Managing
HER2- Positive
Breast Cancer in the
Metastatic Setting:
The Evolution of
Targeted Therapies
Howard A. Burris III, MD, FACP
Chief Medical Officer and Director of Drug Development
Sarah Cannon Research Institute
Memphis, TN
Lee Schwartzberg, MD
Medical Director, West Clinic
Chief, Division of Hematology/Oncology
Professor of Medicine
University of Tennessee Health Science Center
Memphis, TN
Breast Cancer Mortality
Breast cancer mortality has dropped by
nearly one-third since 1990
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Lancet. 2011.
1
HER2+ Breast Cancer Subtypes
N=114,786
~21% HER2+
~79% HER2-
7.1%
10.8%
Breakdown of the 21%
HER2+
3.3%
ER+/PR+/HER2+
0.5%
ER+/PR-/HER2+
ER-/PR+/HER2+
ER-/PR-/HER2+
Bauer K., Cancer. 2010;10:228.
2
Survival for HER2+ Subtypes
•
•
•
Clinical and pathologic
features and survival of
the four subtypes were
compared
In ER/PR+,HER2-,
chemotherapy conferred
significant overall survival
advantages
Subtype comparison
revealed statistically
significant differences in
outcomes
Onitilo A. Clin Med Res Opin. 2009;7(2):4-13.
3
Signal Transduction by the HER
Family Promotes Proliferation,
Survival, and Invasiveness
Receptor-specific
ligands
HER2
HER2
HER3
HER1, HER2,
HER3, or HER4
HER4
VEGF
HER1
(EGFR)
Plasma
membrane
P
PI3K
P
SOS
Tyrosine kinase
domains
Akt
P
RAS
RAF
MAPK
Cytoplasm
P
MEK
Cell proliferation
Cell survival
Cell mobility and invasiveness
Nucleus
Ross JS, et al. The Oncologist. 2009;14:320-368.
Transcription
44
Current Assays of HER2/neu
Immunohistochemistry
‘0’ (negative)
‘1+’ (negative)
‘2+’ (equivocal)
‘3+’ (positive)
Fluorescence in situ hybridization (FISH)
HER2 gene no
amplification
FISH negative
Murthy SS, et al. Indian J Pathol Microbiol. 2011;54(3):532-538.
HER2 gene
amplification
FISH positive
5
Optimal Testing Algorithm
Immunohistochemistry (IHC)
Breast Cancer Specimen
(invasive component)
Positive for HER2
protein expression IHC
3+ (defined as uniform
intense membrane
staining of >30% of
invasive tumor cells)
Positive for HER2
gene amplification
HER2 testing by validated IHC
assay for HER2 protein
expression
Equivocal for HER2
protein expression IHC 2+
Test with validated assay for
HER2 gene amplification
Negative for HER2
protein expression
IHC 0 or 1+
Negative for HER2
gene amplification
Equivocal HER2 gene amplification
(Patients with HER2/CEP17 ratio ≥2.0 were
eligible for the adjuvant trastuzumab trials)
6
Optimal Testing Algorithm
FISH
Breast Cancer Specimen
HER2 gene amplification
FISH positive
Positive for HER2 gene
amplification (FISH ratio
>2.2 or HER2 gene copy
>6.0)
HER2 testing by validated FISH
assay for HER2 gene
amplification
Equivocal for HER2 gene
amplification (FISH ratio 1.8-2.2 or
HER2 gene copy 4.0-6.0)
HER2 gene no amplification
FISH negative
Negative for HER2 gene
amplification (FISH ratio
<1.8 or HER2 gene copy
<4.0)
Count additional cells for FISH or
retest, or test with HER2 IHC
Equivocal HER2 gene amplification result
(Patients with HER2/CEP17 ratio ≥2.0 were
eligible for the adjuvant trastuzumab trials)
7
HER2+ Metastatic Disease
Case Review
Treatment of a 53-Year-Old Woman With
HER2-Positive Metastatic Inflammatory
Breast Cancer
• A 53-year-old woman presents with T4 N2 M0
ER–/PR–/HER2+ (by fluorescence in situ
hybridization) right inflammatory breast cancer
• She is treated with preoperative
doxorubicin/cyclophosphamide (AC)
chemotherapy with minimal response in the
breast and axilla and in the diffuse erythema in
the skin of the left breast
• Her disease is not operable with expectation of
clear margins
8
Polling Question 1
Which Neoadjuvant Treatment Would You
Recommend?
