ESMO E-Learning: Present and Emerging Treatment Options in ... · PRESENT AND EMERGING TREATMENT OPTIONS IN HER2/NEU OVEREXPRESSING METASTATIC BREAST CANCER Rupert Bartsch1 and Christoph

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

OS

DFS

BREAST CANCER IS A

HETEROGENEOUS GROUP OF DISEASES

Adapted from Sorlie T, et al. Proc Natl Acad Sci U S A 2001;98(19):10869-10874. Copyright 2001 National Academy of Sciences

INCIDENCE OF METASTASES IN

DEPENDENCE FROM THE

MOLECULAR SUBTYPEC

umul

ativ

e in

cide

nce

of m

etas

tase

s

Time since diagnosis (years)

Luminal A

Luminal B

Luminal HER2+

HER2+ enriched

Basal

Nonbasal TN

p<0.001

Kennecke H, et al. J Clin Oncol 2010;28:3271-3277. Reprinted with permission © 2010 American Society of Clinical Oncology. All rights reserved.

Cumulative incidence curves of first distant metastasis by breast cancer subtype

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)

OVERALL SURVIVAL FROM MBC IN

DEPENDENCE ON MOLECULAR

CHARACTERISTICS

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

Erb-B1

HER1

EGFR

Erb-B2

HER2/neu

Erb-B3

HER3

Tyrosine

kinase

domain

Ligand-

binding

domain

Erb-B4

HER4

TGF-α

EGF

Epiregulin

Betacellulin

HB-EGF

Amphiregulin Heregulin

Heregulin (neuregulin-1)

Epiregulin

HB-EGF

Neuregulins-3, -4

No ligand-

binding

activity*

Ligands

THE HER FAMILY OF RECEPTORS

*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

Dawood S, et al. J Clin Oncol 2010;28(1):92-98. Reprinted with permission © 2010 American Society of Clinical Oncology. All rights reserved.

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

HERCEPTIN SC VIAL VS. SID

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

FEC500/75/500 mg/m2

HER2-positive

EBC (N=596)

Safety, tumour response pCR Safety, EFS, OS

PK

Follow-up:

24 month for EFS, OSHerceptin IV

Herceptin SC

Sur

gery

Trastuzumab SCFixed dose of 600 mg(5 mL over 5 minutes)

Trastuzumab IV8 mg/kg loading dose;6 mg/kg maintenancedose

Docetaxel75 mg/m2

R

1:1

1 year (18 cycles) Herceptin

Primary endpoint

Show non-inferiority of SC vs. IV based on co-primary endpoints

PK: observed Trastuzumab Ctrough pre-dose Cycle 8 (pre-surgery)

Efficacy: pathological complete response (pCR) in the breast

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.

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

HANNAH SUB-ANALYSIS

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 SUBGROUPSSubgroup 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 betterRedrawn from Baselga J, et al. N Engl J Med 2012;366:109-119.

T-DM1: MECHANISM OF ACTION

Emtansine

release

Inhibition of

microtubule

polymerisation

Internalisation

HER2

T-DM1

Lysosome

Nucleus

PP

P

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.

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: ANALYSIS OF EFFICACY

ACCORDING TO LINE OF TREATMENT

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)

T-DM1 IN PRETREATED HER2-

POSITIVE MBC: EMILIA

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

(n=496)

T-DM1

(n=495)

Prior treatment type, n (%)

Taxanes

Anthracyclines

Endocrine agents

494 (100)

302 (61)

204 (41)

493 (100)

303 (61)

205 (41)

Prior therapy for MBC, n (%)

Yes

No

438 (88)

58 (12)

435 (88)

60 (12)

Prior trastuzumab treatment, n (%)

EBC only495 (100)

77 (16)

495 (100)

78 (16)

Duration of trastuzumab treatment, n (%)

<1 yr

≥1 yr212 (43)

284 (57)

210 (42)

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

Median, mos (95% CI)

Cap + Lap 6.5 (5.5, 7.2)

T-DM1 12.6 (8.4, 20.8)

Per

cent

Difference: 12.7% (95% CI, 6.0, 19.4)P=0.0002

0

20

30

40

50

10

T-DM1

173/397120/389

43.6%

30.8%

Cap + Lap

DOR

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

0.0

0.2

0.4

0.6

0.8

1.0

Pro

port

ion

prog

ress

ion-

free

120 105 77 48 32 14 9 8 3 3 1 1 0 0 0 0

173 159 126 84 65 47 42 33 27 19 12 8 2 0 0 0

Cap + Lap

T-DM1

No. at risk0

0

0

0

0

0

Blackwell K, et al. J Clin Oncol 2012;30(18_suppl):abstr LBA1.

