HER2 antibody preventing HER2 / HER3 heterodimerization

PFS 18.5 vs. 12.4 months HR=0.62; 95% CI 0.51−0.75; p<0.001

50 months median follow-up: D+TP 56.5 vs. D+T 40.8 months HR 0.68; 95% CI 0.56–0.84; p=0.0002

1. From N Engl J Med, Baselga J, et al. Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer, 366:109-119. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. 2. From N Engl J Med, Swain S, et al. Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer ,372 (8):724-734. Copyright © 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Swain SM, et al. Lancet Oncol 2013;14:461-471 CLEOPATRA: PROGRESSION-FREE SURVIVAL IN PRESPECIFIED SUBGROUPS

Subgroup No. of patients Hazard ratio (95% CI) All patients 808 0.63 (0.52-0.76) Previous neoadjuvant or adjuvant chemotherapy No 432 0.63 (0.49-0.82) Yes 376 0.61 (0.46-0.81) Geographic region Europe 306 0.72 (0.53-0.97) North America 135 0.51 (0.31-0.84) South America 114 0.46 (0.27-0.78) Asia 253 0.68 (0.48-0.95) Age group <65 yr 681 0.65 (0.53-0.80) ≥65 yr 127 0.52 (0.31-0.86) <75 yr 789 0.64 (0.53-0.78) ≥75 yr 19 0.55 (0.12-2.54) Race or ethnic group White 480 0.62 (0.49-0.80) Black 30 0.64 (0.23-1.79) Asian 261 0.68 (0.49-0.95) Other 37 0.39 (0.13-1.18) Disease type Visceral disease 630 0.55 (0.45-0.68) Nonvisceral disease 178 0.96 (0.61-1.52) Hormone-receptor status ER-positive, PgR-positive, or both 388 0.72 (0.55-0.95) ER-negative and PgR-negative 408 0.55 (0.42-0.72) ER and PgR status unknown 12 - HER2 status IHC 3+ 721 0.60 (0.49-0.74) FISH-positive 767 0.64 (0.53-0.78) 0.0 0.2 0.4 0.6 1.0 2.0 Pertuzumab better Placebo better Redrawn from Baselga J, et al. N Engl J Med 2012;366:109-119. T-DM1: MECHANISM OF ACTION

HER2 T-DM1

Emtansine release

P Inhibition of P microtubule P polymerisation Lysosome

Internalisation

Nucleus

Adapted from LoRusso PM, et al. Clin Cancer Res 2011;17:6437. SCHEMATIC OF TRASTUZUMAB- DM1 (T-DM1) INCLUDING THE [N-MALEIMIDOMETHYL] CYCLOHEXANE-1- CARBOXYLATE (MCC) LINKER

Krop IE, et al. J Clin Oncol 2010;28(16):2698-2704. Reprinted with permission © 2010 American Society of Clinical Oncology. All rights reserved. T-DM1: ANALYSIS OF EFFICACY ACCORDING TO LINE OF TREATMENT

1. Pretreated HER2-positive MBC: EMILIA phase III trial (T-DM1 vs. lapatinib/capecitabine)

2. Pretreated HER2-positive MBC: TH3RESA phase III trial (T-DM1 vs. treatment by physician’s choice)

3. First-line treatment for HER2-positive MBC: MARIANNE phase III trial (T-DM1 vs. trastuzumab + docetaxel vs. T-DM1 + pertuzumab) T-DM1 IN PRETREATED HER2- POSITIVE MBC: EMILIA

 Phase III trial, 991 patients, HER2-positive MBC

 T-DM1 versus lapatinib plus capecitabine

 Second-line after progression on first-line therapy with taxanes plus trastuzumab

 Progression within 6 months after the end of trastuzumab- therapy for early-stage disease

 PFS 9.6 months versus 6.4 months (HR 0.65; 95% CI 0.55- 0.77; p<0.001)

From N Engl J Med, Verma S, et al. Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer, 367:1783-1791. Copyright © 2012. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. EMILIA: PRIOR SYSTEMIC TREATMENT

Cap + Lap T-DM1 (n=496) (n=495) Prior treatment type, n (%) Taxanes 494 (100) 493 (100) Anthracyclines 302 (61) 303 (61) Endocrine agents 204 (41) 205 (41) Prior therapy for MBC, n (%) Yes 438 (88) 435 (88) No 58 (12) 60 (12) Prior trastuzumab treatment, n (%) 495 (100) 495 (100) EBC only 77 (16) 78 (16) Duration of trastuzumab treatment, n (%) <1 yr 212 (43) 210 (42) ≥1 yr 284 (57) 285 (58) Median time since last trastuzumab, mos (range) 1.5 (0–98) 1.5 (0–63)

