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Should clinicians routinely recommend trastuzumab (Herceptin) as part of the adjuvant therapy for all patients with Her2 positive early breast cancer? A review of recent data, and reflections on how these results relate to the use of Adjuvant!. Details Of Use Of These Slides

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Should clinicians routinely recommend trastuzumab (Herceptin) as part of the adjuvant therapy for all patients with Her2 positive early breast cancer?

A review of recent data, and reflections on how these results relate to the use of Adjuvant!


Details Of Use Of These Slides (Herceptin) as part of the adjuvant therapy for all patients with Her2 positive early breast cancer?

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An Interpretation of Adjuvant Herceptin Results Presented at ASCO May 2005

1) Romond EH, Perez EA, Bryant J, et al.

Doxorubicin and Cyclophosphamide Followed by Paclitaxel with or without Trastuzumab as Adjuvant Therapy for Patients with HER-2 Positive Operable Breast Cancer: Combined Analysis of NSABP B31/NCCTG-N9831

2) Perez EA, Suman VJ, Davidson N, et al.

NCCTG N9831 May 2005 Update

3) Piccart MJ

First Results Of The HERA Trial


NSABP B-31 ASCO May 2005

Arm 1

Arm 2

NCCTG N9831

Arm A

Arm B

Arm C

HERA (Randomization after chemotherapy)

Arm A No Herceptin

Arm B

(1 yr)

Arm C

(2 yr)

AC q 3 wk * 4

= paclitaxel q 1 wk * 12

= paclitaxel q 3 wk * 4

= trastuzumab q 1 w

= trastuzumab q 3 w


Combined analysis of B31 / N9831 ASCO May 2005

Control

Arm 1 (B31)

Arm A (N9831)

Herceptin

Arm 2 (B31)

Arm C (N9831)

Combined: n = 3,351; median follow-up 2.0 yr

NSABP B-31: n = 1,736; median follow-up 2.4 yr

N9831: n = 1,615; median follow-up 1.5 yr


Eligibility ASCO May 2005

NSABP B-31 / N9841

  • Definitively resected primary adenocarcinoma of the breast.

  • Axillary node positive (N9841 was amended to allow high risk node negative).

  • No locally advanced or metastatic disease.

  • Normal hematologic, hepatic, and renal function.

  • No prior anthracycline or taxane therapy.

  • No significant sensory or motor neuropathy.

  • No past or current cardiac history.

  • Normal LVEF.

  • Her2 IHC +++ or FISH + (N9831 by central lab, B31 by approved reference laboratory).


Patient / Tumor: Characteristics ASCO May 2005

No Imbalances Between Treatment Arms

(numbers shown are % of total)

Age

< 50 51

50 - 59 33

> 59 16

Nodes

N0 6

NP (1-3) 53

NP (4-9) 27

NP (> 9) 14

Tumor Size

T < 2cm 39

T 2.1-4.0 cm 45

T > 4 cm 15

ER and PgR Status

ER + 52

ER - 48

PgR + 40

PgR - 59


Combined Analysis for ASCO May 2005DFS of

NSABP B-31 / NCCTG – N9831

ACTH

87%

85%

ACT

75%

%

67%

N Events

ACT 1679 261

ACTH 1672 134

HR=0.48, 2P=3x10-12

Years From Randomization


Combined Analysis for DFS of ASCO May 2005

NSABP B-31 / NCCTG – N9831

Subset Analysis For DFS

Herceptin Benefit

In all age subsets

In all tumor size subsets

In all nodal subsets (NN CI very broad)

In ER positive and negative subsets

In both N9831 and B31


Forest Plot For DFS: B31/N9831 ASCO May 2005

ALL DATA

Age

≥60

50-59

40-49

≤39

Positive

Negative

Hormone

Receptor

≥ 4.1cm

2.1- 4.0 cm

<2.0 cm

Tumor

Size

No.