EMILIA: 2ND INTERIM ANALYSIS

OF OS

0 2 10 14 18 24 26 280

20

40

60

80

100

Ove

rall

surv

ival

(%

)

MonthsNo. 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

Stratified hazard ratio, 0.68

(95% CI, 0.55-0.85)

p<0.001

Efficacy stopping boundary,

p=0.0037 or hazard ratio, 0.73

12 3020 221684 6

T-DM1

Lapatinib-capecitabine

Median no. of months No. of events

Lapatinib-capecitabine 25.1 182

T-DM1 30.9 149

32 34 36

51.8% (95% CI, 45.9-57.7)

78.4% (95% CI, 74.6-82.3)

85.2% (95% CI, 82.0-88.5)

64.7% (95% CI, 59.3-70.2)

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 .

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

T-DM1 IN PRETREATED HER2-

POSITIVE MBC: TH3RESA

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.

Pro

gres

sion

-fre

e su

rviv

al (

%)

Physician’s

choice

(n=198)

Trastuzumab

emtansine

(n=404)

Median PFS (95% CI),

months3.3 (2.89-4.14) 6.2 (5.59-6.87)

Events 129 219

0

20

40

60

80

100

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

Physician’s choice

Trastuzumab emtasine

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?

CURRENT STANDARDS

AND CAVEATS

Baselga J, et al. N Engl J Med 2012;366:109-119; Dzimitrowicz H, et al. J Clin Oncol 2016;34:3511-3517.

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

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

T-DM1 AS FIRST-LINE TREATMENT

IN HER2-POSITIVE MBC: MARIANNE

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.

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

• HER2-positive (central)

LABCa or MBC

• No prior chemotherapy for

LABC/MBC

• >6 months from prior neo-

/adjuvant vinca alkaloid or

taxane chemotherapy

N=1095

Trastuzumab + docetaxel

(8 mg/kg then 6 mg/kg + 100 or 75 mg/m2 q3w)

Trastuzumab + paclitaxel

(4 mg/kg LD then 2 mg/kg + 80 mg/m2 qw)

T-DM1 + placebob

(3.6 mg/kg + 840 mg LD then 420 mg q3w)

T-DM1 + pertuzumab

(3.6 mg/kg + 840 mg LD then 420 mg q3w)

Median follow-up 35 months

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

T-DM1 AS FIRST-LINE TREATMENT

IN HER2-POSITIVE MBC: MARIANNE

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/.

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

MARIANNE: UPDATE OS

Perez EA, et al. Abst. #1003; presented at the 2017 ASCO Annual Meeting, June 2017, Chicago, USA. By permission of Prof EA Perez.


Disease progression on or after first-line trastuzumab

Prior taxane-treatment required

TRASTUZUMAB/PERTUZUMAB AS

SECOND-LINE TREATMENT: PHEREXA

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

• HER2-positive MBC

(centrally confirmed)

• Prior taxane and H

• Progression during or after

H-based therapy for MBC

N=452

Arm A

H (8 mg/kg→6 mg/kg) + X (1,250 mg/m2)

n=224

Arm B

H (8 mg/kg→6 mg/kg) + X (1,000 mg/m2) + P (840 mg→420 mg)

n=228

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)

First pt included: Jan 30, 2010

Last pt included: Aug 12, 2013

Clinical cut-off: May 29 2015

1

1

Day 0 Day 21

Lapatinib: First-generation (reversible) inhibitor of the tyrosine-kinase domains of

HER2 and EGFR

Inhibits Akt and ERK1/2, resulting in upregulation of pro-apoptotic genes1-3

Increased rate of apoptosis is associated with clinical response (n=33 biopsy

samples)4

LAPATINIB:

MECHANISMS OF ACTION

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.