Blackwell K, et al. J Clin Oncol 2012;30(18_suppl):abstr LBA1. EMILIA: OBJECTIVE RESPONSE RATE (ORR) AND DURATION OF RESPONSE (DOR) IN PATIENTS WITH MEASURABLE DISEASE ORR DOR Difference: 12.7% (95% CI, 6.0, 19.4) P=0.0002

43.6% Median, mos (95% CI) 50 1.0

Cap + Lap 6.5 (5.5, 7.2) free

- 0.8 T-DM1 12.6 (8.4, 20.8) 40 30.8% 0.6 30 0.4

Percent 20

0.2 Proportion progression Proportion

10 0.0 120/389 173/397 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 No. at risk 0 Cap + Lap 120 105 77 48 32 14 9 8 3 3 1 1 0 0 0 0 0 0 0 Cap + Lap T-DM1 T-DM1 173 159 126 84 65 47 42 33 27 19 12 8 2 0 0 0 0 0 0

Blackwell K, et al. J Clin Oncol 2012;30(18_suppl):abstr LBA1. EMILIA: 2ND INTERIM ANALYSIS OF OS

Median no. of months No. of events Lapatinib-capecitabine 25.1 182 T-DM1 30.9 149 100 85.2% (95% CI, 82.0-88.5)

80 64.7% (95% CI, 59.3-70.2) 78.4% (95% CI, 74.6-82.3) 60 T-DM1

40 Stratified hazard ratio, 0.68 51.8% (95% CI, 45.9-57.7) (95% CI, 0.55-0.85) Lapatinib-capecitabine

Overallsurvival (%) p<0.001 20 Efficacy stopping boundary, p=0.0037 or hazard ratio, 0.73 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Months No. at risk Lapatinib- 496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0 capecitabine T-DM1 495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0 Redrawn from N Engl J Med , Verma S, et al. Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer, 367:1783-1791. Copyright © 2012. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society . T-DM1 IN PRETREATED HER2- POSITIVE MBC: TH3RESA

 Phase III trial, 603 patients, HER2-positive MBC

 T-DM1 versus treatment by physician’s choice (TPC)

 Prior treatment with ≥2 treatment line for MBC

 2:1 randomisation, cross-over allowed

 >80% trastuzumab-base therapy as TPC Physician’s Trastuzumab choice emtansine (n=198) (n=404) 100 Median PFS (95% CI), 3.3 (2.89-4.14) 6.2 (5.59-6.87) months 80 Events 129 219

60 Stratified HR 0.528 (95% CI 0.422-0.661); p<0.0001

Unstratified HR* 0.521 (95% CI 0.418-0.648); p<0.0001

free survival (%) free - 40

20 Physician’s choice

Progression Trastuzumab emtasine 0

Reprinted from Lancet Oncol, 2014; 15, Krop IE, et al. Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. 689-699. Copyright 2014, with permission from Elsevier. CURRENT STANDARDS AND CAVEATS

 First-line: trastuzumab/pertuzumab/docetaxel (CLEOPATRA)

 PFS 18.5 vs. 12.4 months (HR 0.62)

 ~10% of pts. prior exposure to adj. trastuzumab

 PFS: 16.9 vs. 10.4 months (HR 0.62)

 Second-line (and early relapse): T-DM1 (EMILIA)

 Caveat: None of the pts. in EMILIA treated with dual HER2-inhibition in the first-line setting

 Activity of T-DM1 in pts. pretreated with trastuzumab/pertuzumab: Treatment duration ≥6 months 30.8% (95% CI 20.6-41.1)

 Median treatment duration: 4 months (95% CI 2.7-5.1)

 Further questions:

 T-DM1 first-line?

 TP in the second-line setting?

 Beyond second-line? The role of lapatinib?

Baselga J, et al. N Engl J Med 2012;366:109-119; Dzimitrowicz H, et al. J Clin Oncol 2016;34:3511-3517. T-DM1 AS FIRST-LINE TREATMENT IN HER2-POSITIVE MBC: MARIANNE

 Phase III trial, 1,095 patients, HER2-positive MBC

 First-line; >6 months from prior adjuvant/neoadjuvant taxane- or vinorelbine-containing chemo

Trastuzumab + docetaxel • HER2-positive (central) (8 mg/kg then 6 mg/kg + 100 or 75 mg/m2 q3w) LABCa or MBC Trastuzumab + paclitaxel • No prior chemotherapy for (4 mg/kg LD then 2 mg/kg + 80 mg/m2 qw) LABC/MBC