Please see the multiple answer options on the right and select an answer. Once you submit your
answer, your answer selection will be compared with your peers’ responses. The best answer(s)
will be discussed in the subsequent slides and commentary.
9
Discussion
Case Review – Progression I
Howard A. Burris III,
MD, FACP
Lee Schwartzberg, MD
Case Review – Progression I
The patient is subsequently treated with
3 cycles of preoperative weekly
paclitaxel/trastuzumab with no response,
followed by worsening erythema extending
onto her chest wall below her breast and
ipsilateral and contralateral supraclavicular
fossa.
11
Polling Question 2
Which Treatment Would You Recommend
for Case Progression I ?
Please see the multiple answer options on the right and select an answer. Once you submit your
answer, your answer selection will be compared with your peers’ responses. The best answer(s)
will be discussed in the subsequent slides and commentary.
12
Discussion
Case Review – Progression II
Howard A. Burris III,
MD, FACP
Lee Schwartzberg, MD
Case Review – Progression II
• The patient is treated with capecitabine/lapatinib
for 6 cycles, with improvement in the erythema
and a 30% reduction in tumor volume in breast
and all nodal metastatic disease
• She undergoes a left modified radical
mastectomy and has diffuse residual disease in
her breast and axilla with diffuse skin and tumor
lymphovascular invasion
• The margins of resection are clear
• She receives radiation therapy and resumes
capecitabine/lapatinib postoperatively; however,
she develops signs of coronary spasm that
require discontinuation of capecitabine
14
Polling Question 3
Which Treatment Do You Recommend for
Case Progression II?
Please see the multiple answer options on the right and select an answer. Once you submit your
answer, your answer selection will be compared with your peers’ responses. The best answer(s)
will be discussed in the subsequent slides and commentary.
15
Discussion
Case Review – Progression III
Howard A. Burris III,
MD, FACP
Lee Schwartzberg, MD
Case Review – Progression III
• The patient continues lapatinib/trastuzumab for
9 months and then develops progressive disease
over the right chest wall as well as bilateral
supraclavicular adenopathy
• Restaging reveals new pulmonary metastases
• Her physician is interested in enrolling her
in a trial evaluating investigational HER2-targeted
agents and refers her to the ongoing phase IB trial
of trastuzumab emtansine
(T-DM1)/paclitaxel/pertuzumab
17
Polling Question 4
Which of the Following Statements Regarding
Novel HER2-Targeted Agents Is Correct?
Please see the multiple answer options on the right and select an answer. Once you submit
your answer, your answer selection will be compared with your peers’ responses. The best
answer(s) will be discussed in the subsequent slides and commentary.
18
Discussion
Howard A. Burris III,
MD, FACP
Lee Schwartzberg, MD
Targeted Agents for HER2+
Breast Cancer
Trastuzumab
Bevacizumab
VEGF
T-DM1
EGFR
VEGFR
P
P
P
P
PI3-K
HER2
P
P
P
P
Pertuzumab
Akt/PKB
PTEN
mTOR
Lapatinib
Neratinib
4E-BP1
S6K1
elF-4E
Protein synthesis
Cell growth, proliferation, survival, metastasis, angiogenesis
20
Proposed Mechanisms of
Action of Trastuzumab
Spector N., J Clin Oncol. 2009;27:5838.
21
HER2 Targeting With Trastuzumab
Has Changed the Natural History of
HER2-Positive Advanced Breast Cancer
1991-2007
Dawood S., et al. J Clin Oncol. 2009;28:92.
22
Polling Question 5
With which of the following statements regarding
HER2+ MBC do you agree?
Please see the multiple answer options on the right and select an answer. Once you submit your
answer, your answer selection will be compared with your peers’ responses. The best answer(s)
will be discussed in the subsequent slides and commentary.
23
Trastuzumab in
First-Line Treatment
Slamon et al,
20011
Vogel et al,
20022
Burstein et al,
20033
Marty et al,
20054
Kaufman et
al, 20095
Valero et al
20116
469
114
54
186
207
263
Treatment
AC/EC + H or
T+H vs
chemo
H
VH
D+H vs
D
Anas + H vs
Anas
DCbH vs
D+H
Response
Rate
50% vs 32%*
35% (IHC 3+)
34% (FISH+)
68%
61% vs
34%*
20.3% vs
6.8%*
72% vs 72%
Median
TTP
7.4 vs 4.6
mo*
3.8 mo (H at 4
mg/kg)
3.5 mo
(H at 2 mg/kg)
NR
11.7 vs 6.1
mo*
4.8 vs
2.4 mo*
10.3 vs 11.1
mo
Median
PFS
NR
NR
NR
NR
4.8 vs
2.4 mo*
NR
25.1 vs 20.3
mo*
24.4 mo
NR
31.2 vs 22.7
mo*
28.5 vs 23.9
mo
37.4 vs 37.1
mo
Studies
N
Median OS
AC, anthracycline + cyclophosphamide; Anas, anastrozole; T, paclitaxel; D, docetaxel; EC, epirubicin +
cyclophosphamide; H, trastuzumab; mo, months; PFS, progression-free survival; OS, overall survival; RR,
response rate; TTP, time to progression; VH, vinorelbine + trastuzumab; *statistically significant
