Herceptin Pivotal Studies · 2013. 5. 29. · Herceptin following adjuvant CT significantly prolongs DFS in women with HER2-positive breast cancer Herceptin significantly reduces

Herceptin® Pivotal Studies

Nuhad K Ibrahim, MD, FACP

Associate Professor of Medicine

Breast Medical Oncology Department

MD Anderson Cancer Center

Houston, TX, USAE-mail:

[email protected]

Herceptin® (trastuzumab): History and Introduction

Phase

III

Human

HER2 gene

cloned

trastuzumab

FDA approval

9/25/98

Phase II Phase I IND

for rhuMAb

HER2

muMAb

4D5

1992 1993 1994 1997 1995 1996 1998 1985 1991 1990

1981 1987

Association

of HER2 with

poor clinical

outcome

Murine

HER2/neu

gene

cloned

Targets HER2 protein

High affinity (Kd = 0.1 nM)

and specificity

95% human, 5% murine

– Decreases potential

for immunogenicity

– Increases potential for

recruiting immune effector

mechanisms

HER2 epitopes recognized by

hypervariable murine

antibody fragment

Human

IgG-1

Herceptin®: Humanized Anti-HER2 Antibody

Baselga. Satellite Symposium, 23rd Annual San Antonio Breast Cancer Symposium 2000.

Baselga and Albanell. Ann Oncol. 2001;12(suppl 1):S35.

Potential Mechanisms of Action of Trastuzumab: Preclinical Studies

Cytostatic

– Inhibits tumor cell proliferation by downregulating HER2 expression

and blocking heterodimerization with other HER members

– Induces G1 arrest and p27 cell cycle inhibitor

– Blocks HER2 cleavage/constitutive activation

Cytotoxic

– Initiates Fc-receptor–mediated antibody-dependent cellular

cytotoxicity and complement-mediated cytolysis

– Potentiates chemotherapy (promotes apoptosis)

• N = 469

• MBC

• HER2 positive

• No prior CT for MBC

• Measurable disease

• KPS ≥ 60%

AC = doxorubicin (60 mg/m2) [or epirubicin (75 mg/m2)] + cyclophosphamide (600 mg/m2) q3w for 6 cycles;

Taxol (175 mg/m2 x 3 h) q3w for 6 cycles; Herceptin (4 mg/kg) loading dose, 2 mg/kg qw until progression.

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

Herceptin® Combination Pivotal Trial in First-Line MBC: Schema

No prior adjuvant AC Prior adjuvant AC

Taxol (n = 96)

Herceptin + Taxol® (n = 92)

AC (n = 138)

Herceptin + AC (n = 143)

STRATIFY

RANDOMIZE RANDOMIZE

Herceptin Herceptin Herceptin + AC AC + Taxol® Taxol + CT CT Parameter (n = 143) (n = 138) (n = 92) (n = 96) (n = 235) (n = 234)

ORR (%) 56 42 41 17 50 32

p value < 0.02 < 0.001 < 0.001

Median DR (mo) 9.1 6.7 10.5 4.5 9.1 6.1

p value 0.005 < 0.01 < 0.001

Median TTP (mo) 7.8 6.1 6.9 3.0 7.4 4.6

p value < 0.001 < 0.001 < 0.001

Median survival (mo) 26.8 21.4 22.1 18.4 25.1 20.3

p value 0.16 0.17 0.046

Subgroup Overall

Herceptin® Combination Pivotal Trial: Efficacy Summary

Herceptin Package Insert 2000.

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

Herceptin Herceptin + CT CT + CT CT Parameter (n = 180) (n = 180) (n = 55) (n = 54)

Response rate (%) 94 (52) 59 (33) 24 (44) 15 (28) p value < 0.001 < 0.01

Median survival (mo) 26 23 19 14 Risk reduction 0.85 0.64 95% CI 0.66–1.09 0.41–0.99

60 Years 60 Years

Update of Fyfe et al. Proc Am Soc Clin Oncol. 2001;20:48a. Abstract 189.

