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

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!

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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 MJFirst Results Of The HERA Trial

NSABP B-31

NCCTG N9831

Arm 1

Arm 2

Arm A

Arm B

Arm C

AC q 3 wk * 4= paclitaxel q 3 wk * 4 = paclitaxel q 1 wk * 12= trastuzumab q 1 w

HERA (Randomization after chemotherapy)Arm A No Herceptin

Arm B

Arm C

(1 yr)

(2 yr)

= trastuzumab q 3 w

Combined analysis of B31 / N9831

Control

Herceptin

Arm 1 (B31)

Arm 2 (B31)

Arm A (N9831)

Arm C (N9831)

Combined: n = 3,351; median follow-up 2.0 yrNSABP B-31: n = 1,736; median follow-up 2.4 yrN9831: n = 1,615; median follow-up 1.5 yr

EligibilityNSABP B-31 / N9841

1) Definitively resected primary adenocarcinoma of the breast.

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

3) No locally advanced or metastatic disease.4) Normal hematologic, hepatic, and renal function.5) No prior anthracycline or taxane therapy.6) No significant sensory or motor neuropathy.7) No past or current cardiac history.8) Normal LVEF.9) Her2 IHC +++ or FISH + (N9831 by central lab, B31

by approved reference laboratory).

Patient / Tumor: Characteristics No Imbalances Between Treatment Arms

(numbers shown are % of total)

Age < 50 5150 - 59 33> 59 16

NodesN0 6NP (1-3) 53NP (4-9) 27NP (> 9) 14

Tumor SizeT < 2cm 39T 2.1-4.0 cm 45T > 4 cm 15

ER and PgR StatusER + 52ER - 48PgR + 40PgR - 59

87%87%85%85%

67%

75%

N EventsACT 1679 261ACTH 1672 134

%

HR=0.48, 2P=3x10-12

ACACTHTH

ACT

Years From Randomization

Combined Analysis for DFS of NSABP B-31 / NCCTG – N9831

Combined Analysis for DFS of NSABP B-31 / NCCTG – N9831

Subset Analysis For DFS

Herceptin Benefit

In all age subsetsIn all tumor size subsetsIn all nodal subsets (NN CI very broad)In ER positive and negative subsetsIn both N9831 and B31

Hazard Ratio0.2 0.4 0.6 0.8 1.0 1.2 1.4

Forest Plot For DFS: B31/N9831

Protocol

No.PositiveNodes

TumorSize

HormoneReceptor

Age

N9831NSABP B-31

≥ 4.1cm2.1- 4.0 cm<2.0 cm

PositiveNegative

≥6050-5940-49≤39

ALL DATA

10+4-91-30

90%90%

81%

74%

AC->T+H 1672 96AC->T 1679 194

HR=0.47, 2P=8x10-10

N Events

AC->T+H

AC->T

0 1 2 3 4 5

50

60

70

80

90

100

90%90%

81%

74%

ACTH 1672 96ACT 1679 194

HR=0.47, 2P=8x10-10

N Events

ACACTHTH

ACT

Years From Randomization

90%90% 90%90%

81%

74%%

Combined Analysis for DDFS of NSABP B-31 / NCCTG – N9831

Annual 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

Combined Analysis for OS of NSABP B-31 / NCCTG – N9831

ACACTHTH94%94%

91%91%

87%

92%ACT

N DeathsACT 1679 92ACTH 1672 62

HR=0.67, 2P=0.015

Years From Randomization B31/N9831

Cardiac Monitoring ~ 20% of the patients discontinued Herceptinbecause of symptomatic or asymptomatic

heart problems

Baseline 3 mns 6 mns 9 mns 18 mns15 mns

AC * 4

Taxol * 4

Herceptin * 12 mns

2.1% 7.7% 10.1%

% stopping Herceptin by time period

LVEF measurements

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

This analysis from B31data alone.

