•Harold Burstein, MD
•Assistant Professor of Medicine •Dana-Farber Cancer Institute
•Boston, MA
First line therapeutic options forHER2 positive metastatic breast cancer
Trastuzumab in advanced/metastatic breast cancer
3. Burstein et al, Cancer. 2007;110:965-72.4. Robert et al, J Clin Oncol. 2006;24:2786-92.
H0468g1 M770012 TRAVIOTA3 Robert et al4
Patients enrolled
469 186 81 (early termination)
196
Treatment arms
Doxorubicin orEpirubicin +
cyclophosphamide or Paclitaxel
vsDoxorubicin or
Epirubicin + cyclophosphamide
or Paclitaxel + H
Docetaxelvs
Docetaxel + H
Vinorelbine + Hvs
Taxane + H
H + paclitaxel Hvs
H + paclitaxel + carboplatin H
ORR (%) 32 vs 50(p<0.001)
34 vs 61(p=0.0002)
51 vs 40 (p=NS)
36 vs 52(p=0.04)
Median OS (mo)
20.3 vs 25.1(HR 0.80 [0.64–1.00];
p=0.046)
22.7 vs 31.2(p=0.0325)
N/R 32.2 vs 35.7(p=NS)
Median TTP (mo)
4.6 vs 7.4(HR 0.51 [0.41–0.63];
p<0.001)
6.1 vs 11.71(p=0.0001)
8.5 vs 6.5 (p=NS)
7.1 vs 10.7(p=0.03) [PFS]
1. Slamon et al, N Engl J Med. 2001;344:783-92.2. Marty et al, J Clin Oncol. 2005;23:4265-74.
Effect of trastuzumab added tocytotoxic chemotherapy: PFS
Slamon et al, N Engl J Med. 2001;344:783-92.
Months after enrollment
Progression-free survival (%)
p<0.001
Chemotherapy + trastuzumab
Chemotherapy alone
0 5 10 15 20 25
100
80
60
40
20
0
No. at risk:
Chemotherapy+trastuzumab
Chemotherapy alone
226
224
122
183
60
25
15
0
Effect of trastuzumab added tocytotoxic chemotherapy: OS
Slamon et al, N Engl J Med. 2001;344:783-92.
Months after enrollment
Survival (%)
p<0.001
Chemotherapy + trastuzumab
Chemotherapy alone
100
80
60
40
20
0
No. at risk:
Chemotherapy+trastuzumab
Chemotherapy alone
236
234
102
160
134
116
96
76
0 5 20 30 40 5010 15 25 35 45
214
205
105
136
114
97
47
27
11
13
Cell cycle progressionProliferation
Differentiation
HER2–EGFR HER2–HER2 HER2–HER3
Ra
sR
af
MA
PKPL
C
PK
C
PPP PPP
HER2–HER3
mTOR
BAD
p27
Cyclin MDM2
HIF-1α
GSK3
Foxo
PI3K
AKT
PPP
HER2 mediated signaling
Rosen et al, The Oncologist. 2010;15:216-35.
ApoptosisTranscriptionAngiogenesis
Mechanisms of resistance toHER2 targeted therapy
Garrett and Artega, Cancer Biol Ther. 2011;11:793-800.Gajra and Chandarlapaty, Expert Rev Anticancer Ther. 2011;11:263-75.
Mechanisms Comments
Barriers to antibody binding
Increased expression of p95-HER2 Constitutively active tyrosine kinase with no extracellular domain
Epitope masking MUC4 overexpressionCD44/hyaluron complexes activate PI3K and RAS
Upregulation of downstream signaling
PTEN loss Constitutive activation of PI3k/Akt
PI3K mutations PI3K pathway mutations allow continued signaling
Increased Akt kinase activity
Crosstalk Increased IGF-IR signaling Results in PI3K activation
Signaling from HER2/HER3 heterodimers Upregulation of HER3 EGFR upregulation
Allows continued signaling of PI3k pathway
Increased c-Met expression Results in sustained Akt activation
Upregulation of ER signaling May be particularly important for lapatinib resistance
Increased AXL signaling Activates an alternative survival pathway
Failure of ADCC Fc receptor polymorphisms
Pohlmann, Clin Cancer Res. 2009;15:7479-7491Liu et al, Cancer Res. 2009;69:6861-78.
