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 MJ First Results Of The HERA Trial

NSABP B-31
Arm 1 Arm 2

NCCTG N9831
Arm A Arm B Arm C

HERA (Randomization after chemotherapy)

Arm A Arm B
No Herceptin (1 yr) (2 yr)

Arm C
AC q 3 wk * 4 = paclitaxel q 3 wk * 4 = trastuzumab q 1 w

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

Combined analysis of B31 / N9831 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

NSABP 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).

Eligibility

No Imbalances Between Treatment Arms

(numbers shown are % of total) Tumor Size
51 33 16 6 53 27 14 T < 2cm T 2.1-4.0 cm T > 4 cm ER + ER PgR + PgR 39 45 15 52 48 40 59

Patient / Tumor: Characteristics

Age
< 50 50 - 59 > 59

Nodes
N0 NP (1-3) NP (4-9) NP (> 9)

ER and PgR Status

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

ACTH 87% ACT 75% % 67% ACT ACTH N 1679 1672 Events 261 134 85%

HR=0.48, 2P=3x10-12
Years From Randomization

Combined Analysis for DFS of 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

ALL DATA Age 60 50-59 40-49 39 Hormone Positive Receptor Negative Tumor Size No. Positive Nodes Protocol 4.1cm 2.1- 4.0 cm <2.0 cm 10+ 4-9 1-3 0 N9831 NSABP B-31

0.2

0.4

0.6

0.8 1.0 Hazard Ratio

1.2

1.4

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

100 90 80

AC TH AC->T+H 90% 90% 90% ACT AC->T

81% 81% 81%

90% 90% 90%

%
70 60 50 0 N

ACTH 1672 96 AC->T 1679 194 ACT 1679 194 AC->T+H 1672 96
1 2

Events N Events

74% 74% 74%

HR=0.47, 2P=8x10-10

HR=0.47, 2P=8x10-10
3 4 5

Years From Randomization

Annual Hazard of Distant Recurrence

120

Rate per 1000 Women /Yr

100 80 60 40 20 0 0

ACT

AC TH

Years From Randomization

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

94% ACT 92% 87% ACTH 91%

ACT ACTH

N 1679 1672

Deaths 92 62

HR=0.67, 2P=0.015
Years From Randomization B31/N9831

~ 20% of the patients discontinued Herceptin because of symptomatic or asymptomatic heart problems
Herceptin * 12 mns
AC * 4 Taxol * 4

Cardiac Monitoring

Baseline

3 mns

6 mns

9 mns

15 mns

18 mns

2.1%

7.7%

10.1%

% 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.

Rules for action for asymptomatic patients

Absolute Decrease in LVEF < 10 % Normal LVEF 1-5% below LLN of LVEF > 5% below LLN or LVEF Continue Continue Continue * 10-15% Continue Hold * Hold * > 15% Hold * Hold * Hold *

Cardiac Monitoring

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

Age and Post AC LVEF were predictors of the risk of developing CHF
Risk of CHF (%) Age younger than 50 Initial LVEF 50 - 54 Initial LVEF 55 - 64 Initial LVEF > 65 6.3 % 2.2 % 0.6 % Age 50 and older 19.1 % 5.2 % 1.3 %

Cardiac Safety

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.

(no strong evidence of an major delayed toxicity)

% Risk of Cardiac Event 5 4 3 2 1 0 0 1 2 3 Years Since Starting Herceptin
Control Herceptin

Risk of Cardiac Events

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.

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

NSABP B-31

Total symptomatic cardiac events during Herceptin 4.28 % in Herceptin group 0.78 % in Control group
of these 33% had LVEF < 30%, 52% LVEF 3039%

Cardiac Safety Analysis For First 1000 Patients

Herceptin Related Fall In LVEF Was Largely Reversible In Patients With A Cardiac Event (n=27)
60 50 40 30 20 10
~ 68% < 30 30-39 40-49 symptoms resolve within 6 months of the patients had 50-59 60-69

NSABP B-31

During Event On Recovery

Analysis of Three Arms of N9831 NCCTG N9831

Arm A Arm B Arm C

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

N9831 Disease-Free Survival Control vs Concurrent

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

AC T + H H AC T

Hazard ratio = 0.55

Stratified logrank 2P = 0.0005
0 1 2 Years 3 4

N9831 Disease-Free Survival Control vs Sequential

100 90 80 70 60 % 50 40 30 20 10 0 0 1

AC T H AC T

Hazard ratio = 0.87

Stratified logrank 2P = 0.29
2 Years 3 4

N9831 Disease-Free Survival Sequential vs Concurrent

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

AC T + H H AC T H

Hazard ratio = 0.64

Stratified logrank 2P = 0.0114
0 1 2 Years 3 4

Cardiac Safety in 9831

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* with paclitaxel

therapy

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

HERA Trial HERA (Randomization after chemotherapy)

Arm A Arm B Arm C
No Herceptin (1 yr) (2 yr)

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

HERA 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).

