Herceptin® adjuvant therapy:

“a triumphal narrative of translational research”

Brian Leyland-Jones

McGill University

Department of Oncology

Montreal, Quebec, Canada

Burstein, H. NEJM 2005:353;1652

NSABP B-31 (US)(n=1960)

Paclitaxel q3w x 4 or qw x 12

Paclitaxel q3w x 4 or qw x 12 + H qw

HERA Trial (ex-US) (n=5090)

Observation

H q3w* x 12 months

H q3w* x 24 months

Any CT ± RT

Intergroup N9831 (US) (n=3046)

Paclitaxel qw x 12

Paclitaxel qw x 12

Paclitaxel qw x 12 + H qw

BCIRG 006 (global)(n=3222)

Carboplatin + docetaxel q3w x 6 + H qw

Herceptin® adjuvant trials (>13,000 patients)

H qw

AC x 4

AC x 4

Docetaxel q3w x 4

Docetaxel q3w x 4 + H qw

*q3w at 6mg/kgH = Herceptin®

H q3w*

H q3w*

AC x 4

AC x 4

AC x 4

AC x 4

AC x 4

Herceptin® in the adjuvant setting: how four trials complement each other

Covers all currently accepted EU and US treatment strategies

Combinations of a number of regimens and both taxanes

Compares AC followed by H with novel treatment concepts

Investigates optimal treatment duration

Investigates sequential versus combination therapy

Joint analysis: disease-free survival

Years from randomisation

Romond et al 2005

87% 85%

67%

75%

HR=0.48; p<0.0001

100

90

80

70

60

500 1 2 3 4 5

2-year median follow-up

Patients (%)

AC T

AC TH

n EventsAC TH 1672 133

AC TP 1679 261

Joint analysis:time to first distant recurrence

N Events

0 1 2 3 4 5

50

60

70

80

90

100

ACTH 1672 96ACT 1679 194

HR=0.47, 2P=8x10-10

ACACTHTH

ACT

Years from randomization

90%90%90%90%

81%

74%

%

Romond et al 2005

Joint analysis: hazard of distant recurrence

0 1 2 3 4

0

20

40

60

80

100

120

Rat

e p

er 1

000

Wo

men

/Y

r

Years from randomization

ACACTHTH

ACT

Romond et al 2005

Joint analysis: overall survival

Romond et al 2005

ACTH94%

91%

87%

92%

ACT

N Deaths

ACT 1679 92

ACTH 1672 62 HR=0.67, 2P=0.015

%

100

90

80

70

60

50 0 1 2 3 4 5Years from randomisation

0.5 0.3 2.6 1472

1.0 0.5 3.6 1202

1.5 0.5 3.9 983

2.0 0.5 4.1 775

2.5 0.8 4.1 595

3.0 0.8 4.1 405

NSABP B-31: cumulative incidence ofcardiac events in the evaluable cohort

Yrs

Po

st D

ay 1

C

yc 5

Cu

m I

nc

Arm

1

(%

)

Cu

m I

nc

Arm

2 (%

)

Nu

mb

er A

t R

isk

Cohort Arm 1 Evaluable CohortArm 2 Evaluable Cohort

%

0

2

4

6

Years Post Day 1 Cyc 50.0 0.5 1.0 1.5 2.0 2.5 3.0

Arm 2: AC→PTX + HN=850, 31 CHFs,No Cardiac Deaths

Arm 1: AC→PTX N=814, 4 CHFs, 1 Cardiac Death

HR=5.94.1%

0.8%

NSABP-B31: post – AC LVEF and age are independent predictors of Herceptin®-

associated CHF

Age and LVEF were statistically significant predictors of CHF. Careful cardiac monitoring must be done.

LVEF Age < 50 Age ≥ 50

50 – 54 3/48 (6.3%) 9/47 (19.1%)

55 – 64 5/229 (2.2%) 10/194 (5.2%)

65+ 1/160 (0.6%) 2/159 (1.3%)

P(Age) = 0.04

P(LVEF) < 0.001

Joint analysis: conclusions 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 number of cardiac events was low– <4% incidence, Herceptin® versus non-Herceptin® in

both trials

HERA: key inclusion criteria Centrally confirmed HER-2 overexpression or Centrally confirmed HER-2 overexpression or

amplificationamplification

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

Completed Completed 4 cycles of approved (neo)adjuvant 4 cycles of approved (neo)adjuvant chemotherapy regimenchemotherapy regimen

Baseline LVEF Baseline LVEF 55% (Echo or MUGA) 55% (Echo or MUGA)