1. Slamon DJ, et al. N Engl J Med. 2001:344(11):783-792; 2. Vogel CL, et al. J Clin Oncol. 2002;20:719-726; 3.
Burstein HJ, et al. J Clin Oncol. 2003;21(15):2889-2895; 4. Marty M, et al. J Clin Oncol. 2005;23(19):4265-4274;
5. Kaufman B, et al. J Clin Oncol. 2009;27(33):5529-5537; 6. Valero V, et al. J Clin Oncol. 2011;29:149-156. 24
NCCN Guidelines
•
•
•
•
Preferred agents for trastuzumabexposed HER2 + disease
Lapatinib + capecitabine
Trastuzumab + other first-line agents
Trastuzumab + capecitabine
Lapatinib + trastuzumab
National Comprehensive Cancer Network (NCCN) Breast Cancer Guidelines, 2012 available at
www.nccn.org.
25
Lapatinib: Targeting HER2 and
EGFR
• Lapatinib oral tyrosine
kinase inhibitor of ErbB1
and ErbB2
– Blocks signaling through
EGFR and HER2
homodimers and
heterodimers
– May also prevent
signaling between
ErbB1/ErbB2 and other
ErbB family members
Phospholipid cell
membrane
PTEN
P13K
Lapatinib
Shc
Grb2
Ras
Raf
So8
pAkt
Rusnak DW, et al. Mol Cancer Ther. 2001;1:85-94; Xia W, et al. Oncogene. 2002;21:6255-6263.
pErk
26
Randomized Phase III Study
EGF10015
• Progressive, HER2+ MBC
or LABC
• Previously treated with
anthracycline, taxane, and
trastuzumab*
• No prior capecitabine
Stratification:
• Disease sites
• Stage of disease
R
A
N
D
O
M
I
Z
E
N=528
Lapatinib 1250 mg po qd
continuously +
Capecitabine 2000 mg/m2/d
po days 1-14 q 3 wk
Capecitabine 2500 mg/m2/d po
days 1-14 q 3 wk
Patients on treatment until
progression or unacceptable
toxicity, then followed for
survival
* Trastuzumab must have been administered for metastatic disease
Geyer C, et al. N Engl J Med. 2006;355:2733-2743.
27
Progression-Free Survival
Lapatinib +
Capecitabine Capecitabine
No. of pts
160
161
Progressed or died 45 (28%)
73 (45%)
Median PFS, wk
36.9
17.9
Hazard ratio (95% CI)
0.48 (0.33, 0.70)
P-value (log-rank, 1-sided) 0.000045
Cumulative Progression-Free
Survival(%)
100
90
80
70
60
50
40
30
20
Lapatinib + Capecitabine
10
Capecitabine
0
0
10
20
Geyer C, et al. N Engl J Med. 2006;355:2733-2743.
30
40
Time (weeks)
50
60
70
28
Overall Survival:
Capecitabine ± Lapatinib
100
Lapatinib + Capecitabine
Cumulative Survival (%)
90
Capecitabine
80
70
60
50
40
Lapatinib +
Capecitabine
160
29 (18%)
NR
No. of pts
Deaths
Median OS
30
20
Capecitabine
161
29 (18%)
NR
Hazard ratio (95% CI)
0.93 (0.55, 1.59)
P-value (log-rank, 2-sided)
0.800
10
0
0
10
20
30
Geyer C, et al. N Engl J Med. 2006;355:2733-2743.
40
50
Time (weeks)
60
70
80
90
29
Alive without Progression (Cumulative %)
OS With Lapatinib ±
Trastuzumab in MBC
100
80%
80
OS Outcome
L
(n=145)
L+T
(n=146)
Died, n (%)
113 (78)
105 (72)
Median, mo
9.5
14
HR (95% CI)
60
56%
70%
0.74 (0.57-0.97)
Log-rank P-value
0.026
6 Month OS
40
41%
L
L+T
20
12 Month OS
0
0
Patients at Risk, n
L
148
L + T 148
5
10
121
102
88
65
15
20
25
Months From Randomization
64
47
43
28
25
13
Blackwell KL, et al. San Antonio Breast Cancer Symposium (SABCS) 2009. Abstract 61.