Cell cycle progressionProliferation
Differentiation
HER2–EGFR HER2–HER2 HER2–HER3
Ra
sR
af
MA
PKPL
C
PK
C
PPP PPP
HER2–HER3
mTOR
BAD
p27
Cyclin MDM2
HIF-1α
GSK3
Foxo
PI3K
AKT
PPP
HER2 mediated signaling: Effect of trastuzumab
ApoptosisTranscriptionAngiogenesis
YY
YY
Cell cycle progressionProliferation
Differentiation
HER2–EGFR HER2–HER2 HER2–HER3
Ra
sR
af
MA
PKPL
C
PK
C
PPP PPP
HER2–HER3
mTOR
BAD
p27
Cyclin MDM2
HIF-1α
GSK3
Foxo
PI3K
AKT
PPP
HER2 mediated signaling: Effect of trastuzumab and pertuzumab
ApoptosisTranscriptionAngiogenesis
YY
YY YY
Pertuzumab monotherapy and the effect of addition of trastuzumab in trastuzumab refractory MBC
29 patients with progressive MBC after trastuzumab therapy
Pertuzumab 840 mg then 420 mg q3wORR: 3.4% (1 PR lasting 24 weeks)CBR: 10.3% (+ 2 SD lasting ≥8 weeks)Disease progression: 29/29 (median 3 cycles)PFS: 7.2 weeks
17 patients received add-on trastuzumab ORR: 17.6% (3 PR)CBR: 41.2% (+ 4 SD lasting ≥8 weeks)PFS: 17.4 weeks
Cortes et al, J Clin Oncol. 2012;30:1594-600.
CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: Study design
Baselga et al, N Engl J Med. 2012;366:109-19.
Pertuzumab840 mg 420 mg q3wTrastuzumab 8 mg/kg 6 mg/kg q3wDocetaxel75 mg/m2 100 mg/m2* q3w
(n=402)
Trastuzumab 8 mg/kg 6 mg/kg q3wDocetaxel75 mg/m2 100 mg/m2* q3w
(n=406)
*Investigators’ discretion
Primary endpoint: PFSR
Patients with HER2+ metastatic
treatment-naïve MBC(n=808)
Recommended minimum of 6 cycles docetaxel
Antibody therapy continued to disease progression
CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: PFS
Baselga et al, N Engl J Med. 2012;366:109-19.
No. at risk:
Pertuzumab
Control
402
406
345
311
267
209
139
93
83
42
32
17
10
7
0
0
0
0
Months
Progression-free survival (%)
Hazard ratio, 0.62(95% CI, 051–0.75)
p<0.001
Pertuzumab + trastuzumab + docetaxel (median, 18.5 months)
Trastuzumab + docetaxel (median, 12.4 months)
100
80
60
40
20
00 5 10 15 20 25 30 35 40
Subgroup No of patients
Hazard ratio (95% CI)
All patients 808 0.63 (0.52-0.76)
Previous record or chemotherapy
No 432 0.63 (0.49-0.82)
Yes 376 0.61 (0.46-0.81)
Geographic regionEurope 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 yrs 681 0.65 (0.53-0.80)
>65 yrs 127 0.52 (0.31-0.86)
<75 yrs 789 0.64 (0.53-0.78)
>75 yrs 19 0.55 (0.12-2.54)
Race ethnic groupWhite 8 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 typeVisceral disease 630 0.55 (0.45-0.68)
Nonvisceral disease 178 0.96 (0.61-1.52)
Hormone receptor statusGR-positive, PgR-postive, or both 388 0.72 (0.55-0.95)
GR-negative and PgR-negative 408 0.55 (0.42-0.72)
GR and PgR status unknown 12 –
HER2 statusIHC 3+ 721 0.60 (0.49-0.74)
FISH-positive 767 0.64 (0.53-0.78)
CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: PFS (Sub-group analysis)
Baselga et al, N Engl J Med. 2012;366:109-19.