• >6 months from prior neo- b /adjuvant vinca alkaloid or T-DM1 + placebo taxane chemotherapy (3.6 mg/kg + 840 mg LD then 420 mg q3w)

N=1095 T-DM1 + pertuzumab (3.6 mg/kg + 840 mg LD then 420 mg q3w)

 Stratification factors: World region, prior neo-/adjuvant therapy (if yes: prior trastuzumab/lapatinib), visceral disease

 Primary endpoint: PFS by independent review facility (IRF), non-inferiority and superiority assessed

 Key secondary endpoints: OS, PFS by investigator, ORR, safety, patient-reported outcomes

LD, loading dose. aLocally progressive or recurrent and not amenable to resection with curative intent; bPertuzumab placebo. Perez EA, et al. J Clin Oncol 2017;35:141-148. T-DM1 AS FIRST-LINE TREATMENT IN HER2-POSITIVE MBC: MARIANNE

 Median follow-up 35 months

 Prior adjuvant/neoadjuvant trastuzumab: ~30% (CLEOPATRA ~10%)

Perez EA, et al. J Clin Oncol 2017;35:141-148. Reproduced under Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/. MARIANNE: UPDATE OS

 CLEOPATRA (trastuzumab/pertuzumab plus docetaxel) as standard-of-care in the first-line setting but T-DM1 as relevant option in patients not deemed as candidates for standard treatment

Perez EA, et al. Abst. #1003; presented at the 2017 ASCO Annual Meeting, June 2017, Chicago, USA. By permission of Prof EA Perez. TRASTUZUMAB/PERTUZUMAB AS SECOND-LINE TREATMENT: PHEREXA

 Phase III trial, 452 patients, HER2-positive MBC

 Disease progression on or after first-line trastuzumab

 Prior taxane-treatment required

• HER2-positive MBC 1 Arm A (centrally confirmed) H (8 mg/kg→6 mg/kg) + X (1,250 mg/m2) • Prior taxane and H n=224 • Progression during or after H-based therapy for MBC Arm B H (8 mg/kg→6 mg/kg) + X (1,000 mg/m2) + P (840 mg→420 mg) N=452 1 n=228

First pt included: Jan 30, 2010 Last pt included: Aug 12, 2013 Clinical cut-off: May 29 2015

 PFS (independently assessed): 9 vs. 11.1 months (HR 0.82; 95% CI 0.65-1.02; p=0.0731)

 OS 28.1 vs. 36.1 months (HR 0.68; 95% CI 0.51-0.90)

 Formally negative trial – T-DM1 remains the second-line standard in pts. Without prior dual HER2-inhibition (EMILIA)

Urruticoechea A, et al. J Clin Oncol 2017;35:3030-3038. LAPATINIB: MECHANISMS OF ACTION

 Lapatinib: First-generation (reversible) inhibitor of the tyrosine-kinase domains of HER2 and EGFR 1-3  Inhibits Akt and ERK1/2, resulting in upregulation of pro-apoptotic genes

 Increased rate of apoptosis is associated with clinical response (n=33 biopsy samples)4

Day 0 Day 21

1. Rusnak DW et al. Mol Cancer Ther 2001;1:85-94; 2. Hegde PS et al. Mol Cancer Ther 2007;6:1629-1640; 3. Xia W et al. Oncogene 2002;21: 6255-6263; 4. Spector NL et al. J Clin Oncol 2005;23(11):2501-2512. Reprinted with permission © 2011 American Society of Clinical Oncology. All rights reserved. MA.31 (NCT00667251)

First direct comparison of trastuzumab vs. lapatinib in MBC

 Prospective randomised Phase III study

 636 patients, HER2-positive MBC (525 centrally confirmed), first-line treatment

 Trastuzumab plus taxane versus lapatinib plus taxane

 First direct comparison of trastuzumab vs. lapatinib in MBC

 Taxanes: Paclitaxel weekly or docetaxel every three weeks

 Combination therapy for 24 weeks followed by anti-HER2 maintenance

Gelmon KA, et al. J Clin Oncol 2015;33:1574-1583. MA.31 (NCT00667251)1: PFS AND SAFETY

 PFS 9 vs.11.3 months (HR 1.37; 95% CI 1.20 -1.83)

 Safety (647 patients included in the safety analysis):

 Grade 3/4 rash 8% (lapatinib) vs. 0% (trastuzumab)

 Grade 3/4 diarrhoea 19% vs.1%

 Febrile neutropenia rate 17.3% vs. 2%

 Receptor dimerization results in receptor internalisation and degradation in lysosomes