30
35
1
30
Neo-ALTTO: Study Design
Invasive operable
HER2+ BC
T>2 cm
(inflammatory BC
excluded)
LVEF50%
N=450
Stratification:
• T≤5 cm vs. T>5 cm
• ER or PgR + vs.
ER & PgR –
• N 0-1 vs N≥2
• Conservative surgery
or not
lapatinib
paclitaxel
R
A
N
D
O
M
I
Z
E
trastuzumab
paclitaxel
lapatinib
trastuzumab
paclitaxel
lapatinib
S
U
R
G
E
R
Y
F
E
C
trastuzumab
X
6 wks + 12 wks
3
lapatinib
trastuzumab
34 weeks
52 weeks of anti-HER2 therapy
Baselga J, et al. SABCS 2010.
31
Neo-ALLTO:
Pathologic Response
70
P=0.0001
P=0.001
(%) Response
60
50
51.3%
P=0.34
40
46.9%
P=0.13
30
20
24.7%
29.5%
27.6%
20.0%
10
0
L
N=154
T
N=149
L+T
N=152
pCR
Pathologic Complete Response
L
N=150*
T
N=145*
L+T
N=145*
tpCR
Locoregional (total) pCR
L, lapatinib; T, trastuzumab; L+T, lapatinib plus trastuzumab; pCR, pathologic complete response.
* Excludes 15 patients with non-evaluable nodal status
Baselga J, et al. SABCS 2010.
32
Investigational
Anti-HER2 Agents
Polling Question 6
Which of the following have demonstrated
benefit in patients with HER2+ MBC who
experienced disease progression on
trastuzumab?
Please see the multiple answer options on the right and select an answer. Once you submit your
answer, your answer selection will be compared with your peers’ responses. The best answer(s)
will be discussed in the subsequent slides and commentary.
34
Polling Question 7
Which of the following is true of trastuzumabDM1?
Please see the multiple answer options on the right and select an answer. Once you submit your
answer, your answer selection will be compared with your peers’ responses. The best answer(s)
will be discussed in the subsequent slides and commentary.
35
Trastuzumab-DM1
36
T-DM1 Selectively Delivers
a Highly Toxic Payload
to HER2-Positive Tumor Cells
• Trastuzumab-like activity by binding to HER2
• Targeted intracellular delivery of a potent antimicrotubule
agent, DM1
T-DM1 binds to the HER2
protein on cancer cells
Receptor-T-DM1
complex is internalized
into HER2-positive
cancer cell
Potent antimicrotubule
agent is released once
inside the HER2positive tumor cell
37
Trastuzumab-TDM1
• Trastuzumab-DM1 (T-DM1) is a novel anti-HER2
antibody drug conjugate in development for
treatment of HER2-positive metastatic breast
cancer (MBC).T-DM1 combines the HER2targeting properties of trastuzumab2 with
targeted delivery of a highly potent antimicrotubule derivative, DM1
– T-DM1 binds to HER2 with an affinity similar to that of
trastuzumab.
– It is hypothesized that after binding to HER2,
T-DM1 undergoes receptor-mediated internalization,
7 resulting in intracellular release of DM1.
38
TDM1 Versus Trastuzumab +
Docetaxel 1st line
T-DM1
3.6 mg/kg Q3W until PD
HER2-positive, recurrent
locally advanced BC or
MBC (n=137)
1:1
Trastuzumab
8 mg/kg dose; 6 mg/kg Q3W
PD
+ Docetaxel
75 or 100 mg/m2 Q3W
Crossover
T-DM1
• Randomized, phase II, international, open-label study
• HER2-positive, measurable disease required
• Stratification factors
– World region, prior adjuvant trastuzumab therapy, disease-free interval
• Primary endpoints: PFS by INV, safety
• Key secondary endpoints: ORR, clinical benefit, OS, QOL, symptom
control
Perez EA, et al. ESMO 2010. Abstract LBA3.
39
T-DM1 Versus Trastuzumab (T) +
Docetaxel (D) in HER2-Positive MBC
With No Prior Chemotherapy for MBC
T-DM1
(n=67)
T+D
(n=70)
47.8%
41.4%
37.3%
75.0%
Efficacy Summary
Overall response rate (ORR)
Safety Summary
Grade ≥3 adverse event (AE)†
† Most
common AEs, any grade, T + D: alopecia: 66.2%, neutropenia: 57.4%,
diarrhea: 45.6% — these were 1.5%, 7.5%, and 10.4% in pts receiving T-DM1.
