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.
Phase III trial, 452 patients, HER2-positive MBC
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.
Phase III trial, 296 patients, HER2-positive MBC
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
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
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
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 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
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
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.
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
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
1. Wolff AC, et al. J Clin Oncol 2013;31:3997-4014. Reprinted with permission. © 2013. American Society of Clinical Oncology. All rights reserved
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