Cardiac Monitoring Rules for action for asymptomatic patients

Absolute Decrease in LVEF

< 10 % 10-15% > 15%

Normal LVEF Continue Continue Hold *

1-5% below LLN of LVEF Continue Hold * Hold *

> 5% below LLN or LVEF Continue * Hold * Hold *

* Repeat LVEF assessment in 4 weeksIf criteria for continuation met restartIf 2 consecutive holds of a total of 3 holds, discontinue Herceptin

Cardiac Safety Age and Post AC LVEF were predictors of the

risk of developing CHF

Risk of CHF (%)

Age younger than 50

Age 50 and older

Initial LVEF 50 - 54 6.3 % 19.1 %

Initial LVEF 55 - 64 2.2 % 5.2 %

Initial LVEF > 65 0.6 % 1.3 %

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 (no strong evidence of an major delayed toxicity)

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

0

1

2

3

4

5

0 1 2 3

Years Since Starting Herceptin

% R

isk

of

Car

dia

c E

ven

t

Control

Herceptin

End of Herceptin treatment period

This analysis from B31 data alone.

NSABP B-31 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 Herceptin4.28 % 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 Cardiac Safety Analysis For First 1000 Patients

Herceptin Related Fall In LVEF Was Largely ReversibleIn Patients With A Cardiac Event (n=27)

0

10

20

30

40

50

60

< 30 30-39 40-49 50-59 60-69

During Event

On Recovery

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

NCCTG N9831Arm A

Arm B

Arm C

Analysis of Three Arms of N9831

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

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4

Years

AC → T

AC → T + H → H

%

Hazard ratio = 0.55Stratified logrank 2P = 0.0005

N9831 Disease-Free Survival Control vs Concurrent

N9831 Disease-Free Survival Control vs Sequential

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4

Years

AC → T

Hazard ratio = 0.87Stratified logrank 2P = 0.29

AC → T → H

%

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4

Years

AC → T → H

AC → T + H → H

%

Hazard ratio = 0.64Stratified logrank 2P = 0.0114

N9831 Disease-Free Survival Sequential vs Concurrent

• 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

Cardiac Safety in 9831

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

HERA (Randomization after chemotherapy)

Arm A No Herceptin

Arm B

Arm C

(1 yr)

(2 yr)

Only Arms 1 and 2 analyzed in this interim analysisn = 3,307, median follow-up ~ 1 year

HERA Trial

EligibilityHERA Trial

1) Definitively resected primary adenocarcinoma of the breast.

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

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

4) Normal LVEF by MUGA or echo of > 55%.5) Her2 IHC +++ or FISH + by central lab.6) Known (and centrally reviewed ER status).

HERA Trial: Patient / Tumor: Characteristics

No Imbalances Between Treatment Arms(numbers shown are % of total)