Positive

Nodes

10+

4-9

1-3

0

Protocol

N9831

NSABP B-31

0.2

0.4

0.6

0.8

1.0

1.2

1.4

Hazard Ratio


Combined Analysis for ASCO May 2005DDFS of

NSABP B-31 / NCCTG – N9831

100

ACTH

AC->T+H

90%

90%

90%

90%

90%

90%

90

ACT

AC->T

80

81%

81%

81%

%

74%

74%

74%

70

N Events

N Events

ACTH 1672 96

ACT 1679 194

AC->T 1679 194

60

AC->T+H 1672 96

HR=0.47, 2P=8x10-10

HR=0.47, 2P=8x10-10

50

0

1

2

3

4

5

Years From Randomization


Annual Hazard of Distant Recurrence ASCO May 2005

120

100

ACT

80

Rate per 1000 Women /Yr

60

40

ACTH

20

0

0

1

2

3

4

Years From Randomization


Combined Analysis for ASCO May 2005OS of

NSABP B-31 / NCCTG – N9831

ACTH

94%

91%

ACT

92%

87%

N Deaths

ACT 1679 92

ACTH 1672 62

HR=0.67, 2P=0.015

Years From Randomization

B31/N9831


Cardiac Monitoring ASCO May 2005

~ 20% of the patients discontinued Herceptin

because of symptomatic or asymptomatic

heart problems

Herceptin * 12 mns

AC * 4

Taxol * 4

3 mns

6 mns

9 mns

15 mns

18 mns

Baseline

7.7%

10.1%

2.1%

% stopping Herceptin by time period

~ 4 % of patients never got Herceptin because of developing a low LVEF post AC * 4.

LVEF measurements

This analysis from B31data alone.


Cardiac Monitoring ASCO May 2005

Rules for action for asymptomatic patients

* Repeat LVEF assessment in 4 weeks

If criteria for continuation met restart

If 2 consecutive holds of a total of 3 holds, discontinue Herceptin


Cardiac Safety ASCO May 2005

Age and Post AC LVEF were predictors of the risk of developing CHF

In both age groups about 10% of the patients had a LVEF of 50-54,

about 50% of the patients had a LVEF of 55-64, and 35% had a LVEF of > 65%. Average risk of early CHF for patient younger than 50 is 2 % and older than 50 is ~ 5%

This analysis from B31data alone.


Risk of Cardiac Events ASCO May 2005

(no strong evidence of an major delayed toxicity)

End of Herceptin treatment period

The only cardiac death that occurred during this study occurred in a control patient.

This analysis from B31 data alone.


NSABP B-31 ASCO May 2005

Cardiac Safety Analysis For First 1000 Patients

Baseline all patients normal LVEF (median 63%)

After 3 months of AC

LVEF median 61% (lower, p<0.001)

4.2% of patients with LVEF < 50%

Total symptomatic cardiac events during Herceptin

4.28 % in Herceptin group

0.78 % in Control group

Patients with low LVEF did not go on to get Herceptin.

of these 33% had LVEF < 30%, 52% LVEF 30-39%


NSABP B-31 ASCO May 2005

Cardiac Safety Analysis For First 1000 Patients

Herceptin Related Fall In LVEF Was Largely Reversible

In Patients With A Cardiac Event (n=27)

~ 68% of the patients had symptoms resolve within 6 months


Analysis of Three Arms of N9831 ASCO May 2005

NCCTG N9831

Arm A

Arm B

Arm C

n = 2,804; median follow-up 1.5 yr


N9831 disease free survival control vs concurrent
N9831 Disease-Free Survival ASCO May 2005Control vs Concurrent

AC → T + H → H

100

90

80

70

60

50

40

30

20

10

0

AC → T

%

Hazard ratio = 0.55

Stratified logrank 2P = 0.0005

0 1 2 3 4

Years


N9831 disease free survival control vs sequential
N9831 Disease-Free Survival ASCO May 2005Control vs Sequential

