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First line therapeutic options for HER2 positive metastatic breast cancer. Harold Burstein, MD Assistant Professor of Medicine Dana-Farber Cancer Institute Boston , MA . Trastuzumab in advanced/metastatic breast cancer. 1. Slamon et al, N Engl J Med. 2001;344:783-92.

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first line therapeutic options for her2 positive metastatic breast cancer
First line therapeutic options forHER2 positive metastatic breast cancer
  • Harold Burstein, MD
  • Assistant Professor of Medicine
  • Dana-Farber Cancer Institute
  • Boston, MA
trastuzumab in advanced metastatic breast cancer
Trastuzumab in advanced/metastatic breast cancer
  • 1. Slamon et al, N Engl J Med. 2001;344:783-92.
  • 2. Marty et al, J ClinOncol. 2005;23:4265-74.

3. Burstein et al, Cancer. 2007;110:965-72.

4. Robert et al, J ClinOncol. 2006;24:2786-92.

effect of trastuzumab added to cytotoxic chemotherapy pfs
Effect of trastuzumab added tocytotoxic chemotherapy: PFS

Progression-free survival (%)

100

Chemotherapy + trastuzumab

Chemotherapy alone

80

60

40

p<0.001

20

0

0

5

10

15

20

25

Months after enrollment

No. at risk:

Chemotherapy+trastuzumab

Chemotherapy alone

226

224

122

183

60

25

15

0

Slamon et al, N Engl J Med. 2001;344:783-92.

effect of trastuzumab added to cytotoxic chemotherapy os
Effect of trastuzumab added tocytotoxic chemotherapy: OS

Survival (%)

100

Chemotherapy + trastuzumab

Chemotherapy alone

80

60

40

p<0.001

20

0

30

0

5

10

15

20

25

35

40

45

50

Months after enrollment

No. at risk:

Chemotherapy+trastuzumab

Chemotherapy alone

11

13

236

234

214

205

102

160

105

136

134

116

114

97

96

76

47

27

Slamon et al, N Engl J Med. 2001;344:783-92.

her2 mediated signaling
HER2 mediated signaling

HER2–EGFR

HER2–HER2

HER2–HER3

HER2–HER3

Ras

PI3K

P

P

P

P

P

P

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;15:216-35.

mechanisms of resistance to her2 targeted therapy
Mechanisms of resistance toHER2 targeted therapy
  • Pohlmann, Clin Cancer Res. 2009;15:7479-7491
  • Liu et al, Cancer Res. 2009;69:6861-78.

Garrett and Artega, Cancer BiolTher. 2011;11:793-800.

Gajraand Chandarlapaty, Expert Rev Anticancer Ther. 2011;11:263-75.

her2 mediated signaling effect of trastuzumab
HER2 mediated signaling: Effect of trastuzumab

HER2–EGFR

HER2–HER2

HER2–HER3

HER2–HER3

Y

Y

Y

Y

Ras

PI3K

P

P

P

P

P

P

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

her2 mediated signaling effect of trastuzumab and pertuzumab
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

P

P

P

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

pertuzumab monotherapy and the effect of addition of trastuzumab in trastuzumab refractory mbc
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 ClinOncol. 2012;30:1594-600.

cleopatra pertuzumab trastuzumab docetaxel study design
CLEOPATRA – Pertuzumab + trastuzumab+ docetaxel: Study design
  • Pertuzumab840 mg  420 mg q3w
  • Trastuzumab 8 mg/kg  6 mg/kg q3w
  • Docetaxel75 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

Primary endpoint: PFS

R

Trastuzumab 8 mg/kg  6 mg/kg q3w

Docetaxel75 mg/m2  100 mg/m2*q3w

(n=406)

*Investigators’ discretion

Baselgaet al, N Engl J Med. 2012;366:109-19.

cleopatra pertuzumab trastuzumab docetaxel pfs
CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: PFS

100

Progression-free survival (%)

80

Pertuzumab + trastuzumab + docetaxel(median, 18.5 months)

Trastuzumab + docetaxel(median, 12.4 months)

60

40

20

Hazard ratio, 0.62

(95% CI, 051–0.75)

p<0.001

0

0

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

0

0

0

0

Baselga et al, N Engl J Med. 2012;366:109-19.

cleopatra pertuzumab trastuzumab docetaxel pfs sub group analysis
CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: PFS (Sub-group analysis)

0.0

0.2

0.4

0.6

2.0

2.0

Pertuzamab better

Placebo better

Baselga et al, N Engl J Med. 2012;366:109-19.

cleopatra pertuzumab trastuzumab docetaxel key secondary endpoints
CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: Key secondary endpoints

Baselga et al, N Engl J Med. 2012;366:109-19.

cleopatra pertuzumab trastuzumab docetaxel tolerability
CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: Tolerability

*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;366:109-19.

current standards of care for her2 positive mbc first line therapy nccn
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
MARIANNE – Pertuzumab + trastuzumab emtansine for MBC

Trastuzumabemtansine

HER2 + MBC

First line

(Target n=1,092)

Primary endpoints: PFS and safety

R

Trastuzumabemtansine+ pertuzumab

Trastuzumab + taxane

(open label)

Ellis et al, J ClinOncol. 2011;29 (suppl); abstrTPS102.

summary
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