Age < 50 5150 - 59 32> 59 16

NodesN0 33NP (1-3) 29NP > 4 28NeoAdj 11

Adjuvant RegimenAnthracyclines 68Anathra + Taxane 26No A or Taxane 6

ER and PgR StatusER + 51ER - 49

Months from randomizationMonths from randomization00 55 1010 1515 2020 2525

16931693 14281428 994994 580580 280280 8787

16941694 14721472 10671067 629629 303303 102102

EventsEvents2-yr2-yr

DFS %DFS % HRHR [95% CI][95% CI] p valuep value

127127 85.885.8 0.540.54[0.43, 0.67][0.43, 0.67]<0.0001<0.0001

220220 77.477.4

Trastuzumab 1 yrTrastuzumab 1 yr

ObservationObservation

% alive and % alive and disease disease

freefree

10010090908080707060605050404030302020101000

No. No. at riskat risk

DFS: HERA Trial

0 1 2

All

Any, neo-adjuvant chemotherapyNodalstatus

0 pos, no neo-adjuvant chemotherapy

3387

3581100

872

2032307

n

0.54

0.530.52

0.77

0.640.43

Hazardratio

1-3 pos, no neo-adjuvant chemotherapy4 pos, no neo-adjuvant chemotherapy

No anthracycline or taxaneAdjuvant chemotherapy regimen

Anthracycline, no taxaneAnthracycline + taxane

NegativeReceptor status/endocrine therapy

Pos + no endocrine therapyPos + endocrine therapy

<35 yrs35-49 yrs50-59 yrs

60 yrs

972953

0.510.53

1674 0.514671234

0.490.68

251 0.4714901091

0.520.53

549 0.70

All

Any, neo-adjuvant chemotherapyNodalstatus

0 pos, no neo-adjuvant chemotherapy

3387

3581100

872

2032307

n

0.54

0.530.52

0.77

0.640.43

Hazardratio

1-3 pos, no neo-adjuvant chemotherapy4 pos, no neo-adjuvant chemotherapy

No anthracycline or taxaneAdjuvant chemotherapy regimen

Anthracycline, no taxaneAnthracycline + taxane

NegativeReceptor status/endocrine therapy

Pos + no endocrine therapyPos + endocrine therapy

<35 yrsAge group

35-49 yrs50-59 yrs

60 yrs

972953

0.510.53

1674 0.514671234

0.490.68

251 0.4714901091

0.520.53

549 0.70

TrastuzumabBetter

DFS In Patient Subsets: HERA Trial

ObservationBetter

Cardiac Safety in HERA(very early 1 year median follow-up report)

ObservationObservation

N=1736N=1736

1 Year trastuzumab1 Year trastuzumab

N=1677N=1677

LVEF < 50% and LVEF < 50% and decrease by decrease by 10 10 EF pointsEF points

2.2 %2.2 % 7.1 %7.1 %

CHF grade III/IV, CHF grade III/IV, and / orand / or cardiac cardiac deathdeath

0 %0 %

(95% CI: 0.00-(95% CI: 0.00-0.21)0.21)

0.5%0.5%

(95% CI: 0.25-1.02)(95% CI: 0.25-1.02)

BCIRG 006Arm 1

Arm 2

AC q 3 wk * 4= docetaxel q 3 wk * 4= trastuzumab q 1 w = trastuzumab q 1 w

Arm 3

= docetaxel/platinum q 3 wk * 6

BCIRG 006 (n ~ 3000)Will Arm 3 (a non-anthracycline adjuvant regimen)

be the answer ?

Expected efficacy report SABCS December 2005Current reported cases of Grade 3/4 CHFArm 1 / Arm 2 / Arm 3 = 1, 18, 1Current reported cases LVEF 15% < LLNArm 1 / Arm 2 / Arm 3 = 6, 25, 4

Baseline 10 Year OS

With Tam and Chemo

Added Herceptin

Benefit Due to

Herceptin

NP (1-3) T2 45 % 64 % 72 % 8 %

NN T2 59 % 74 % 79 % 5 %

NN T1c 81 % 86 % 88 % 2 %

NN T1ab 88 % 90 % 91 % 1 %

So Is Adjuvant Herceptin For All Breast Cancer Patients? Informed 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 Results of 9344, 9741, and B-31 /N9831

No major difference in outcome of this arm between trials.

9344 9741B31/

N9831

Age < 50 60 49 51

NN (0) 0 0 6

NP (1 – 3) 46 59 53

NP (4 – 9) 42 29 27

NP >10 12 1 14

T > 2 65 60 61

ER + 59 65 52

DFS (3yr) 79 % 81% 75 %

Her2+++

Early ResultsTriumphs 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 ReflectLate Results In Adjuvant Therapy

0

10

20

30

40

50

0 - 2 2 - 5 5 - 10

0

10

20

30

40

50

60

70

0 - 2 2 - 5 5 - 10

Time Periods (yrs) Time Periods (yrs)

Pro

po

rtio

nal

Ris

k R

edu

ctio

n

Du

rin

g T

ime

Inte

rval

Poly Chemotherapy Tamoxifen (5 yrs)

Recurrence Breast Cancer Specific Mortality

NSABP/Intergroup Recommendations For Control Patients

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.