 Lapatinib blocks ubiquitination and inhibits degradation by receptor stabilisation within the membrane

 Potentially improves activity of anti-HER2-mABs

Scaltriti M, et al. Oncogene 2009;28:803-814. T PLUS L: DUAL HER2 INHIBITION IN MBC: PFS AND OS BENEFIT

 Phase III trial, 296 patients, HER2-positive MBC

 Lapatinib vs. lapatinib plus trastuzumab

 Median number of prior trastuzumab-based regimens for MBC: 3 PFS OS

Evidence for targeted treatment

Current standards

 Chemotherapy plus trastuzumab

 Chemotherapy plus trastuzumab/pertuzumab

 T-DM1

 Trastuzumab/lapatinib

 Lapatinib/capecitabine

Specific treatment situations

 Trastuzumab or lapatinib plus aromatase-inhibitors

 Brain metastases

Novel approaches

 Second- and third-generation TKIs (neratinib, tucatinib)

 Immunotherapy with checkpoint inhibitors

 Optimised antibodies and ADCs HER2-TARGETED TREATMENT PLUS ENDOCRINE THERAPY IN LUMINAL B/HER2-POSITIVE MBC

1,2  Evidence from two randomised Phase III studies

 First-line therapy AI +/- HER2-directed therapy

 PFS on AI alone approximately 3 months in both trials indicating primary resistance to endocrine therapy alone

 Limited PFS improvement by the addition of lapatinib or trastuzumab

 No OS benefit

 RR trastuzumab 20.3% vs. 6.8%; RR lapatinib 28% vs. 15%

1. Kaufman B, et al. J Clin Oncol 27(33), 2009:5529–37; 2. Johnston S, et al. J Clin Oncol 27(33), 2009: 5538–46. Both reprinted with permission. ©2009. American Society of Clinical Oncology. All rights reserved. HER2-POSITIVE MBC

Evidence for targeted treatment

Current standards

 Chemotherapy plus trastuzumab

 Chemotherapy plus trastuzumab/pertuzumab

 T-DM1

 Trastuzumab/lapatinib

 Lapatinib/capecitabine

Specific treatment situations

 Trastuzumab or lapatinib plus aromatase-inhibitors

 Brain metastases

Novel approaches

 Second- and third-generation TKIs (neratinib, tucatinib)

 Immunotherapy with checkpoint inhibitors

 Optimised antibodies and ADCs BREAST CANCER - BRAIN METASTASES: INCIDENCE

 Breast cancer is the second most common cause for brain metastases among solid tumours

 Most common cause of leptomeningeal carcinosis

 Increasing incidence since 2000

 Retrospective analysis of >50.000 pts.

 OR for BM 2004-2006 compared to 1998-2000: 1.44, 95% CI 1.13-1.85

 Increased incidence in HER2-positive and TNBC

 HER2-positive: BM in up to 40%;

 Non-luminal/HER2-positive associated with earlier development of BM (shorter BMFS)

Bendell JC, et al. Cancer 2003;97:2972-2977; Clyton AJ, et al. Br J Cancer 2004;91:639-643; Shmueli E, et al. Eur J Cancer 2004;40:379-382; Weil RJ, et al. Am J Pathol 2005;167:913-920; Stemmler HJ and Heinemann V. Oncologist 2008;13:739-750; Bartsch R, et al. BMC Cancer 2009;9:367; Frisk G, et al. Br J Cancer 2012;106:1850-1853; Berghoff A, et al. Br J Cancer 2012;106:440-446. BREAST CANCER – BRAIN METASTASES The patients’ perspective

 Brain metastases (BM) increase morbidity

 BM reduce quality of life

 BM shorten survival

 Greatest conceivable threat for pts. at risk

 Today, OS >24 months is possible in patients with BM

 Prolonged survival of patients with BM – issue of WBRT-associated late toxicity

Slimane K, et al. Ann Oncol 2004;15:1640-1644; Mayer M. Clin Cancer Res 2007;13:1623-1624; Bartsch R, et al. BMC Cancer 2009; 9:367; Chang EL, et al. Lancet Oncol 2009;10:1037-1044; Bartsch R, et al. Br J Cancer 2012;106:25-31. IMPACT OF ANTI-HER2 AFTER DIAGNOSIS OF BRAIN METASTASES1

Survival depends upon ongoing systemic therapy:

 No further treatment: 3 months (95% CI 2.37-3.63)

 Chemotherapy only: 9 months (95% CI 0-20.69)

 + Trastuzumab: 13 months (95% CI 8.85-17.15)