Herceptin® Combination Pivotal Trial: Results (Age 60 vs 60 y)

• Compared with CT alone, Herceptin + CT significantly improved response rate, regardless of age;

median survival was improved in both age groups, with the greatest improvement in patients

> 60 years old

Herceptin Herceptin

+ CT CT + CT CT

Parameter (n = 97) (n = 87) (n = 98) (n = 106)

Response rate (%) 51 (53) 29 (33) 53 (54) 35 (33)

p value NS NS

Median TTP (mo) 7.4 4.7 7.4 4.5

p value NS NS

Risk reduction, survival 0.90 0.81

(range) (0.65–1.25) (0.56–1.16)

ER+ ER–

Update of Bolton et al. Proc Am Soc Clin Oncol. 2001;20:44a. Abstract 172.

Herceptin® Combination Pivotal Trial: Effect of ER Status

Similar Herceptin benefit was seen in both ER+ and ER– patients

60

50

40

30

20

10

0

% o

f p

ati

en

ts im

pro

ved

p = 0.003

p = 0.07

p = 0.08

p = 0.03

Global Physical Role Fatigue Social Emotional

QOL

p = NS

p = NS

Herceptin + CT CT

Update of Osoba et al. Proc Am Soc Clin Oncol. 2000;19:436a. Abstract 1710.

Herceptin® Combination Pivotal Trial: QOL Improvements (QLQ-C30)

Months

0.2

0

0.4

0.6

0.8

1.0

FISH+

Months

0.2

0

0.4

0.6

0.8

1.0 Herceptin + CT (n = 176)

CT (n = 169)

Pro

ba

bil

ity o

f su

rviv

al

RR = 0.71 p = 0.007

0 10 20 30 40 50

20.0 mo

26.2 mo

FISH–

RR = 1.11 p = NS

0 10 20 30 40 50

19.8 mo

24.0 mo

Herceptin + CT (n = 50)

CT (n = 56)

Herceptin® Combination Pivotal Trial: Overall Survival

Update of Mass et al. Proc Am Soc Clin Oncol. 2001;20:22a. Abstract 85.

Herceptin® after adjuvant chemotherapy

significantly improves disease-free survival

in HER2-positive early breast cancer

Michael Untch

Ludwig-Maximilians-Universität

München, Germany

on behalf of the HERA Study Team

HERA trial

HER2 and Herceptin

HER2-positive breast cancer is associated with early progression and poor overall prognosis

20-25% of women with breast cancer have HER2-positive disease

Targeting HER2 with Herceptin is associated with significant survival benefits in women with metastatic breast cancer

Early and accurate determination of HER2 status has prognostic and therapeutic importance

IHC

FISH or CISH

FISH or CISH

Herceptin

therapy

Herceptin

therapy

0 1+ 2+ 3+

Patient tumour sample

– +

Herceptin

therapy

– +

Bilous et al 2003

IHC, immunohistochemistry; FISH, fluorescence in situ

hybridisation; CISH, chromogenic in situ hybridisation

Importance of HER2 testing

Surgery + (neo)adjuvant CT ± RT

Stratification

Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age, region

Randomisation

2 years Herceptin

8 mg/kg 6 mg/kg

3 weekly schedule

1 year Herceptin

8 mg/kg 6 mg/kg

3 weekly schedule

Observation

Women with HER2-positive invasive

early breast cancer (IHC 3+ or FISH+

centrally confirmed)

HERA, HERceptin Adjuvant; CT, chemotherapy; RT, radiotherapy

HERA trial design

Key inclusion criteria

Centrally confirmed HER2 overexpression

(IHC 3+) or amplification (FISH+)

Node-positive or (sentinel) node-negative with >T1c

Completed >4 cycles of approved adjuvant or neoadjuvant CT

Baseline LVEF >55% (Echo or MUGA scan) after completion of (neo)adjuvant CT

and RT

Known hormone receptor status (ER / PgR or

ER alone)