AC → T → H

100

90

80

70

60

50

40

30

20

10

0

AC → T

%

Hazard ratio = 0.87

Stratified logrank 2P = 0.29

0 1 2 3 4

Years


N9831 disease free survival sequential vs concurrent
N9831 Disease-Free Survival ASCO May 2005Sequential vs Concurrent

AC → T + H → H

100

90

80

70

60

50

40

30

20

10

0

AC → T → H

%

Hazard ratio = 0.64

Stratified logrank 2P = 0.0114

0 1 2 3 4

Years


Cardiac safety in 9831
Cardiac Safety in 9831 ASCO May 2005

  • Difference in the incidence of cardiac events (CHF and cardiac deaths) between non-H and H arms is < 4%

  • 9 month (post finishing AC * 4) analysis; 500 per arm with normal LVEF or LVEF decrease  15% from baseline (after AC)

    • 0.0% with events (95% CI,0.0-0.7%) for control

    • 2.2% with events (95% CI,1.1-3.8%) for control vs sequential

    • 3.3% with events (95% CI,2.0-5.1%) for control vs concurrent* therapy with paclitaxel

* at month 9, concurrent pts have received 3 additional months of Herceptin compared to sequential


HERA Trial ASCO May 2005

HERA (Randomization after chemotherapy)

Arm A No Herceptin

Arm B

(1 yr)

Arm C

(2 yr)

Only Arms 1 and 2 analyzed in this interim analysis

n = 3,307, median follow-up ~ 1 year


Eligibility ASCO May 2005

HERA Trial

  • Definitively resected primary adenocarcinoma of the breast.

  • Received and completed neoadjuvant and/or adjuvant chemotherapy. Chemotherapy must have been at least 4 cycles of an approved regimen.

  • If node negative tumor size must have been T1c or larger (for adjuvant patients).

  • Normal LVEF by MUGA or echo of > 55%.

  • Her2 IHC +++ or FISH + by central lab.

  • Known (and centrally reviewed ER status).


HERA Trial: ASCO May 2005

Patient / Tumor: Characteristics

No Imbalances Between Treatment Arms

(numbers shown are % of total)

Age

< 50 51

50 - 59 32

> 59 16

Nodes

N0 33

NP (1-3) 29

NP > 4 28

NeoAdj 11

Adjuvant Regimen

Anthracyclines 68

Anathra + Taxane 26

No A or Taxane 6

ER and PgR Status

ER + 51

ER - 49


DFS: HERA Trial ASCO May 2005

Trastuzumab 1 yr

% alive and disease free

100

90

80

Observation

70

60

50

2-yrDFS %

40

Events

HR

[95% CI]

p value

30

127

85.8

0.54

[0.43, 0.67]