Most common AEs, any grade, T-DM1: nausea: 47.8%, fatigue: 46.3%,
pyrexia: 35.8% — these were 39.7%, 46.2%, and 20.6% in pts receiving T + D.
Perez EA, et al. Proc ESMO 2010. Abstract LBA3.
40
Median Progression-Free Survival
(months)
T-DM1 Activity: Improved PFS
15
P=0.035
10
14.2
9.2
5
Treatment with T-DM1
reduced the probability
of disease progression
or death by 41%
compared with
Trastuzumab +
Docetaxel
HR=0.59, P=0.035
0
T-DM1
trastuzumab +
docetaxel
HER2+ locally advanced or metastatic
Hurvitz S, et al. ECCO-ESMO 2011. Abstract 5001.
41
EMILIA (TDM4370g) Phase III Study:
T-DM1 Versus Lapatinib/Capecitabine
in HER2+ MBC
PD or unacceptable toxicity
Patients with HER2+ locally
advanced or metastatic
breast cancer following
treatment with a taxane
and trastuzumab
(N=980)
T-DM1 q3w
(n=490)
Lapatinib + Capecitabine q3w
(n=490)
• Primary endpoint: PFS by IRF, OS, safety
• Secondary endpoints: QoL (FACT B), DOR, PFS
by investigator assessment
ClinicalTrials.gov. NCT00829166.
42
Phase III MARIANNE Study:
T-DM1 ± Pertuzumab in HER2+
MBC
PD
Trastuzumab + Taxane
(n=364)
Patients with HER2+,
previously untreated MBC
T-DM1 + Pertuzumab
(n=364)
(N=1092)
T-DM1 + Placebo
(n=364)
• Primary endpoints: PFS as assessed by IRF, AEs
– Superiority design with a noninferiority analysis
– Interim futility analysis: option to drop experimental arm
• Secondary endpoints: OS, TTF by IRF, ORR, CBR, DOR
ClinicalTrials.gov. NCT01120184.
43
HER2-Targeted Therapy With
Pertuzumab
• Monoclonal antibody and pan-HER inhibitor
• Binds to a distinct epitope on the HER2
extracellular domain
• Prevents dimerization
Trastuzumab
Fisher, et al. J. Mol. Biol. 2010;402:217-229.
Pertuzumab
44
Pertuzumab Recognizes
Different Epitopes
HER2
Ligand-binding domain
(inactive)
Pertuzumab
Trastuzumab
Cell membrane
Tyrosine kinase domain
45
Pertuzumab Demonstrates Synergistic
Activity With Trastuzumab
HER2 receptor
Pertuzumab
Trastuzumab
Subdomain IV of
HER2
• Preferentially inhibits ligandindependent HER2 signaling
• Prevents shedding of HER2 ECD
• Flags cells for destruction by the
immune system
Junttila, et al. Cancer Cell. 2009.
Dimerization domain
of HER2
• Inhibits formation of HER2 dimer pairs
• Suppresses multiple HER signaling
pathways, leading to a more
comprehensive blockade of HER2driven signaling
• Flags cells for destruction by the
immune system
46
HER2:HER3 Dimers May Provide an
Escape Mechanism From Trastuzumab
Homodimers
HER2:HER2
HER3:HER3
Heterodimers
HER4:HER4
HER1:HER2
HER1:HER3
HER1:HER4
HER2:HER3
HER2:HER4
HER1:HER1
+
HER3:HER4
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Signaling activity
Tzahar E., et al. Mol Cell Biol. 1996. Sergina NV, et al. Nature. 445:437-441.
47
CLEOPATRA: Phase III Trial
Evaluating Adding Pertuzumab
N=808 HER2-positive
Metastatic Breast Cancer
Primary Outcome:
Progression-Free Survival
R
First-Line
HER2-positive
MBC
First-Line MBC
Could have received prior adjuvant trastuzumab
Treatment A: 400 patients
Docetaxel* + Trastuzumab + Pertuzumab
Treatment B: 400 patients
Docetaxel* + Trastuzumab + Placebo
1:1 randomization
stratification by (1. pretreated
or de novo, 2. region)
* At least 6 cycles of docetaxel
Baselga J, et al. N Engl J Med. 2012;366:109-119.