LVEF, left ventricular ejection fraction;

ER, oestrogen receptor; PgR, progesterone receptor

100

80

60

40

20

0

Patients

(%)

Months from randomisation

6 12 18 24

1693 1108 767 445 224

1694 1172 885 532 268

127 127

220 220

1 year Herceptin

Observation

0

No.

at risk

Events HR 95% CI p value

0.54 0.43, 0.67 <0.001

2-year

DFS

85.8

77.4

Disease-free survival

Median follow-up: 1 year HR, hazard ratio; CI, confidence interval

Cardiac safety

Decrease by >10 EF points

and LVEF <50%a,b

Symptomatic CHF, including

severe CHFc

Severe CHFc

Cardiac deathc

Observation

34 (2.21)

1 (0.06)

0

1 (0.06)

1 year Herceptin

113 (7.08)

29 (1.73)

9 (0.54)

0

No. patients (%)

aMany were single observations not confirmed at subsequent time points bObservation, n=1540; Herceptin, n=1595 cObservation, n=1710; Herceptin, n=1677 CHF, congestive heart failure

p value

<0.001

<0.001

0.002

1.00

Conclusions

Herceptin following adjuvant CT significantly prolongs DFS in women with HER2-positive breast cancer

Herceptin significantly reduces the risk of distant metastases

Herceptin was associated with a low incidence of severe CHF (0.5%)

Long-term follow-up will provide

– clarification of the survival gain

– further safety data

– information on optimum Herceptin treatment duration (1 vs 2 years)

NSABP-B31 / NCCTG N9831: interim combined analysis

Edith Perez

Mayo Clinic, Jacksonville, FL, USA

National Cancer Institute sponsored 2 trials

of adjuvant Herceptin

– NSABP-B31

– NCCTG N9831

Control and concurrent treatment groups similar

– compared standard chemotherapy (AC) followed by paclitaxel with

or without concurrent Herceptin therapy

Joint analysis plan was agreed with the FDA

Rationale for combined analysis

NSABP-B31

NCCTG N9831

Arm 1

Arm 2

Arm A Arm B

Arm C

= doxorubicin / cyclophosphamide (AC) 60 / 600 mg/m2 q3w x 4

= paclitaxel (P) 175 mg/m2 q3w x 4

= P 80 mg/m2 qw x 12

= Herceptin (H) 4 mg/kg loading dose 2 mg/kg qw x 51

NSABP-B31 and NCCTG N9831 trial designs

Control

Herceptin

Arm 1 (B31)

Arm A (N9831)

Arm C (N9831)

n=3351

Median follow-up: 2 years

Arm 2 (B31)

Combined analysis

= doxorubicin / cyclophosphamide (AC) 60 / 600 mg/m2 q3w x 4 = paclitaxel (P) 175 mg/m2 q3w x 4 = P 80 mg/m2 qw x 12 = Herceptin (H) 4 mg/kg loading dose 2 mg/kg qw x 51

Years from randomisation

87% 85%

67%

75%

100

90

80

70

60

50

0

1

2

3

4

5

2-year median

follow-up

Patients

(%)

Combined analysis: DFS

HR=0.48; p<0.0001

ACPH

ACP

Events

133

261

n

1672

1679

Romond et al 2005

Subgroup analyses: DFS

HR

0.2 0.4 0.6 0.8 1.0 1.2 1.4

Protocol N9831

Tumour size, cm >4.1

All data

No. positive nodes 10+

<39

Age, years >60

50-59

40-49

Hormone receptor Positive

Negative

<2.0 2.1-4.0

0

4-9

1-3

B31

Romond et al 2005

194 1679

81%

74%

90% 90%

0 1 2 3 4 5

50

60

70

80

90

100

Years from randomisation

Time to 1st distant recurrence

HR=0.47; p<0.0001

Events n 96 1672

Patients

(%)