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%

MA.31 (NCT00667251)1:

PFS AND SAFETY

Gelmon KA, et al. J Clin Oncol 2015;33:1574-1583. Reprinted with permission. © 2015. American Society of Clinical Oncology. All rights reserved.

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

LAPATINIB: ALTERNATIVE

MECHANISMS OF ACTION

Scaltriti M, et al. Oncogene 2009;28:803-814.


Lapatinib vs. lapatinib plus trastuzumab

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

T PLUS L: DUAL HER2 INHIBITION

IN MBC: PFS AND OS BENEFIT

PFS OS

Blackwell KL, et al. J Clin Oncol 2010;28:1124-1130. Reprinted with permission © (2012) American Society of Clinical Oncology. All rights reserved.

HER2-POSITIVE MBC


Current standards



T-DM1





Brain metastases

Novel approaches




Evidence from two randomised Phase III studies1,2

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%

HER2-TARGETED TREATMENT

PLUS ENDOCRINE THERAPY IN

LUMINAL B/HER2-POSITIVE MBC

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


Current standards



T-DM1





Brain metastases

Novel approaches




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)

BREAST CANCER - BRAIN

METASTASES: INCIDENCE

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.

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

IMPACT OF ANTI-HER2 AFTER

DIAGNOSIS OF BRAIN METASTASES1

Survival functions

Cum

ulat

ive

surv

ival

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.

[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)

THE BLOOD-BRAIN-BARRIER

A

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.

Decreased concentration of anti-cancer

drugs in brain metastases as compared

with extracranial lesions, even with small

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

THE BLOOD-BRAIN-BARRIER

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

64Cu-DOTA-trastuzumab PET images of metastatic brain

tumours in patients with HER2-positive primary breast tumours4

Retrospective case series; T-DM1:

Newly diagnosed or progressive

brain metastases1

n=10 patients; 80% prior local therapy;

60% prior lapatinib

Response: PR (RANO3) 30%; SD 40%

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

OS: not reached at 8.5 months median FU

T-DM1 IN BRAIN METASTASES

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.

cMRT before and after

administration of 4 cycles

of T-DM12

TRASTUZUMAB RESISTANCE

Redundancy of signal transduction

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.

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

DIFFERENT MOLECULAR

MECHANISMS DETERMINE RESPONSE AND

RESISTANCE TO TRASTUZUMAB AND LAPATINIB

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.

PI3K / AKT activation as resistance mechanism in HER2/neu overexpressing breast cancer

resulted in clinical trials of PI3K inhibitors in trastuzumab-resistance

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.

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

HER2/NEU SOMATIC MUTATIONS IN

BREAST CANCER

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


Current standards



T-DM1





Brain metastases

Novel approaches




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

OUTLOOK: NERATINIB IN FIRST

LINE, THE NEFERT-T1 STUDY

1. Awada A, et al. JAMA Oncol 2016;2:1557-1564.

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

OUTLOOK: TUCATINIB –

3RD-GENERATION HER2-TKI1,2

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

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

Primary endpoint Phase II:

Safety and efficacy in PD-L1 expressing cancers

Patients• Centrally confirmed HER2+

• ECOG 0-1

• Tumour biopsy sample <1 yr

• Measurable disease RECIST 1.1

• No limit of prior systemic

treatment

• Documented PD on trastuzumab

or TDM-1

PD-L1+

PD-L1 -

Phase Ib

Pembrolizumab

2 mg/kg and 10 mg/kg IV+

Trastuzumab Q3W

Phase II

Pembrolizumab 200 mg IV+

trastuzumab Q3W

Phase II

Pembrolizumab 200mg IV+

Trastuzumab Q3W

Protocol-specified

follow-up treatment until

progression, toxicity,

patient withdrawal,

investigator decision,

or maximum 2 years

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

HER2: PANACEA1

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

http://www.meduniwien.ac.at/index.php?id=164

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)

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

Response-

Evaluable

Patients¹

Disease

Control

Rate

Partial

Response

Stable

Disease

Progressive

Disease

Total (n=42) 33 18 (55%) 12 (36%) 6 (18%) 15 (45%)

Breast Cancer

(n=20)18 9 (50%) 6 (33%) 3 (17%) 9 (50%)

Gastroesophageal

Cancer (n=13)9 5 (56%) 4 (44%) 1 (12%) 4 (44%)

Other cancers (n=9) 6 4 (67%) 2 (33%) 2 (33%) 2 (33%)

Colorectal (n=5) 3 2 (67%) 1 (33%) 1 (33%) 1 (33%)

Other (n=4) 3 2 (67%) 1 (33%) 1 (33%) 1 (33%)

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.

