1. Assistant Professor of Medicine Dana-Farber Cancer Institute
First line therapeutic options for HER2 positive metastatic breast cancer
Harold Burstein, MD
Assistant Professor of Medicine
Dana-Farber Cancer Institute
Boston, MA

2. Trastuzumab in advanced/metastatic breast cancer
H0468g1
M770012
TRAVIOTA3
Robert et al4
Patients enrolled
469
186
81 (early termination)
196
Treatment arms
Doxorubicin or
Epirubicin + cyclophosphamide
or Paclitaxel vs
or Paclitaxel + H
Docetaxel
vs Docetaxel + H
Vinorelbine + H
vs Taxane + H
H + paclitaxel  H
vs 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
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
7.1 vs 10.7
(p=0.03) [PFS]
1. Slamon et al, N Engl J Med. 2001;344:
2. Marty et al, J Clin Oncol. 2005;23:
3. Burstein et al, Cancer. 2007;110:
4. Robert et al, J Clin Oncol. 2006;24:

3. Effect of trastuzumab added to cytotoxic chemotherapy: PFS
Progression-free survival (%)
100 80 60 40 20
Chemotherapy + trastuzumab
Chemotherapy alone
p<0.001 5 10 15 20 25
Months after enrollment
No. at risk:
Chemotherapy +trastuzumab
Chemotherapy alone
226
224
122
183 60 25 15
Slamon et al, N Engl J Med. 2001;344:

4. Effect of trastuzumab added to cytotoxic chemotherapy: OS
Survival (%)
100 80 60 40 20
Chemotherapy + trastuzumab
Chemotherapy alone
p<0.001 5 20 30 40 50 10 15 25 35 45
Months after enrollment
No. at risk:
Chemotherapy +trastuzumab
Chemotherapy alone
236
234
214
205
102
160
105
136
134
116
114 97 96 76 47 27 11 13
Slamon et al, N Engl J Med. 2001;344:

5. HER2 mediated signaling
HER2–EGFR
HER2–HER2
HER2–HER3
HER2–HER3
Ras
PI3K P P P
Raf
AKT
MAPK
mTOR
Foxo
PLC
PKC
BAD
GSK3
p27
HIF-1α
Cell cycle progression
Proliferation
Differentiation
Cyclin
MDM2
Apoptosis
Transcription
Angiogenesis
Rosen et al, The Oncologist. 2010;15:

6. Mechanisms of resistance to HER2 targeted therapy
Comments
Barriers to antibody binding
Increased expression of p95-HER2
Constitutively active tyrosine kinase with no extracellular domain
Epitope masking
MUC4 overexpression
CD44/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:
Liu et al, Cancer Res. 2009;69:
Garrett and Artega, Cancer Biol Ther. 2011;11:
Gajra and Chandarlapaty, Expert Rev Anticancer Ther. 2011;11:

7. HER2 mediated signaling: Effect of trastuzumab
HER2–EGFR
HER2–HER2
HER2–HER3
HER2–HER3 Y Y Y Y 
Ras
PI3K P P P
Raf
AKT
MAPK
mTOR
Foxo
PLC
PKC
BAD
GSK3
Cell cycle progression
Proliferation
Differentiation
p27
HIF-1α
Cyclin
MDM2
Apoptosis
Transcription
Angiogenesis

8. HER2 mediated signaling: Effect of trastuzumab and pertuzumab
HER2–EGFR
HER2–HER2
HER2–HER3
HER2–HER3 Y Y Y Y Y Y    
Ras
PI3K P P P
Raf
AKT
MAPK
mTOR
Foxo
PLC
PKC
BAD
GSK3
Cell cycle progression
Proliferation
Differentiation
p27
HIF-1α
Cyclin
MDM2
Apoptosis
Transcription
Angiogenesis

9. 29 patients with progressive MBC after trastuzumab therapy
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 q3w
ORR: 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:

10. CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: Study design
Pertuzumab 840 mg  420 mg q3w
Trastuzumab 8 mg/kg  6 mg/kg q3w
Docetaxel 75 mg/m2  100 mg/m2* q3w
(n=402)
Patients with HER2+ metastatic treatment-naïve MBC
(n=808)
Recommended minimum of 6 cycles docetaxel
Antibody therapy continued to disease progression R
Primary endpoint: PFS
Trastuzumab 8 mg/kg  6 mg/kg q3w
Docetaxel 75 mg/m2  100 mg/m2* q3w
(n=406)
*Investigators’ discretion
Baselga et al, N Engl J Med. 2012;366:

11. CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: PFS
Progression-free survival (%)
100 80 60 40 20
Pertuzumab + trastuzumab + docetaxel (median, 18.5 months)
Trastuzumab + docetaxel (median, 12.4 months)
Hazard ratio, 0.62
(95% CI, 051–0.75)
p<0.001 5 10 15 20 25 30 35 40
Months
No. at risk:
Pertuzumab
Control
402
406
345
311
267
209
139 93 83 42 32 17 10 7
Baselga et al, N Engl J Med. 2012;366:

12. CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: PFS (Sub-group analysis)
No of patients
Hazard ratio (95% CI)
All patients
808
0.63 ( )
Previous record or chemotherapy No
432
0.63 ( )
Yes
376
0.61 ( )
Geographic region
Europe
306
0.72 ( )
North America
135
0.51 ( )
South America
114
0.46 ( )
Asia
253
0.68 ( )
Age group
<65 yrs
681
0.65 ( )
>65 yrs
127
0.52 ( )
<75 yrs
789
0.64 ( )
>75 yrs 19
0.55 ( )
Race ethnic group
White 8
0.62 ( )
Black 30
0.64 ( )
Asian
261
0.68 ( )
Other 37
0.39 ( )
Disease type
Visceral disease
630
0.55 ( )
Nonvisceral disease
178
0.96 ( )
Hormone receptor status
GR-positive, PgR-postive, or both
388
0.72 ( )
GR-negative and PgR-negative
408
0.55 ( )
GR and PgR status unknown 12 –
HER2 status
IHC 3+
721
0.60 ( )
FISH-positive
767
0.0
0.2
0.4
0.6
2.0
2.0
Baselga et al, N Engl J Med. 2012;366:
Pertuzamab better
Placebo better

13. Pertuzumab + trastuzumab + docetaxel (n=402) Trastuzumab + docetaxel
CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: Key secondary endpoints
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
Baselga et al, N Engl J Med. 2012;366:

14. CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: Tolerability
Pertuzumab + trastuzumab + docetaxel (n=407)
Trastuzumab + docetaxel
(n=397)
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
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
3.5
Granulocytopenia
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
Baselga et al, N Engl J Med. 2012;366:

15. 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 V

16. MARIANNE – Pertuzumab + trastuzumab emtansine for MBC
HER2 + MBC
First line
(Target n=1,092) R
Primary endpoints: PFS and safety
Trastuzumab emtansine + pertuzumab
Trastuzumab + taxane
(open label)
Ellis et al, J Clin Oncol. 2011;29 (suppl); abstr TPS102.

17. 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