48
CLEOPATRA: Response Data
100
90
4.2
5.5
Patients (%)
80
70
60
74.6
50
40
ORR:
80.2%
65.2
ORR:
69.3%
0
PR
SD
PD
30
20
10
CR
20.8
1.5
14.6
3.8
Trastuzumab + Docetaxel
+ Pertuzumab
(n=343)
Baselga J, et al. N Engl J Med. 2012;366:109-119.
1.5
Not evaluable
8.3
Trastuzumab +
Docetaxel + Placebo
(n=336)
49
CLEOPATRA:
Independently Assessed PFS
100
Ptz + T + D: median 18.5 months
Pbo + T + D: median 12.4 months
90
80
PFS (%)
70
60
50
40
(HR: 0.62;
95% CI: 0.51-0.75;
P<0.0001)
30
20
10
0
0
Pts at Risk, n
Ptz + T + D 402
Pbo + T + D 406
5
10
15
20
25
30
35
40
32
17
10
7
0
0
0
0
Months
345
311
267
209
139
93
83
42
Stratified by previous treatment status and region
Baselga J, et al. N Engl J Med. 2012;366:109-119.
50
CLEOPATRA: OS Curve
Baselga J, et al. N Engl J Med. 2012;366:109-119.
51
CLEOPATRA: Safety
Trastuzumab + Docetaxel +
Pertuzumab
(n=407)
Adverse Events (%)
Trastuzumab + Docetaxel +
Placebo
(n=397)
All Grades
Grade 3/4
All Grades
Grade 3/4
Diarrhea
66.8
7.9
46.3
5.0
Alopecia
60.9
NR
60.5
NR
Neutropenia
52.8
48.9
49.6
45.8
Nausea
42.3
NR
41.6
NR
Fatigue
37.6
NR
36.8
NR
Rash
33.7
NR
24.2
NR
Decreased appetite
29.2
NR
26.4
NR
Mucosal inflammation
27.8
NR
19.9
NR
Asthenia
26.0
NR
30.2
NR
Peripheral edema
23.1
NR
30.0
NR
Constipation
15.0
NR
24.9
NR
Febrile neutropenia
13.8
13.8
7.6
7.6
Dry skin
10.6
NR
4.3
NR
Leukopenia
NR
12.3
NR
14.6
Baselga J, et al. N Engl J Med. 2012;366:109-119.
52
CLEOPATRA: Conclusions
• Adding pertuzumab to first-line trastuzumab/docetaxel in
HER2+ locally recurrent or MBC improves PFS vs
trastuzumab/docetaxel alone
• Median PFS prolonged 6.1 months according to
independent review
– PFS improvement consistent across nearly all patient subgroups
– ORR higher with addition of pertuzumab to
trastuzumab/docetaxel
• Pertuzumab associated with increased incidence of mild
and manageable diarrhea, rash, mucosal inflammation,
febrile neutropenia, and dry skin
• Incidence of cardiac toxicities comparable between
treatment arms
– Symptomatic LVSD: Ptz + T + D (1.0%) vs Pbo + T + D (1.8%)
Baselga J, et al. SABCS 2011. Abstract S5-5.
53
Inhibitors of EGFR-receptors
Neratinib
Neratinib
Gajria D Chandarlapaty S. Expert Rev Anticancer Ther. 2011;11(2):263-75 Review.
54
Neratinib Description
• Neratinib is an oral, multi-targeted,
irreversible tyrosine kinase inhibitor
• In preclinical studies, has been shown to
target the ErbB1 (EGFR), ErbB2 (HER2),
and ErbB4 (HER4) kinases
• Mechanism: covalently binds to ErbB2 at
ATP binding site and inhibits tyrosine
kinase activity resulting in G0/G1 cell cycle
arrest
55
Randomized Phase II: Neratinib Versus
Lapatinib + Capecitabine in Locally
Advanced or MBC
Progression-Free
Survival
Neratinib
L+C
n
Median PFS
95% CI
P-value
117
116
4.5 mo
6.8 mo
3.1–5.7 mo
5.9–8.2 mo
0.231
L, lapatinib; C, capecitabine; PFS, progression-free survival; CI, confidence interval.
Overall Survival
Neratinib
L+C
n
Median OS
95% CI
P-value
117
116
19.7 mo
23.6 mo
18.2 mo–NE
18.0 mo–NE
0.280
L, lapatinib; C, capecitabine; OS, overall survival; CI, confidence interval; NE, not estimable.