Known hormone receptor statusKnown hormone receptor statusPiccart-Gebhart et al 2005

HERA: patient and tumour characteristics (%)

Observation(n=1,693)

1-year Herceptin

(n=1,694)

Age (years)

<3535–49

50–59

≥60

7.3

43.7

32.7

16.2

7.6

44.3

31.8

16.2

Adjuvant CT (%)

No AC, no T

AC

AC + T

6.1

68.3

25.5

6.2

67.9

26.0

Nodal status

Any (neoadjuvant)

Node-negative

1–3 +

≥4 +

10.2

32.9

28.9

27.9

11.1

32.1

28.5

28.3

Hormone Receptor (%)

HR-negative

HR-positive

49.9

50.0

49.0

50.9AC=anthracycline; T=taxane Piccart-Gebhart et al 2005

HERA: endpoints and analysis plan Target accrual was 4,482 patients, 5,090 enrolled

– HR=0.77 (80% power two sided α=0.025) for nil versus 1 year, nil versus 2 years

Primary endpoint DFS

Secondary endpoints RFS, DDFS, OS, 2 years versus 1-year Herceptin®

One interim efficacy analysis (n=475 events), 1 year median follow up

One primary core analysis (n=951 events)

Safety – tolerability, incidence of cardiac dysfunction

Three safety interim analyses of cardiac endpoints after n=300, 600, 900 patients. Stopping rule ≥4% increase in cardiac events

Piccart-Gebhart et al 2005

100

80

60

40

20

0

Patients(%)

Months from randomisation6 12 18 24

1693 1108 767 445 2241694 1172 885 532 268

127

220

1 year Herceptin®

Observation

0

No. at risk

Events HR 95% CI p value

0.54 0.43, 0.67 <0.0001

2-yearDFS

85.8

77.4

HERA: disease-free survival

Median follow-up: 1 year; DFS, disease-free survival;HR, hazard ratio; CI, confidence interval Piccart-Gebhart et al 2005

HERA: efficacy endpoints

0

50

100

150

200

250

HR95% CIp value 2-year outcome, %

0.490.38, 0.63<0.0001

82.8 vs 90.6

0.760.47, 1.23

0.2695.1 vs 96.0

Distant recurrence

Overall mortality

No. events

171 89 37 29

Observation 1 year Herceptin®

Piccart-Gebhart et al 2005

0.540.43, 0.67<0.0001

77.4 vs 85.8

DFSDFS

220 127

HERA: cardiac safety Cardiac events have been manageable and reversible

Decrease by >10 EF points and LVEF <50%a

Symptomatic CHF, including severe CHF

Severe CHF

Cardiac death

Observation

2.2

0.06

0

0.06

1 year Herceptin

7.1

1.7

0.5

0

% patients

aMany were single observations not confirmed at subsequent time points

p value

<0.001

<0.001

0.002

1.0

Piccart-Gebhart et al 2005CHF = congestive heart failure

HERA: conclusions At 1-year follow up, Herceptin® given after

chemotherapy – significantly reduces the risk of DFS events

by 46%– significantly reduces the risk of distant recurrence

by 51%– is associated with a low incidence of severe

CHF (0.5%)

Piccart-Gebhart et al 2005

BCIRG 006: disease-free survival

% D

ise

as

e F

ree

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5

Year from randomization

77%

86%

80%

73%

84%

80%86%

93%

91%

Patients Events

1073 147 AC->T

1074 77 AC->TH

1075 98 TCH

HR (AC->TH vs AC->T) = 0.49 [0.37;0.65] P<0.0001

HR (TCH vs AC->T) = 0.61 [0.47;0.79] P=0.0002

Slamon et al SABCS 2005

BCIRG 006: mean LVEF - all observations

59

60

61

62

63

64

65

66

0 100 200 300 400 500 600 700 800

Days

LV

EF

AC->T (N=1012) AC->TH (N=1040) TCH (N=1029)

