Metastatic HER2-Positive Breast Cancer:
Treatment Selection and Sequencing in the
First Line and Beyond
Moderator:
Panelist:
Joseph Gligorov, MD, PhD
Javier Cortés, MD, PhD
Head, Cancer Coordination Center HUEP
University Cancer Institute
Sorbonne University
Paris, France
Head, Breast Cancer Program
Department of Oncology
Vall d'Hebron University Hospital
Barcelona, Spain
Panelist:
Panelist:
Carlos H. Barrios, MD
David W. Miles, MD
Professor of Internal Medicine;
Director, Oncology Research Unit
Pontifícia Universidade Católica
Porto Alegre, Brazil
Consultant Medical Oncologist
Mount Vernon Cancer Centre
London, United Kingdom
This Program Will Review:
• Recent clinical trial data on the management of
HER2+ advanced and MBC
• Challenges of integrating HER2-targeting agents into
clinical practice
–
–
–
–
Selecting a first-line treatment
Sequencing treatments in second line and beyond
Knowing how to proceed when evidence is unclear
Balancing treatment efficacy with patient quality of
life
HER2 = human epidermal growth factor 2; MBC = metastatic breast cancer
Historical Context: Targeting HER2
• First demonstration of clinical benefit with HER2 targeting:
the addition of trastuzumab to chemotherapy*
Chemotherapy +
Trastuzumab
(n=236)
Chemotherapy
Alone
(n=234)
P value
Median time to
disease progression
7.4 months
4.6 months
HR=0.51
P<.001
Median TTF
6.9 months
4.5 months
HR=0.58
P<.001
Median OS
25.1 months
20.3 months
HR=0.80
P=.046
*Either anthracycline + cyclophosphamide or paclitaxel
HR = hazard ratio; OS = overall survival; TTF= time to treatment failure
Slamon DJ, et al. N Engl J Med. 2001;344(11):783-792.
Historical Context: Targeting HER2 (cont)
Paclitaxel +
Trastuzumab
(n=92)
Paclitaxel
Alone
(n=96)
P value
Median time to
disease progression
6.9 months
3.0 months
HR=0.38
P<.001
Median TTF
5.8 months
2.9 months
HR=0.46
P<.001
Median OS
22.1 months
18.4 months
HR=0.80
P=.17
Slamon DJ, et al. N Engl J Med. 2001;344(11):783-792.
Pertuzumab and Trastuzumab:
Mechanisms of Action
Trastuzumab
binds to subdomain IV
and inhibits
downstream signalling
Pertuzumab binds to a
specific domain II and
inhibits ligand-activated
dimerization
HER2
HER1-4
Cell membrane
The combined regimen of pertuzumab and trastuzumab offers the potential
for a more comprehensive HER blockade
Franklin MC, et al. Cancer Cell. 2004;5(4):317-328.
Phase 2 Study: Pertuzumab + Trastuzumab in
Patients Progressing on Trastuzumab
Objective response rate
Clinical benefit rate*
Pertuzumab +
Trastuzumab[a]
(n=66)
Pertuzumab
Alone[c]
(n=29)
Pertuzumab 
Pertuzumab +
Trastuzumab[c]
(n=17)
24.2%
3.4%
17.6%
50%
10.3%
41.2%
*Defined as complete response, partial response, and stable disease ≥ 6 months
a. Baselga J, et al. J Clin Oncol. 2010;28(7):1138-1144.
b. Cortes J, et al. J Clin Oncol. 2012;30(14):1594-1600.
CLEOPATRA: Trastuzumab + Docetaxel +
Pertuzumab or Placebo
808 patients
with centrally
confirmed
HER2+ MBC
1:1
R
A
N
D
O
M
I
Z
E
Trastuzumab + pertuzumab until
progressive disease
≥ 6 cycles of docetaxel
recommended
Trastuzumab + placebo until
progressive disease
≥ 6 cycles of docetaxel
recommended
Study dosing every 3 weeks
• Pertuzumab/Placebo: 840 mg loading dose, 420 mg maintenance
• Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance
• Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated
Baselga J, et al. N Engl J Med. 2012;366(2):109-119.