Most Common Adverse Events
Most frequently observed severe adverse events in the trial were diarrhea and
hand-foot syndrome; 28% of the patients in the neratinib arm and 10% of the
patients in the L/C arm of the trial experienced rade 3/4 diarrhea.
56
Combination
Treatments of
Novel Anti-HER2
Agents
57
Phase II Trial of Trastuzumab + Pertuzumab
in HER2-Positive MBC Patients Progressing
During Trastuzumab-Based Therapy
Cohorts
1 and 21
Cohort
32
HER2-positive MBC
Progressed on trastuzumab +
chemotherapy
(Cohorts 1 and 2, n=66)
Pertuzumab +
trastuzumab
(n=66)
HER2-positive MBC
Progressed on trastuzumab +
chemotherapy (n=29)
Pertuzumab
(n=29)
Pertuzumab +
trastuzumab
(n=15)
Primary objectives
• Safety and efficacy
Population
• ≤3 prior lines cytotoxic therapy (including adjuvant treatment)
1. Baselga J, et al. J Clin Oncol.. 2010; 28;1138-1144. Baselga J, et al. SABCS 2009.
58
Pertuzumab/Trastuzumab Combination
Therapy More Active Than Treatment
With Either Agent Alone
Cohorts 1 and 2
(P+H) (n=66)
Cohort 3 (P)
(n=27)
Cohort 3
(P&H)
CR (%)
7.6
0.0
0.0
PR (%)
16.7
3.4
21.4
ORR (%)
24.2
3.4
21.4
SD (%)
25.8
6.9
21.4
CBR
50.0
10.3
37.5
50.0
82.8
57.1
(CR+PR+SD> 6 months)
PD (%)
CR, complete response; PR, partial response; SD, stable disease
* n=27, as at data cut-off 2/29 patients had not reached overall best response endpoint (8 cycles of
assessment during this phase); †n=11, as at data cut-off 4/15 patients had not reached overall best
response endpoint (8 cycles of assessment during this phase); ‡at data cut-off, 21 (31.8%) patients had
not experienced PD
1. Gelmon, et al. ASCO 2008; 2. Baselga, et al. JCO. 2010; 3. Baselga, et al. SABCS 2009.
59
Phase IB/II Trial of T-DM1 + Pertuzumab in
Patients With Locally Advanced and MBC Who
Were Previously Treated With Trastuzumab
Phase IB/II: HER2-positive MBC
in all therapeutic lines
(n=67)
Primary endpoints
• Safety
• ORR by RECIST 1.0
Secondary endpoints
• PFS
• DoR
Dose escalation phase
(completed)
Expansion phase
(completed)
T-DM1 + pertuzumab
(n=9)
T-DM1 + pertuzumab
(n=58, including
22 first line)
Phase IB: 3+3 dose escalation
• Cohort I: T-DM1 3.0 mg/kg; pertuzumab
(840 mg loading dose, 420 mg maintenance dose)
• Cohort II: T-DM1 3.6 mg/kg; pertuzumab
(840 mg loading dose, 420 mg maintenance dose)
Phase II
• Expansion at dose level established in Phase Ib
Heavily pretreated population
• Median of 6 prior therapeutic agents
in the metastatic setting
Miller K, et al. ASCO 2010.
60
T-DM1 + Pertuzumab Shows Promising
Efficacy in Patients Pretreated With
Trastuzumab + Lapatinib
Results
Total, n (%)
(n=28)
PR
10 (35.7)
SD
13 (46.4)
PD
4 (14.3)
Missing
1 (3.6)
• ORR was 35.7% (10/28 patients), per investigator assessment
– All responses were confirmed PRs
– 1/13 patients with SD had an unconfirmed response
Miller K, et al. ASCO 2010.
61
T-DM1 + Pertuzumab Has an
Encouraging Safety and Tolerability
Profile
Key AE (%)
Grade 3 (%)
Grade 4 (%)
Total (all grades) (%)*
Any Events
36.4
4.5
100
Fatigue
13.6
0
52.3
Nausea
4.5
0
5 .0
Thrombocytopenia
6.8
4.5
27.3
Diarrhea
2.3
0
25.0
Vomiting
4.5
0
22.7
AST increase
6.8
0
20.5
Dyspnea†
2.3
0
20.5
AST, aspartate aminotransferase
* One Grade 5 AE was reported (pneumonia) in a patient who died before her first tumor assessment. This
AE was considered to be unrelated to study treatment; †Primarily attributed to pneumonia or the disease
under study (lung metastases and pleural effusions).
Miller K, et al. ASCO 2010 Poster 1012.
