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

•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.


Differentiation


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


YY

YY


Differentiation


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


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


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)


0.0 0.2 0.4 0.6 2.0 2.0Pertuzamab better Placebo better

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

CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: Tolerability


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

Documents

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