<0.0001

20

220

77.4

10

0

0

5

10

15

20

25

Months from randomization

No. at risk

1694

1472

1067

629

303

102

1693

1428

994

580

280

87


DFS In Patient Subsets: HERA Trial ASCO May 2005

Hazard

Hazard

ratio

ratio

n

n

All

All

3387

3387

0.54

0.54

Nodal

Nodal

status

status

Any, neo

Any, neo

-

-

adjuvant chemotherapy

adjuvant chemotherapy

358

358

0.53

0.53

0 pos, no neo

0 pos, no neo

-

-

adjuvant chemotherapy

adjuvant chemotherapy

1100

1100

0.52

0.52

1

1

-

-

3 pos, no neo

3 pos, no neo

-

-

adjuvant chemotherapy

adjuvant chemotherapy

972

972

0.51

0.51

³

³

4 pos, no neo

4 pos, no neo

-

-

adjuvant chemotherapy

adjuvant chemotherapy

953

953

0.53

0.53

Adjuvant chemotherapy regimen

Adjuvant chemotherapy regimen

No anthracycline or taxane

No anthracycline or taxane

203

203

0.64

0.64

Anthracycline, no taxane

Anthracycline, no taxane

2307

2307

0.43

0.43

Anthracycline + taxane

Anthracycline + taxane

872

872

0.77

0.77

Receptor status/endocrine therapy

Receptor status/endocrine therapy

Negative

Negative

1674

1674

0.51

0.51

Pos + no endocrine therapy

Pos + no endocrine therapy

467

467

0.49

0.49

1234

1234

0.68

0.68

Pos + endocrine therapy

Pos + endocrine therapy

Age group

<35 yrs

<35 yrs

251

251

0.47

0.47

35

35

-

-

49 yrs

49 yrs

1490

1490

0.52

0.52

50

50

-

-

59 yrs

59 yrs

1091

1091

0.53

0.53

³

³

60 yrs

60 yrs

549

549

0.70

0.70

Trastuzumab

Better

Observation

Better

0

1

2


Cardiac Safety in HERA ASCO May 2005

(very early 1 year median follow-up report)


BCIRG 006 (n ~ 3000) ASCO May 2005

Will Arm 3 (a non-anthracycline adjuvant regimen) be the answer ?

BCIRG 006

Arm 1

Arm 2

Arm 3

Expected efficacy report SABCS December 2005

Current reported cases of Grade 3/4 CHF

Arm 1 / Arm 2 / Arm 3 = 1, 18, 1

Current reported cases LVEF 15% < LLN

Arm 1 / Arm 2 / Arm 3 = 6, 25, 4

AC q 3 wk * 4

= docetaxel/platinum q 3 wk * 6

= docetaxel q 3 wk * 4

= trastuzumab q 1 w

= trastuzumab q 1 w


So Is Adjuvant Herceptin For All Breast Cancer Patients? ASCO May 2005Informed Speculation !

60 Year Old Women. ER +, Her2 +, average comorbidity.

Competeing mortality about 8%. To Get Tam + CA * 4, T * 4q3w.

Her2 FISH +. Additional RR conferred by Her2 1.5.

Risk of developing CHF 5%, 2/3 have symptoms resolve in 6 months. Cardiac status at 10 years??


CA * 4 then T * 4 ASCO May 2005

Results of 9344, 9741, and B-31 /N9831

No major difference in outcome of this arm between trials.


Early Results ASCO May 2005

Triumphs and Cautionary Tales

Tam vs Obs Her vs Obs

(Overview) (B31/N9831)

Proportional risk reductions at 2 Years for DFS

53 % 52%

Proportional risk reductions at 10 years for DFS

39 % ???

Durable but Durable ?

Late Toxicity Late Toxicity ?


Early Results Do Not Always Reflect ASCO May 2005

Late Results In Adjuvant Therapy

Poly Chemotherapy

Tamoxifen (5 yrs)

Proportional Risk Reduction

During Time Interval

Time Periods (yrs)

Time Periods (yrs)

Recurrence

Breast Cancer Specific Mortality


NSABP/Intergroup Recommendations For Control Patients ASCO May 2005

The recommendations were covered in letters to the patients and clinicians. The recommendations were complex because the letter had to deal with the spectrum of possible treatment points that the patient might be at. Of special relevance to patients who were not trial participants were the following:

Patients in the control (non-trastuzumab) arms with adequate cardiac function, and within 6 months of finishing chemotherapy were offered trastuzumab.

The NSABP suggested that trial patients who had not yet started the paclitaxel/trastuzumab, who were > 50 years old and who had a post AC *4 LVEF of 50-54%, consider the option of starting the trastuzumab only after completing the paclitaxel.


Should clinicians routinely recommend trastuzumab (Herceptin) as part of the adjuvant therapy for all patients with Her2 positive early breast cancer?

Adjuvant Herceptin should only recommended as a part of a process that includes both information about the early gains and warns the patient that she faces some increased risk of developing CHF. Although early results are very encouraging, information about long term benefits and risks is not yet available.


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