62
NEOSPHERE: Study Design
TH (n=107)
docetaxel +
trastuzumab
Patients with
operable or
locally advanced
/inflammatory*
HER2-positive BC
Chemo-naïve and
primary tumors
>2 cm (N=417)
FEC q3w x 3
trastuzumab q3w cycles 5–17
S
THP (n=107)
docetaxel +
trastuzumab +
pertuzumab
U
R
FEC q3w x 3
trastuzumab q3w cycles 5–17
G
HP (n=107)
trastuzumab +
pertuzumab
TP (n=96)
docetaxel +
pertuzumab
E
docetaxel q3w x 4→FEC q3w x 3
trastuzumab q3w cycles 5–17
R
Y
FEC q3w x 3
trastuzumab q3w cycles 5–21
Study dosing: q3w x 4
BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide; H, trastuzumab; P, pertuzumab; T,
docetaxel
* Locally advanced=T2-3, N2-3, M0 or T4a-c, any N, M0; operable=T2-3, N0-1, M0; inflammatory=T4d, any N, M0
63
Gianni L, et al. SABCS 2010.
NEOSPHERE: pCR Rates
P=0.0198
P=0.0141
50
P=0.003
pCR, %  95% CI
40
45.8
30
20
29.0
24.0
10
0
16.8
TH
H, trastuzumab; P, pertuzumab; T, docetaxel
Gianni L, et al. SABCS 2010.
THP
HP
TP
64
Summary: Pertuzumab and T-DM1
Are Promising New Therapeutic
Agents for HER2-Positive MBC
Pertuzumab
• First HER2 dimerization inhibitor
• Has demonstrated encouraging clinical efficacy and
tolerability in combination with trastuzumab
• Offers a more comprehensive approach to blocking
HER2-driven signaling than trastuzumab alone
T-DM1
• First HER2-directed ADC delivering cytotoxic drug
specifically to HER2-positive tumor cells while retaining
the biological activity of trastuzumab
• Has demonstrated encouraging clinical efficacy and
tolerability in heavily pretreated patients
Clinical trials of both agents are ongoing, including pertuzumab and T-DM1 in combination
65
AVEREL: Study Design
Women with
previously untreated
HER2-positive locally
recurrent/metastatic
breast cancer
(N=424)
Trastuzumab 6 mg/kg† +
Docetaxel 100 mg/m2 +
Bevacizumab 15 mg/kg, all given q3w
(n=216)
Trastuzumab 6 mg/kg† +
Docetaxel 100 mg/m2,
both given q3w
(n=208)
Stratified by previous (neo)adjuvant taxane,
adjuvant trastuzumab, hormone receptor status,
measurable disease
Treatment until disease progression
or unacceptable toxicity*
• Primary endpoint: PFS (investigator assessed)
• Secondary endpoints: OS, ORR, duration of response, TTF, safety
* Planned minimum of 6 docetaxel cycles administered; †Trastuzumab 8 mg/kg loading dose given.
Gianni L, et al. SABCS 2011. Abstract S4-8.
66
AVEREL: PFS, Interim OS
Analysis, and Response
T + Doc + Bev
(n=216)
T + Doc
(n=208)
Median PFS
(Investigator assessment)
16.5
Median PFS
(IRC assessment)
Median OS
Outcome, Months
•
•
HR (95% CI)
P Value
13.7
0.82
(0.65-1.02)
0.0775
16.8
13.9
0.72
(0.54-0.94)
0.0162
38.5
38.3
1.01
(0.74-1.38)
(unstratified)
0.9543
0.94
(0.68-1.30)
(stratified)
0.7078
ORR similar between T + Doc + Bev and T + Doc in investigator assessment
(74.3% vs 69.9, respectively; P=0.3492)
ORR significantly higher with addition of Bev in IRC assessment
(76.5% vs 65.9, respectively; P=0.0265)
Gianni L, et al. SABCS 2011. Abstract S4-8.
67
AVEREL: Conclusions
• Addition of bevacizumab to first-line treatment with
trastuzumab and docetaxel in patients with HER2positive advanced breast cancer may prolong PFS
– Findings not significant according to
investigator-assessed PFS (primary endpoint;
P=0.0775)
– Findings significant according to independent
review of PFS (exploratory endpoint; P=0.0162)
• Bevacizumab-associated AEs led to higher
incidence of discontinuation of any study drug
Gianni L, et al. SABCS 2011. Abstract S4-8.
68
Discussion
Thank You!
Howard A. Burris III,
MD, FACP
Lee Schwartzberg, MD