 + Lapatinib: Median OS not reached at 24 months median time of observation

Survival functions Cumulative survival Cumulative

TOO

1. Adapted from Bartsch R, et al. Br J Cancer 2012;106(1):25-31. BREAST CANCER – BRAIN METASTASES Evidence for systemic therapy I

Prospective single-arm phase II trial 242 pts., HER2-positive MBC, progressing after local therapy (~95% WBRT); amendment: Lap+Cap upon PD on lapatinib (50 Pat.) RR lapatinib 6%; minor response 21% RR lapatinib+capecitabine 20%; minor response 40% PFS lapatinib: 2.40 months (95% CI 1.87-2.79) PFS Lap+Cap: 3.65 months (95% CI 2.43- 4.37)

Reprinted from Clin Cancer Res, Copyright 2009, 15:1452-1459, Lin NU, et al. Multicenter Phase II Study of Lapatinib in Patients with brain metastases from HER2-Positive Breast Cancer. With permission from AACR . BREAST CANCER – BRAIN METASTASES Evidence for systemic therapy II

 LANDSCAPE: Primary treatment with lapatinib plus capecitabine in HER2-positive patients with brain metastases – aiming to delay WBRT

 Single-arm Phase II trial

 Primary endpoint RR (CNS): 66%

 Secondary endpoint time-to-WBRT: 8.3 months

 Caveat: non-randomised, 40% of pat. asymptomatic, 95% ECOG <2, no data regarding QoL

 Potential standard in this specific patient subset?

Chang EL, et al. Lancet Oncol 2009;10:1037-1044; Bachelot T, et al. Lancet Oncol 2013;14:64-71; Bartsch R and Preusser M. Lancet Oncol 2013;14:8-9. BREAST CANCER – BRAIN METASTASES Prevention by systemic therapy?

Does modern systemic therapy offer a chance for BM prevention?

CLEOPATRA:1 Improved systemic disease control prolongs BMFS but does not reduce to overall incidence of BM

 (BMFS 11.9 versus 15.0 months; 95% CI, 0.39–0.85; p=0.0049)

CEREBEL:2 Prospective randomised Phase III trial, 540 patients, HER2-positive, Lap+Cap vs. Trast+Cap after progression

 BM incidence (early switch to lapatinib 3% versus 5% (ns)

 Superior PFS (A) and OS (B) with trastuzumab (ITT)

1. Swain SM, et al. Ann Oncol 2014 Jun;25:1116-1121; 2. Pivot X, et al. J Clin Oncol 33(14), 2015:1564–73. Reprinted with permission. © 2015 American Society of Clinical Oncology. All rights reserved. THE BLOOD-BRAIN-BARRIER

A  [11C]lapatinib as PET-Tracer in HER2- positive MBC patients with or without BM

 Three patients with BM, three patients control

 No significant uptake of [11C]lapatinib in healthy brain tissue, significant uptake in BM only (A)

 Clinical relevant concentration of lapatinib and capecitabine in resected BM without prior WBRT (n=12) – high variability (B)

1) Saleem A, et al. EJNMMI Research 2015;5:30. Reprodiced under Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0); 2) Morikawa A, et al. Neuro Oncol 2015;17:289-295 by permission of Oxford University Press. THE BLOOD-BRAIN-BARRIER

 Decreased concentration of anti-cancer drugs in brain metastases as compared 64Cu-DOTA-trastuzumab PET images of metastatic brain with extracranial lesions, even with small tumours in patients with HER2-positive primary breast tumours4 molecules

 Activity of conventional cytotoxics in brain metastases – response rate 50%

 Blood-brain-barrier impaired in the region of metastatic lesions enabling the penetration of anti-cancer drugs into brain metastases

 In principle, large molecules such as chemotherapeutics and even antibodies could provide activity in brain metastases – even trastuzmab can penetrate into brain metastases, but activity of trastuzumab in brain metastases is not proven

1. Rosner D, et al. Cancer 1986;58:832-839; 2. Taskar KS, et al. Pharm Res 2012;29:770-781; 3. Bartsch R, et al. J Neurooncol 2014;116:205-206; 4. Kurihara H, et al. EJNMMI Research 2015;5:8. Reproduced under Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0 T-DM1 IN BRAIN METASTASES

cMRT before and after  Retrospective case series; T-DM1: administration of 4 cycles Newly diagnosed or progressive of T-DM12 brain metastases1

 n=10 patients; 80% prior local therapy; 60% prior lapatinib 3  Response: PR (RANO ) 30%; SD 40%

 PFS: median 5 months (95% CI 3.69-6.32)