ACPH ACP

Romond et al 2005

Hazard of distant recurrence

0

20

40

60

80

100

120 Rate

per 1000

women/

year

0

1

2

3

4

Years from randomisation

ACP ACPH

Romond et al 2005

Overall survival

94% 91%

87% 92%

0 1 2 3 4 5 50

60

70

80

90

100

Years from randomisation

HR=0.67; p=0.015

Deaths n

62 92

1672 1679

Patients

(%)

ACPH

ACP

Romond et al 2005

N9831: DFS

87%

86%

68%

78%

0 1 2 3 4 5 50

60

70

80

90

100

Years from randomisation

HR=0.55; 2p=0.0005

Events n

51 90

808 807

Patients

(%)

ACPH

ACP

Romond et al 2005

Combined analysis: summary of efficacy end points

DFS

Time to distant

recurrence

Overall survival

No. events

H vs obs

HR

(95% CI)

133 vs 261 0.48

(0.39-0.59)

96 vs 193 0.47

(0.37-0.61)

0.67

(0.48-0.93)

62 vs 92

0.0

0.5

1.0

1.5

HR

Median follow-up: 2 years Romond et al 2005

LVEF evaluation schedule

MUGA (B31 and N9831) or echo scan (N9831)

Post-AC LVEF >LLN or decrease <16 points from baseline to initiate

Herceptin

0 months

3 months

(post-AC)

6 months

(post-P or -PH)

9 months

18 months

MUGA, multiple-gated acquisition; LLN, lower limit of normal

N9831: 3-year cumulative

incidence of cardiac events

39 cardiac events were reported in 3 treatment arms over 3 years

– 2 cardiac deaths, 37 CHFs

Cumulative incidence, %

Time since

registration, years

Arm A

ACP

(n=670)

0.0

0.0

0.0

0.3

Arm B

ACPH

(n=718)

0.8

1.4

2.5

2.5

Arm C

ACPH

(n=579)

2.6

3.5

3.5

3.5

0.5

1

2

3

Perez et al 2005

N9831: radiotherapy does not increase the

incidence of cardiac events

Cumulative incidence, %

Radiotherapy

Yes

No

Arm B

ACPH

1 year

1.6

0.6

2 years

2.2

2.8

Arm C ACPH

1 year

2.3

4.6

2 years

2.3

4.6

n

508

160

n

399

131

Perez et al 2005

Summary

Herceptin given concurrently with paclitaxel following AC

– significantly reduces the risk of DFS events by 52%

– significantly reduces the risk of distant recurrence by 53%

– significantly improves overall survival, with a 33% reduced risk of

mortality

The risk of cardiac events was low

– <4% incidence, Herceptin vs non-Herceptin in both trials

– risk of cardiac events may increase with age

Conclusions

Adjuvant Herceptin is recommended for patients with HER2-

positive early breast cancer

– unless a specific contraindication exists

– can be administered concomitantly with radiotherapy

Careful monitoring of cardiac function is essential with adjuvant

Herceptin therapy

BCIRG 006

John Crown

St Vincent’s Hospital,

Dublin, Ireland

Trial design

6 x D and Carbo

1 year Herceptin

ACD

ACDH

DCarboH

1 year Herceptin

HER2 positive (FISH positive)

Node positive or

high-risk node negative

n=3222

Stratified by nodes

and hormonal receptor status

AC, doxorubicin + cyclophosphamide; D, docetaxel; Carbo, carboplatin

4 x AC 4 x D

4 x AC 4 x D

DFS Patients

(%)

Years

100

90

80

70

0

1

2

3

4

5

93%

86% 84%

80% 80%

91%

86%

77% 73%

n

1074

1075

1073

Events

77

98

147

ACDH

DCarboH

ACD

60

50

HR=0.49

HR=0.61

Slamon et al 2005

0

10

20

30

40

50

60

70

80

Grade 3/4 haematological toxicity

Patients

(%)