CLEOPATRA: Updated Survival Results
Median PFS
Pertuzumab +
Trastuzumab +
Docetaxel
(n=402)
Placebo +
Trastuzumab +
Docetaxel
(n=406)
18.7 months
12.4 months
Improvement: 6.3 months
Median OS
56.5 months
40.8 months
Improvement: 15.7 months
PFS = progression-free survival
Swain SJ, et al. ESMO 2014. Abstract 350O_PR.
P value
HR=0.68
P<.0001
HR=0.68
P<.0002
CLEOPATRA: Adverse Events
Pertuzumab +
Trastuzumab +
Docetaxel
(n=408)
Placebo +
Trastuzumab +
Docetaxel
(n=396)
Leukopenia
12.3%
14.9%
Neutropenia
49.0%
46.2%
Febrile neutropenia
13.7%
7.6%
Diarrhea (grade 3/4)
9.3%
5.1%
LVEF decline to < 50% and by
≥ 10% points from baseline
6.1%
7.4%
Grade 3/4 hematologic AEs
AE = adverse event; LVEF = left ventricular ejection fraction
Swain SJ, et al. ESMO 2014. Abstract 350O_PR.
PERUSE: Pertuzumab + Trastuzumab +
Investigator’s Choice of Taxane
Select Grade 3/4 AEs (Initial Results)
All patients (N=704)
Docetaxel (n=320)
Paclitaxel (n=331)
Nab-paclitaxel (n=45)
14
Patients (%)
12
10
8
6
4
2
0
Neutropenia
Diarrhea
Bachelot T, et al. ASCO 2014. Abstract 548.
Febrile
neutropenia
Anemia
Mucosal
inflammation
Fatigue
Asthenia
VELVET: Pertuzumab + Trastuzumab + Vinorelbine
Selected AEs (Interim Analysis)
VELVET[a]
HERNATA[b]
Diarrhea
49.1%
11.6%
Alopecia
23.6%
NR
Neutropenia (grade 3/4)
23.6%
41.5%
Febrile neutropenia
5.7%
10.8%
Leukopenia (grade 3/4)
8.5%
21
a. Perez E, et al. SABCS 2013. Abstract P2-16-10.
b. Andersson M, et al. J Clin Oncol. 2011;29(3):264-271.
MARIANNE: T-DM1 + Pertuzumab or Placebo vs
Trastuzumab + Taxane
Arm A
1092 patients
with HER2+
MBC
1:1:1
R
A
N
D
O
M
I
Z
E
Trastuzumab + taxane until
progressive disease
Arm B
T-DM1 + pertuzumab until
progressive disease
Arm C
T-DM1 + placebo until progressive
disease
Primary endpoint: PFS (independent assessment)
T-DM1 = trastuzumab emtansine
Ellis PA, et al. ASCO 2011. Abstract TPS102.
First-Line Treatment: Applying Trial Data to
Clinical Practice
• Patients on HER2-blocking regimens have better
outcomes than ever before
• Dual blockade with trastuzumab + pertuzumab is the
standard of care -- maximal blockade of HER2 is clearly
critical
• Choice of chemotherapy may not be as important for
treatment outcomes; choice of chemotherapy arm is
important to minimize side effects
• More research will help determine whether some
populations might do well with dual HER2 blockade
only, without chemotherapy
The Benefits of Continued HER2 Blockade
Beyond Progression
Trastuzumab +
Capecitabine vs
Capecitabine[a]
Lapatinib +
Capecitabine vs
Capecitabine[b,c]
Median TTP
8.2 vs 5.6 months
HR=0.69; P=.0338
6.2 vs 4.3 months
HR=0.57; P<.001
Median OS
25.5 vs 20.4 months
HR=0.76; P=.257
75.0 vs 64.7 weeks
HR=0.87; P=.206
TTP = time to progression
a. Von Minckwitz G, et al. J Clin Oncol. 2009;27(12):1999-2006.
b. Cameron D, et al. Breast Cancer Res Treat. 2008;112(3):533-543.
c. Cameron D, et al. Oncologist. 2010;15(9):924-934.