 OS: not reached at 8.5 months median FU

1. Reprinted by permission from Springer Nature, Clin Exp Metastasis, Activity of T-DM1 in Her2-positive breast cancer brain metastases, Bartsch R, et al., copyright 2015; 2. Reprinted by permission from Springer Nature, J Neurooncol, Activity of T-DM1 in Her2-positive breast cancer brain metastases, Bartsch R, et al. Copyright 2014; 3. Lin NU, et al. Lancet Oncol 2015;16:e270-278. TRASTUZUMAB RESISTANCE

Redundancy of signal transduction

Preclinical models suggest increased EGFR-expression, increased EGFR- phosphorylation and increased heregulin-expression1

Upregulation of HER2/EGFR-heterodimers1

Increased HER2/HER3 signalling2,3

Increased activity of the IGF-1 pathway4,5

Neoadjuvant trial: IGF-1 receptor-expression correlates inversely with trastuzumab response6

1. Ritter CA, et al. Clin Cancer Res 2007;13:4909-4919; 2. Sergina NV et al. Nature 2007;445:537-441; 3. Chen FL, et al. Clin Cancer Res 2008;14:6730-6734; 4. Nahta R et al. Cancer Res 2005;65:11118-11128; 5. Lu Y, et al. J Natl Cancer Inst 2001;93:1852-1857; 6. Harris LN et al. Cancer Res 2007;13:1198-1207. DIFFERENT MOLECULAR MECHANISMS DETERMINE RESPONSE AND RESISTANCE TO TRASTUZUMAB AND LAPATINIB

PI3K / AKT activation as resistance mechanism in HER2/neu overexpressing breast cancer resulted in clinical trials of PI3K inhibitors in trastuzumab-resistance

Reprinted from Mol Cancer Ther, Copyright 2010, 9(6): 1489-1502, O’Brien NA, et al. Activated Phosphoinositide 3-kinase/AKT Signaling Confers resistance to Trastuzumab but not Lapatinib, with permission from AACR. NEOALTTO1: BENEFIT FOR COMBINATION

Adapted from The Lancet, 379(9816), Baselga J, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open- label, multicentre, phase 3 trial, 633-640, Copyright 2012, with permission from Elsevier. HER2/NEU SOMATIC MUTATIONS IN BREAST CANCER

Reprinted from Cancer Discovery, © 2013, 3(2): 145-147, Weigelt B and Reis-Filho JS, Activating Mutations in HER2: New Opportunities and New Challenges, with permission from AACR. HER2/NEU SOMATIC MUTATIONS IN BREAST CANCER

 Single-arm phase II study of neratinib activity in HER2/neu mutated (HER2- negative) MBC

 Background: 2% of HER2-negative MBC cases have activating HER2/neu mutations

 Activity of neratinib may be retained

 22 /517 patients with activating HER2/neu mutations (4.3%)

 95% ER-positive

 Higher mutation rate in lobular tumours (7.8%)

 CR 1, PR 1, SD ≥6 months 3 (CBR 36%)

 PFS 16 weeks (90% CI 8-31)

 ctDNA sequencing identified the same HER2/neu mutation in 11/14 tumour-positive samples

Bose R, et al. Cancer Discov 2013;3:224-237; Ma CX et al. J Clin Oncol 2016;34(suppl; abstr 516); Reprinted from Clin Cancer Res, Copyright 2017;23:5687-5695, Ma CX, et al. Neratinib Efficacy and Circulating Tumor DNA Detection of HER2 Mutations in HER2 Nonamplified Metastatic Breast Cancer, with permission from AACR. HER2-POSITIVE MBC

Evidence for targeted treatment

Current standards

 Chemotherapy plus trastuzumab

 Chemotherapy plus trastuzumab/pertuzumab

 T-DM1

 Trastuzumab/lapatinib

 Lapatinib/capecitabine

Specific treatment situations

 Trastuzumab or lapatinib plus aromatase-inhibitors

 Brain metastases

Novel approaches

 Second- and third-generation TKIs (neratinib, tucatinib)

 Immunotherapy with checkpoint inhibitors

 Optimised antibodies and ADCs OUTLOOK: NERATINIB IN FIRST LINE, THE NEFERT-T1 STUDY

 Second-generation (irreversible) TKI of EGFR and HER2

 NEfERT-T: Prospective randomised phase III study, trastuzumab plus paclitaxel vs. neratinib plus paclitaxel

 479 pts., MBC, first-line, primary EP: PFS

 PFS neratinib 12.9 months (95% CI 11.1-14.9) vs. trastuzumab 12.9 months (95% CI 11.1-14.8) (HR 1.02; 95% CI 0.81-1.27; p=0.89)