ACD (n=1050)

ACDH (n=1068)

DCarboH (n=1056)

Slamon et al 2005

Grade 3/4 non-haematological toxicity

0

5

10

15

20

25

30Patients

(%)

ACD (n=1050)

ACDH (n=1068)

DCarboH (n=1056)

Slamon et al 2005

Cardiovascular risk factors ACD

(n=1073)

49

23-74

38

54

20

27

16

638

335

ACDH

(n=1074)

49

22-74

34

45

10

36

16

625

307

DCarboH

(n=1075)

49

23-73

30

43

12

37

17

647

323

Age, years

median

range

Risk factors, no. patients

diabetes

hypercholesterolaemia

hyperlipidaemia

obesity

hypertension

Radiotherapy, no. patients

after chemotherapy

to left chest

Slamon et al 2005

Clinically significant cardiac events

statistical analysis

p=0.016

ACD

(n=1050)

10

0.95

0.46-1.74

ACDH

(n=1068)

25

2.34

1.52-3.44

DCarboH

(n=1056)

14

1.33

0.73-2.21

Patients

%

95% CI

p=0.11

p=0.54

Slamon et al 2005

Clinically significant cardiac events as per

independent review panel

Cardiac death, n

Grade 3/4 cardiac

ischaemia / infarction, n

Grade 3/4 arrhythmia, n

Grade 3/4 CHF, n

ACD

(n=1050)

0

0

7*

3

ACDH

(n=1068)

0

4

4*

17

DCarboH

(n=1056)

0

1

9*

4

*5 / 20 arrhythmias not yet adjudicated by independent

review panel (2 in ACD, 1 in ACDH, 2 in DCarboH) Slamon et al 2005

Mean LVEF: all observations LVEF

66

65

63

62

60

59

0

100

300

400

600

800

Days

200

500

700

64

61

205 pts

290 pts

189 pts

DCarboH

ACD

ACDH

(n=1029)

(n=1012)

(n=1040)

Slamon et al 2005

HER2

core region

17 q 12 17 q 21.1 17 q 21.2

n=2120

1285 pts

(60%)

91 pts

(4%)

Topo II

non-co-

amplified

Topo II

region

744 pts

(35%) Co-amplified

Normal Amplified Deletion

HER2 and topo II in BCIRG 006: 2120 / 3222 patients analysed

Topo II, topoisomerase II

DFS topo II co-amplified vs non-co-amplified: all patients

Patients

(%) 100

90

80

70

60

50

0

1

2

3

4

5

Years

Patients

744

1376

Events

57

191

Topo II

Co-amplified

Non-co-amplified p<0.001

Slamon et al 2005

DFS co-amplified topo II 100

90

80

70

60

50

0

6

24

36

42

54

Months

Patients

265

227

252

Events

13

23

98

ACDH

ACD

DCarboH

12

18

32

48

p=0.24

Patients

(%)

Slamon et al 2005

DFS non-co-amplified topo II 100

90

80

70

60

50

0

6

24

36

42

54

Months

Patients

472

446

458

Events

45

54

92

ACDH

DCarboH

ACD

12

18

32

48

p<0.001

Patients

(%)

Slamon et al 2005

Conclusions

BCIRG 006 has confirmed the benefit of Herceptin in early breast cancer

With a favourable overall safety profile, the

risk : benefit ratio warrants the use of Herceptin

in early breast cancer

Preliminary data on topo IIα status suggest that

not all patients benefit equally from anthracyclines

Cardiac safety improves with DCarboH

Further follow-up is required to determine whether efficacy differs

between ACDH and DCarboH

Neoadjuvant therapy with paclitaxel followed by FEC chemotherapy with

trastuzumab in HER-2 positive operable breast cancer

PI. Aman Buzdar, MD

Who benefits from a particular adjuvant chemotherapy?