Best RECIST 1.1 Response to Single Agent ZW25 Safety Overview

No dose-limiting toxicities

• Treatment-related AEs all Grade 1 or 2 except in one

patient Reversible Grade 3 hypophosphatemia,

arthralgia and fatigue (10 mg/kg QW)

• No treatment-related serious adverse events or

discontinuations

• No LVEF decreases ≥ 10% during treatment

• No new detectable anti-drug antibodies

Data cut-off date 18 April 2018; n=42 patients receiving ˂1 to 15+

treatment cycles (1 cycle = 28 days)

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%)

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

HER2-Positive

BC N=111

HER2-Low

BC N=34

HER2-Positive

GC N=44

Other Cancers

N=51

Confirmed ORR*,

% (n/N)54.5% (54/99) 50.0% (17/34) 43.2% (19/44) 38.7% (12/31)

DCR, % (n/N) 93.9% (93/99) 85.3% (29/34) 79.5% (35/44) 83.9% (26/31)

ORR in modified

ITT**, % (n/N)48.6% (54/111) 50.0% (17/34) 43.2% (19/44) 23.5% (12/51)

DOR

Median, (95% CI),

monthsNR 11.0 (NA) 7.0 (NA) 12.9 (2.8, 12.9)

PFS

Median, (95%, CI),

monthsNR 12.9 (NA) 5.6 (3.0, 8.3) 12.1 (2.7, 14.1)

Min, max 1.0,22.2 0.5, 19.6+ 1.2, 19.6+ 0.7, 14.1+

Efficacy Outcomes by Cancer Type (5.4) or 6.4 mg/kg)

*Confirmed response includes subjects who had ≥2 postbaseline scans, had progressive disease, or discontinued

treatment for any reason prior to second postbaseline scan.

**modified ITT population included all subjects who received ≥1 dose of DS-8201a at either 5.4 or 6.4 mg/kg, including

those subjects who were too early to assess, but are ongoing on study.

+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.

Overall N=241*

Any TEAEs 238 (98.8%)

Grade ≥3 TEAEs 121 (50.2%)

Drug-related TEAEs 235 (97.5%)

Grade ≥3 drug-related TEAEs 101 (41.9%)

Serious TEAEs 50 (20.7%)

Drug-related serious TEAEs 27 (11.2%)

TEAEs leading to treatment

discontinuation23 (9.5%)

TEAEs leading to death** 10 (4.1%)

Overall Safety Profile (5.4 or 6.4 mg/kg)

*Included all subjects who received ≥1 dose of DS-8201a at either 5.4 or 6.4 mg/kg.

**Cause of death included pneumonitis (4), disease progression (2), interstitial lung disease (1),

Ileus (1), pneumonia aspiration (1), pneumonia (1), TEAE, treatment-emergent adverse event.

Data cut-off for this analysis is April 18, 2018.

CONCLUSIONS

Evidence for ameliorated efficacy of HER2-targeting MBC

Targeted monotherapy

Trastuzumab

Lapatinib, reversible TKI

T-DM1

Targeted combinations

Trastuzumab + lapatinib

Trastuzumab + pertuzumab


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

1. Wolff AC, et al. J Clin Oncol 2013;31:3997-4014. Reprinted with permission. © 2013. American Society of Clinical Oncology. All rights reserved

THANK YOU!

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ESMO E-Learning: Present and Emerging Treatment Options in ... · PRESENT AND EMERGING TREATMENT OPTIONS IN HER2/NEU OVEREXPRESSING METASTATIC BREAST CANCER Rupert Bartsch1 and Christoph