 Lower rate of CNS recurrences and longer brain metastases-free survival (BMFS) with neratinib (RR CNS metastases 0.48; 95% CI 0.29-0.79; p=0.002; BMFS HR 0.45; 95% CI 0.26-0.78; p=0.004)

 Grade 3/4 diarrhoea 30.4% in the neratinib arm

1. Awada A, et al. JAMA Oncol 2016;2:1557-1564. OUTLOOK: TUCATINIB – 3RD-GENERATION HER2-TKI1,2

 Third-generation (irreversible) TK: lower diarrhoea rate due to lower anti-EGFR activity

 Phase Ib study, 60 pts., MBC, prior treatment with trastuzumab, pertuzumab, T-DM1

 Tucatinib plus trastuzumab or capecitabine or both drugs

 Recommended phase II dose 300 mg BID

 Grade 3 diarrhoea 7%

 Response rate 83% (capecitabine), 40% (trastuzumab), 61% (trastuzumab plus capecitabine)

 Preliminary anti-tumour activity in a phase Ib study evaluating the combination of tucatinib and T-DM1

1. Murthy R, et al. Lancet Oncol 2018;19:880-888; 2. Borges VF, et al. JAMA Oncol 2018;4:1214-1220. OUTLOOK Immune checkpoint inhibition in HER2/neu overexpressing breast cancers: KEYNOTE-014 (PANACEA)1

Phase Ib Pembrolizumab Patients 2 mg/kg and 10 mg/kg IV+ • Centrally confirmed HER2+ PD-L1+ Trastuzumab Q3W Protocol-specified • ECOG 0-1 Phase II follow-up treatment until • Tumour biopsy sample <1 yr Pembrolizumab 200 mg IV+ progression, toxicity, • Measurable disease RECIST 1.1 trastuzumab Q3W patient withdrawal, • No limit of prior systemic investigator decision, treatment or maximum 2 years • Documented PD on trastuzumab Phase II PD-L1 - or TDM-1 Pembrolizumab 200mg IV+ Trastuzumab Q3W

Primary endpoint Phase II: Safety and efficacy in PD-L1 expressing cancers

1. Loi S, et al. GS2-06; SABCS 2017. HER2: PANACEA1

 ORR (PD-L1 pos.) 15% (90% CI 7-29)

 DCR (CR+PR+SD ≥6 months) 25% (90% CI 14-49)

 No efficacy in the PD-L1 negative cohort

1. Loi S, et al. GS2-06; SABCS 2017. OUTLOOK

Optimising HER2-directed antibodies – Margetuximab1

Margetuximab: HER2-directed antibody binding with higher affinity to CD16A (Fc-receptor important for antibody dependent cell-mediated cytotoxicity (ADCC) against tumour cells) Phase 1 study, 66 pre-treated patients, different HER2-overexpressing tumours (27 BC), no standard treatment-option available MTD not reached Mainly grade 1/2 toxicity (pyrexia, nausea, anaemia, diarrhoea, fatigue) PR 12%, SD 50% Margetuximab treatment resulted in enhanced ADCC activity compared with trastuzumab SOPHIA phase III trial ongoing (NCT02492711): margetiximab plus chemotherapy vs. trastuzumab plus chemotherapy

1. Bang YJ, et al. First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors, Ann Oncol 2017;28 (4):855–61, by permission of Oxford University Press on behalf of the European Society for Medical Oncology. OUTLOOK

Optimising HER2-directed antibodies – ZW251

ZW25: Bispecific HER2-directed antibody targeting HER2 extracellular domains ECD4 and ECD2 (binding sites of trastuzumab and pertuzumab) Phase Ib study, 42 pts., different HER2-overexpreesing tumours 20 pts. MBC, heavily pre-treated (100% trastuzumab, 95% T-DM1, 85% pertuzumab, 50% lapatinib, 35% other study drugs)

Best RECIST 1.1 Response to Single Agent ZW25 Safety Overview Response- Disease Partial Stable Progressive No dose-limiting toxicities Evaluable Control Response Disease Disease Patients¹ Rate • Treatment-related AEs all Grade 1 or 2 except in one Total (n=42) 33 18 (55%) 12 (36%) 6 (18%) 15 (45%) patient Reversible Grade 3 hypophosphatemia, Breast Cancer 18 9 (50%) 6 (33%) 3 (17%) 9 (50%) arthralgia and fatigue (10 mg/kg QW) (n=20) • No treatment-related serious adverse events or Gastroesophageal 9 5 (56%) 4 (44%) 1 (12%) 4 (44%) discontinuations Cancer (n=13) • No LVEF decreases ≥ 10% during treatment Other cancers (n=9) 6 4 (67%) 2 (33%) 2 (33%) 2 (33%) • No new detectable anti-drug antibodies Colorectal (n=5) 3 2 (67%) 1 (33%) 1 (33%) 1 (33%) Data cut-off date 18 April 2018; n=42 patients receiving ˂1 to 15+ Other (n=4) 3 2 (67%) 1 (33%) 1 (33%) 1 (33%) treatment cycles (1 cycle = 28 days)

