AdjHer2Slides

8/6/2019 AdjHer2Slides

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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!


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An Interpretation of Adjuvant HerceptinResults Presented at ASCO May 2005

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

Doxorubicin and Cyclophosphamide Followed byPaclitaxel with or without Trastuzumab as AdjuvantTherapy for Patients with HER-2 Positive Operable

Breast Cancer: Combined Analysis of NSABPB31/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


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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


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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 yr

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

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


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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).


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Patient / Tumor: CharacteristicsNo Imbalances Between Treatment Arms

(numbers shown are % of total)

Age< 50 51

50 - 59 33

> 59 16

NodesN0 6

NP (1-3) 53

NP (4-9) 27

NP (> 9) 14

Tumor SizeT < 2cm 39

T 2.1-4.0 cm 45

T > 4 cm 15

ER and PgR StatusER + 52

ER - 48

PgR + 40

PgR - 59


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87%87%85%85%

67%

75%

N EventsACT 1679 261

ACTH 1672 134

%

HR=0.48, 2P=3x10-12

ACACTHTH

ACT

Years From Randomization

Combined Analysis forDFS ofNSABP B-31 / NCCTG N9831


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Combined Analysis for DFS ofNSABP 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 subsetsIn both N9831 and B31


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Hazard Ratio

0.2 0.4 0.6 0.8 1.0 1.2 1.4

Forest Plot For DFS: B31/N9831

Protocol

No.

Positive

Nodes

TumorSize

Hormone

Receptor

Age

N9831

NSABP B-31

4.1cm2.1- 4.0 cm


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90%90%

81%

74%

AC->T+H 1672 96

AC->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 96

AC

T 1679 194HR=0.47, 2P=8x10-10

N Events

ACACTHTH

ACT


90%90% 90%90%

81%

74%%

Combined Analysis forDDFS ofNSABP B-31 / NCCTG N9831


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Annual Hazard of Distant Recurrence

0 1 2 3 4

0

20

40

60

80

100

120

Rat

eper1000W

omen/Yr


ACAC

THTH

ACT


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Combined Analysis forOS ofNSABP B-31 / NCCTG N9831

ACACTHTH94%94%91%91%

87%

92%ACT

N DeathsACT 1679 92

AC

TH 1672 62

HR=0.67, 2P=0.015

Years From Randomization B31/N9831


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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.


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Cardiac MonitoringRules 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 weeks

If criteria for continuation met restart

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


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Cardiac SafetyAge and Post AC LVEF were predictors of the

risk of developing CHF

Risk of CHF (%)

Age youngerthan 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.


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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

iskofCardiacEvent

Control

Herceptin

End of Herceptin treatment period

This analysis from B31 data alone.


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NSABP B-31Cardiac Safety Analysis For First 1000 Patients

Baseline all patients normal LVEF (median 63%)

After 3 months of AC

LVEF median 61% (lower, p


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NSABP B-31Cardiac Safety Analysis For First 1000 Patients

Herceptin Related Fall In LVEF Was Largely Reversible

In Patients With A Cardiac Event (n=27)

0

10

20

30

40

50

60

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

During Even

On Recovery

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


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NCCTG N9831Arm A

Arm B

Arm C

Analysis of Three Arms of N9831

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


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100

90

80

7060

50

40

30

2010

00 1 2 3 4

Years

AC T

AC T + H H

%

Hazard ratio = 0.55Stratified logrank 2P= 0.0005

N9831 Disease-Free SurvivalControl vs Concurrent


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N9831 Disease-Free SurvivalControl vs Sequential

100

90

80

7060

50

40

30

20

10

0

0 1 2 3 4

Years

AC T

Hazard ratio = 0.87Stratified logrank 2P = 0.29

AC T H

%


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100

90

80

70

60

50

40

30

2010

00 1 2 3 4

Years

AC T H

AC T + H H

%

Hazard ratio = 0.64

Stratified logrank 2P= 0.0114

N9831 Disease-Free SurvivalSequential vs Concurrent


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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 normalLVEF 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* therapywith paclitaxel

Cardiac Safety in 9831

* at month 9, concurrent pts have received 3 additional months of

Herceptin compared to sequential


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HERA (Randomization after chemotherapy)

Arm A No Herceptin

Arm BArm C

(1 yr)(2 yr)

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

HERA Trial


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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).


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HERA Trial:Patient / Tumor: Characteristics

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

Age< 50 51

50 - 59 32

> 59 16

NodesN0 33

NP (1-3) 29NP > 4 28

NeoAdj 11

Adjuvant RegimenAnthracyclines 68

Anathra + Taxane 26

No A or Taxane 6

ER and PgR StatusER + 51

ER - 49


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Months from randomizationMonths from randomization00 55 1010 1515 2020 2525

16931693 14281428 994994 580580 280280 8787

16941694 14721472 10671067 629629 303303 102102

EventsEvents

2-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]


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0 1 2

All

Any, neo-adjuvant chemotherapyNodalstatus

0 pos, no neo-adjuvant chemotherapy

3387

358

1100

872

203

2307

n

0.54

0.53

0.52

0.77

0.64

0.43

Hazardratio

1-3 pos, no neo-adjuvant chemotherapy

4 pos, no neo-adjuvant chemotherapy

No anthracycline or taxane

Adjuvant chemotherapy regimen

Anthracycline, no taxane

Anthracycline + taxane

Negative

Receptor status/endocrine therapy

Pos + no endocrine therapy

Pos + endocrine therapy


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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% andLVEF < 50% anddecrease bydecrease by 10 EF10 EFpointspoints

2.2 %2.2 % 7.1 %7.1 %

CHF grade III/IV,CHF grade III/IV, andand/ or/ orcardiac deathcardiac death 0 %0 %

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

0.5%0.5%

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


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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 2005

Current reported cases of Grade 3/4 CHF

Arm 1 / Arm 2 / Arm 3 = 1, 18, 1Current reported cases LVEF 15% < LLN

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


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Baseline 10Year OS

With Tam andChemo

AddedHerceptin

Benefit Dueto 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 CancerPatients? 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??


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CA * 4 then T * 4Results of 9344, 9741, and B-31 /N9831

No major difference in outcome of this arm between trials.

9344 9741 B31/

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+++


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Early Results

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 ?


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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

3040

50

60

70

0 - 2 2 - 5 5 - 10

Time Periods (yrs) Time Periods (yrs)

Pro

por t

ionalRisk

Re

ductio

n

DuringTimeI

nterval

Poly Chemotherapy Tamoxifen (5 yrs)

Recurrence Breast Cancer Specific Mortality


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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.


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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?

Adjuvant Herceptin should only recommendedas 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 veryencouraging, information about long term

benefits and risks is not yet available.

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AdjHer2Slides