AC->T

TCH

AC->TH

189 pts

290 pts

205 pts

Slamon et al SABCS 2005

BCIRG 006: HER2 and TOPO II

HER2core region

17q 12 17q 21.1 17q 21.2

60%

n=2120

4%

Topo IINonco-amplified

Slamon et al 2005

Normal Amplified Deletion

TOPO II region

35% Co-amplified

2120 of 3222 patients analysed

BCIRG 006: disease-free survival non-amplified Topo II by

arm

% D

ise

as

e F

ree

Months

0.0

0.6

0.8

1.0

0 6 12 18 24 30 36 42 48 54

Patients Events Treatment

458 92 AC->T472 45 AC->TH446 54 TCH

Logrank P= <0.001

TCHAC->TH

AC->T

Press et al SABCS 2005

BCIRG 006: disease-free survival amplified Topo II by arm

% D

ise

as

e F

ree

Months

0.5

0.6

0.8

1.0

0 6 12 18 24 30 36 42 48 54

Patients Events Treatment

227 23 AC->T

265 13 AC->TH252 21 TCH

Logrank P= 0.24

TCH

AC->TH

AC->T

Press et al SABCS 2005

BCIRG 006: conclusions Herceptin® provided a significant DFS benefit in

both regimens– in combination with docetaxel after AC (HR=0.49)– in combination with docetaxel and carboplatin

without an anthracycline (HR=0.61)

It is too early to tell whether a non-anthracycline-containing Herceptin® regimen has efficacy comparable to anthracycline-based regimens

Cardiac safety appears to be higher with non-anthracycline-based therapy

Slamon et al 2005

FinHER: trial design

502 pts.Docetaxel

507 pts.Vinorelbine1010 pts.

EBCpN+ or

pN0 (tumour >2 cm,

PR-)

R115 pts.HER2 +

392 pts.HER2 -

116 pts.HER2 +

386 pts.HER2 -

R

R

57 pts. + Herceptin®

58 pts.

58 pts. + Herceptin®

58 pts.

392 pts.HER2 -

386 pts.HER2 -

1010 patients were recruited and after 2 randomisations allocated to 6 treatment arms (1 patient excluded from efficacy analyses)

FinHER: recurrence-free survival in HER2-positive subgroup

100

80

60

40

20

0

Rec

urr

ence

-fre

e su

rviv

al (

%)

0 1 2 3 4Time (years)

89.3%

77.6%

HerceptinEvents=12

No HerceptinEvents=27

FinHER: cardiac safety in HER2-positive subgroup

Cardiac failure

LVEF decrease >15% from baseline

Joensuu et al 2005

Herceptin®

0 (0%)

4 (3%)

No Herceptin®

1 (1%)

7 (6%)

FinHER: conclusions

Compared with vinorelbine, adjuvant docetaxel

– improves DFS

– results in more adverse events

Brief use of adjuvant Herceptin® administered concomitantly with docetaxel or vinorelbine was well-tolerated and effective for HER2-positive breast cancer and warrants further study

Summary: Herceptin® in EBC

0 1 2

HERA 1 year

Combined analysis 2 years

Median follow-up

FavoursHerceptin®

Favours noHerceptin®

HR

BCIRG 006 DCarboH 2 years

2 yearsBCIRG 006 AC DH

FinHER VH / DH CEF 3 years

Piccart-Gebhart et al 2005; Romond et al 2005;Slamon et al 2005; Joensuu et al 2005

Summary: Herceptin® in EBC

Piccart-Gebhart et al 2005; Romond et al 2005;Slamon et al 2005; Tan-Chiu et al 2005

Trial

HERA

NSABPB-31

NCCTG N9831

BCIRG006

FinHER

Arm

H 1 yearNil

ACPACPH

ACP ACPH

ACDACDH

DCarboH

HNo H

BaselineLVEF, %

>55

>50

>50

>50

CHF,n (%)

09 (0.5)

4 (0.8)a 31 (4.1)a

0a

20 (2.9)a

3 (0.3)17 (1.6) 4 (0.4)

0 (0)1 (1)

aCumulative percent

Cardiacdeath, n

10

10

000

00

Herceptin® adjuvant therapy:conclusions and future prospects

Benefits seen with Herceptin® are independent of chemotherapy and patient characteristics

Radiotherapy can be given before or concurrent with Herceptin®

Data are currently not available on benefit of Herceptin®

– as monotherapy or combined with endocrine agents in patients not indicated for chemotherapy

– in patients with primary tumours <1cm

Five studies have demonstrated a substantial DFS advantage with adjuvant Herceptin® in women with HER2-positive EBC

Optimal duration of treatment is uncertain

Herceptin® in the news

Herceptin is the cure for early stages of breast cancer?

MedIndia, India, Jan 06

…thanks to Herceptin, breast cancer

sufferers could now look

forward to a long life

The Observer, UK, Jan 06

…superdrug that h

as

changed the face of m

odern medicine

The Observer, UK, Jan 06

Cancer wonder drug campaigner gets all clear

Mirror.co.uk, Jan 06

“Herceptin is the best chance for women like me”

Barbara Clarke, Telegraph.co.uk, Jan 06