DCR: Disease control rate 0 best response of stable disease or partial response at any time ¹response evaluable = measurable disease per RACIST 1.1 and at least one tumour restaging or unequivocal clinical progression. Not evaluable n=9, including: too early (n=3); no target lesions (n=4); withdrawal of consent (n=1); unrelated SAE (n=1). Data cut-off date 18 April 2018.

1. Meric-Bernstam F, et al. Abst. #2500; 2018 ASCO Annual Meeting. OUTLOOK

Optimising HER2-directed antibodies – trastuzumab-deruxtecan1 DS-8201a: ADC with deruxtecan (toposiomerase-I inhibitor) linked to trastuzumab Phase I study including patients with HER2-overexpressing MBC (prior T-DM1 treatment), gastric cancer (prior trastuzumab treatment), HER2-low MBC (IHC 1+, 2+; ISH negative), and other solid cancers with HER2 expression ≥1+ 2 patients grade 5 pneumonitis; nausea 73.5% (≥ grade 3 3.5%), vomiting 39.5% (≥ grade 3 1.5%)

Efficacy Outcomes by Cancer Type (5.4) or 6.4 mg/kg) Overall Safety Profile (5.4 or 6.4 mg/kg) HER2-Positive HER2-Low HER2-Positive Other Cancers Overall N=241* BC N=111 BC N=34 GC N=44 N=51 Confirmed ORR*, Any TEAEs 238 (98.8%) 54.5% (54/99) 50.0% (17/34) 43.2% (19/44) 38.7% (12/31) % (n/N) Grade ≥3 TEAEs 121 (50.2%) DCR, % (n/N) 93.9% (93/99) 85.3% (29/34) 79.5% (35/44) 83.9% (26/31) Drug-related TEAEs 235 (97.5%) ORR in modified 48.6% (54/111) 50.0% (17/34) 43.2% (19/44) 23.5% (12/51) ITT**, % (n/N) Grade ≥3 drug-related TEAEs 101 (41.9%) DOR Serious TEAEs 50 (20.7%) Median, (95% CI), NR 11.0 (NA) 7.0 (NA) 12.9 (2.8, 12.9) months Drug-related serious TEAEs 27 (11.2%) PFS TEAEs leading to treatment Median, (95%, CI), 23 (9.5%) NR 12.9 (NA) 5.6 (3.0, 8.3) 12.1 (2.7, 14.1) discontinuation months Min, max 1.0,22.2 0.5, 19.6+ 1.2, 19.6+ 0.7, 14.1+ TEAEs leading to death** 10 (4.1%)

*Confirmed response includes subjects who had ≥2 postbaseline scans, had progressive disease, or discontinued *Included all subjects who received ≥1 dose of DS-8201a at either 5.4 or 6.4 mg/kg. treatment for any reason prior to second postbaseline scan. **Cause of death included pneumonitis (4), disease progression (2), interstitial lung disease (1), **modified ITT population included all subjects who received ≥1 dose of DS-8201a at either 5.4 or 6.4 mg/kg, including Ileus (1), pneumonia aspiration (1), pneumonia (1), TEAE, treatment-emergent adverse event. those subjects who were too early to assess, but are ongoing on study. Data cut-off for this analysis is April 18, 2018. +after value indicates censoring DCR, disease control rate, DOR, duration of response, GC, gastric/gastroesophageal junction cancer, NR, not reached, ORR, overall response rate Data cut-off for this analysis is April 18, 2018.

1. Iwata H, et al. Abst. #2501; 2018 ASCO Annual Meeting. CONCLUSIONS

Evidence for ameliorated efficacy of HER2-targeting MBC

Targeted monotherapy Trastuzumab Lapatinib, reversible TKI T-DM1

Targeted combinations Trastuzumab + lapatinib Trastuzumab + pertuzumab

Specific treatment situations HER2-directed therapy in combination with ET Systemic therapy of brain metastases OPTIMISING THE DEFINITION OF HER2 POSITIVITY ASCO/CAP guidelines1

Suggested algorithm for HER2-testing with dual-probe ISH-assay