Eligibility

No Imbalances Between Treatment Arms

(numbers shown are % of total) Age
< 50 50 - 59 > 59 51 32 16 33 29 28 11

HERA Trial: Patient / Tumor: Characteristics

Adjuvant Regimen
Anthracyclines 68 Anathra + Taxane 26 No A or Taxane 6

Nodes
N0 NP (1-3) NP > 4 NeoAdj

ER and PgR Status

ER + ER 51 49

DFS: HERA Trial

% alive and 100 disease 90 free 80 70 60 50 40 30 20 10 0 Trastuzumab 1 yr

Observation
2-yr Events DFS % HR 127 220 77.4

[95% CI] p value

85.8 0.54[0.43, 0.67] <0.0001

No. at risk 1694 1693

5 10 15 20 Months from randomization

1472 1428 1067 994 629 580 303 280

25

102 87

DFS In Patient Subsets: HERA Trial

n All Any, neo adjuvant 0 pos, no neo adjuvant 1- pos, no neo 3 adjuvant pos, no neo 4 adjuvant Nodalstatus chemotherapy chemotherapy chemotherapy chemotherapy 3387 358 1100 972 953 203 2307 872 1674 467 1234 Hazard ratio 0.54 0.53 0.52 0.51 0.53 0.64 0.43 0.77 0.51 0.49 0.68

Adjuvant chemotherapy regimen No anthracycline or taxane Anthracycline, no taxane Anthracycline + taxane Receptor status/endocrine therapy Negative Pos + no endocrine therapy Pos + endocrine therapy Age group <35 yrs 35-49 yrs 50-59 yrs 60 yrs

251 1490 1091 549

0.47 0.52 0.53 0.70

Trastuzumab 1 Better

Observation Better

Cardiac Safety in HERA

(very early 1 year median follow-up report)
Observation N=1736 LVEF < 50% and decrease by 10 EF points CHF grade III/IV, and / or cardiac death 2.2 % 1 Year trastuzumab N=1677 7.1 % 0.5% (95% CI: 0.25-1.02)

0% (95% CI: 0.00-0.21)

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

BCIRG 006 (n ~ 3000)

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 q 3 wk * 4 = trastuzumab q 1 w = docetaxel/platinum q 3 wk * 6 = trastuzumab q 1 w

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.

Baseline 10 With Tam and Year OS Chemo NP (1-3) T2 NN T2 NN T1c NN T1ab 45 % 59 % 81 % 88 % 64 % 74 % 86 % 90 %

Added Herceptin 72 % 79 % 88 % 91 %

Benefit Due to Herceptin 8% 5% 2% 1%

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

9344 Age < 50 NN (0) NP (1 3) NP (4 9) NP >10 T>2 ER + DFS (3yr) 60 0 46 42 12 65 59 79 % 9741 49 0 59 29 1 60 65 81% B31/ N9831 51 6 53 27 14 61 52 75 % Her2+++

No major difference in outcome of this arm between trials.

Early Results Triumphs and Cautionary Tales

Tam vs Obs (Overview) Her vs Obs (B31/N9831)

Proportional risk reductions at 2 Years for DFS 53 % 52%

Proportional risk reductions at 10 years for DFS 39 % Durable but Late Toxicity ??? Durable ? Late Toxicity ?

Early Results Do Not Always Reflect Late Results In Adjuvant Therapy

Poly Chemotherapy
Proportional Risk Reduction During Time Interval
50 40 30 20 10 0 0-2 2-5 5 - 10 70 60 50 40 30 20 10 0 0-2 2-5 5 - 10

Tamoxifen (5 yrs)

Time Periods (yrs) Recurrence

Time Periods (yrs) 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.