0.0 0.2 0.4 0.6 2.0 2.0Pertuzamab better Placebo better
CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: Key secondary endpoints
Baselga et al, N Engl J Med. 2012;366:109-19.
Pertuzumab + trastuzumab +
docetaxel (n=402)
Trastuzumab + docetaxel
(n=406)
Deaths 69 (17.2%) 96 (23.6%)
Hazard ratio 0.64 (0.47 – 0.88); p=0.005
Objective response rate 80.2% 69.32%
Difference 10.8% (4.2–17.5); p=0.001
Cycles (median) 18 15
Duration of treatment (median) 18.1 months 11.8 months
CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: Tolerability
Baselga et al, N Engl J Med. 2012;366:109-19.
Pertuzumab + trastuzumab + docetaxel (n=407)
Trastuzumab + docetaxel (n=397)
Any grade* (%)
Grade 3 or higher**
(%)
Any grade* (%)
Grade 3 or higher** (%)
Diarrhea 66.8 7.9 46.3 5.0
Alopecia 60.9 60.5
Neutropenia 52.8 48.9 49.6 45.8
Febrile neutropenia 13.8 13.8 7.6 7.6
Nausea 42.3 41.6
Fatigue 37.6 2.2 36.8 3.3
Rash 33.7 24.2
Decreased appetite 29.2 26.4
Mucosal inflammation 27.8 19.9
Asthenia 26.0 2.5 30.2 1.5
Peripheral edema 23.1 30.0
Constipation 15.0 24.9
Dry skin 10.6 4.3
Leukopenia 12.3 14.6
Peripheral neuropathy 2.7 1.8
Anemia 2.5 3.5
Granulocytopenia 1.5 2.3
Left ventricular systolic dysfunction
1.2 2.8
Dyspnea 1.0 2.0 *Reported in 25% or more in either group, or at least 5% difference between groups**Reported in 2% or more in either group
Current standards of care for HER2 positive MBC: First line therapy (NCCN)
‘The NCCN Panel recommends pertuzumab plus trastuzumab in combination with a taxane as a preferred option for first-line treatment of patients with HER2-positive metastatic breast cancer’
NCCN Category 1 (with docetaxel)NCCN Category 2A (with paclitaxel)
‘First-line trastuzumab in combination with selected chemotherapeutics or as a single agent is another option for HER2 positive metastatic breast cancer…’ Acceptable combinations with T include paclitaxel ± carboplatin,
docetaxel, vinorelbine
NCCN 2012; Breast cancer V3.2012.
MARIANNE – Pertuzumab + trastuzumab emtansine for MBC
Ellis et al, J Clin Oncol. 2011;29 (suppl); abstr TPS102.
Trastuzumab emtansine
Trastuzumab emtansine + pertuzumab
Primary endpoints:
PFS and safetyR
HER2 + MBCFirst line
(Target n=1,092)
Trastuzumab + taxane(open label)
Summary First line therapy with trastuzumab for metastatic / advanced
HER2 positive breast cancer has had a dramatic effect on clinical outcomes
However, relapse is usual Resistance mechanisms include HER2 heterodimers and
activation of both alternate signaling cascades and changes to downstream pathways
Pertuzumab is a dimerization inhibitor which results in a more profound blockade of HER2 signaling than trastuzumab alone
Pertuzumab is now FDA approved for use in combination with trastuzumab and a taxane Based on the CLEOPATRA study which demonstrated improved
PFS and OS Recommended in the most recent NCCN Guidelines as a first line
option