Mo n th s

Cu

mu

lati

ve

pro

po

rtio

n s

urv

ivin

g d

ise

as

e-f

ree

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 10 20 30 40 50 60 70 80 90 100 110

p C R

< p C R

P = 0.0005

Kuerer H et al. J Clin Oncol 1999

Those who have a complete eradication of their breast cancer

(pCR) by preoperative chemotherapy benefit !

Phase II Trials of Trastuzumab Neoadjuvant Therapy for

Breast Cancer

*42% of patients had <5 mm residual tumors.

Mohsin et al. J Clin Oncol. 2005;23:epub ahead of print; Gennari et al. Clin Cancer Res. 2004;10:5650;

Burstein et al. J Clin Oncol. 2003;21:46; Bines et al. Breast Cancer Res Treat. 2003:82:S56. Abstract 243;

Harris et al. Proc Am Soc Clin Oncol. 2003;22:22. Abstract 86; Limentani et al. Breast Cancer Res Treat.

2003;83:S58. Abstract 251.

Percent

Study (N) Regimen ORR cCR pCR

Mohsin 2005 T qw × 3, T + D qw × 12

Gennari 2004 (11) T qw × 4 36 0 9

Burstein 2003 (40) T qw × 12 + P qw × 4 75 30 18

Bines 2003 (33) T qw × 12 + D q3w × 4 70 24 12

Harris 2003 (42) T qw × 12 + V qw × 12 88 38 19

Limentani 2003 (45) T qw × 12 + DV q2w × 6 100 59 31*

*Paclitaxel 225 mg/m2 q3w.

FEC = 5-fluorouracil 500 mg/m2 d1, 4 + epirubicin 75 mg/m2 d1 +

cyclophosphamide 500 mg/m2 d1, all q3w.

T = trastuzumab 4 mg/kg d1, then 2 mg/kg qwx24 weeks

Buzdar et al. J Clin Oncol. 2005;23:3676-85

Phase III Trial of Neoadjuvant Trastuzumab +

Chemotherapy for Operable Breast Cancer

ARM 1

Paclitaxel 4 +

T 12

ARM 2

Paclitaxel 4

FEC 4 +

T 12

FEC 4

Local and

adjuvant

therapy

R

HER2+

(IHC 3+/FISH+)

N=42*

Additional 22

patients

N=19

N=23

Current Clinical Practices for Herceptin® Patient Selection

Significant false-positive with HercepTest™ suggests in some

cases retesting with FISH may be warranted

High

overexpressors

3+ 2+ 0/1+

IHC FISH

Amplified Nonamplified

Treat with

Herceptin Other

therapies

HER2 results

inconsistent

with clinical

profile

Possible benefit

Sco

re

In current clinical practice, either IHC or FISH is used

for primary testing

Guidelines on HER2 Testing

NCCN Clinical Practice Guideline (2004):

– Recommends HER2 testing for all invasive breast cancer

cases, using IHC and/or FISH

– FISH retesting of IHC 2+ recommended

ASCO Practice Guideline for Tumor Markers (2000):

– HER2 overexpression should be evaluated on every

primary breast cancer either at the time of diagnosis or at

the time of recurrence. Measures of HER2 amplification

may also be of value.

www.nccn.org

www.asco.org

Guidelines on HER2 Testing (cont.)

College of American Pathologists consensus statement (2003):

– Laboratories should calculate their FISH/IHC concordance

rates

– If FISH-neg/IHC 0 and FISH-pos/IHC 3+ concordance is

>95%:

OK to use IHC as screening test

All IHC 1+ and 2+ should be retested by FISH

– If FISH-neg/IHC 1+ concordance is also >95%, OK to not

retest IHC 1+ with FISH, but should document in a path

report comment

– If do not wish to check concordance, or concordance

<95%, consider performing both IHC and FISH on all

samples

Zarbo & Hammond, Arch Pathol Lab Med, 2003

Thank You