T-DM1: Antibody Drug Conjugate
HER2
HER2
Cell membrane
Intracellular emtansine release 
inhibition of microtubule polymerization
LoRusso PM, et al. Clin Cancer Res. 2011;17(20):6437-6447.
EMILIA: T-DM1 vs Lapatinib + Capecitabine
• 991 patients previously treated with trastuzumab and a
taxane
T-DM1
Lapatinib +
Capecitabine
P value
Median PFS
9.4 months
6.4 month
HR=.65
P<.0001
Median OS
30.9 months
25.1 months
HR=.682
P=.0006
12-month
survival rate
85.2%
78.4%
24-month
survival rate
64.7%
51.8%
Verma S, et al. N Engl J Med. 2012;367(19):1783-1791.
EGF104900: Trastuzumab + Lapatinib
• 296 patients previously treated with trastuzumab and a
taxane randomly assigned (1:1) to lapatinib ± trastuzumab
Lapatinib
Lapatinib +
Trastuzumab
P value
Median PFS
8.1 weeks
11.1 weeks
HR=0.74
P=.011
Median OS
9.5 months
14.0 months
HR=0.74
P=.026
12-month
survival rate
80%
56%
24-month
survival rate
70%
41%
Blackwell K, et al. J Clin Oncol. 2012;30(21):2585-9252.
BOLERO-3: Trastuzumab + the mTOR Inhibitor
Everolimus
• PI3K/Akt/mTOR pathway is upregulated in trastuzumab
resistant HER2+ MBC
• Everolimus is an mTORC1 inhibitor that downregulates
activity of the pathway
Design
• 569 patients previously treated with trastuzumab +
taxane
• Treated with trastuzumab + vinorelbine +
everolimus or placebo
Outcomes
• PFS: 7.00 vs 5.78 months; HR=0.78; P=.0067
• ORR: 41% vs 37%; P=.2108
ORR = overall response rate
Andre F, et al. Lancet Oncol. 2014;15(6):580-591.
TH3RESA: T-DM1 in Heavily Pretreated MBC
• 600 patients previously treated with ≥ 2 prior therapies
(trastuzumab, lapatinib, taxane) randomly assigned (2:1) to
T-DM1 or treatment of physician’s choice*
ORR
Median PFS
Median OS
(interim analysis)
T-DM1
Physician’s choice
P value
31.3%
8.6%
P<.0001
6.2 months
3.3 months
HR=0.528
P<.0001
NE
14.9 months
HR=0.552
P=.0034
*Single-agent chemotherapy, hormonal therapy, or HER2-directed therapy, or a combination of a
HER2-directed therapy with a chemotherapy, hormonal therapy, or other HER2-directed therapy.
NE = not estimable
Krop IE, et al. Lancet Oncol. 2014 ;15(7):689-699.
Second-Line and Beyond: Applying Trial Data to
Clinical Practice
• Continued blockade of HER2 is clearly beneficial
• T-DM1 is the standard of care for second-line
treatment; there are no patient populations not
likely to benefit
• More research is needed to define the optimal
treatment regimen in different patient populations
– Role for pertuzumab if not given in the first line
– Sequence of treatments beyond first line
– Using toxicity to drive treatment selection
Conclusions
• Multiple available treatments significantly prolong
OS in patients with HER2+ MBC
• Standard of care at all stages: continued HER2+
blockade
– First-line: trastuzumab + pertuzumab (CLEOPATRA)
– Second-line: T-DM1 (EMILIA)
• Ongoing research will help define the best use of
each agent in each line of therapy
• With appropriate use of these drugs, HER2+ MBC is
beginning to turn into a chronic disease with very
good quality of life
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