ASCO 2005 Adjuvant Breast Cancer

UpdateLori J. Goldstein, MD

Director, Breast Evaluation Center

Leader, Breast Cancer Research Program

Fox Chase Cancer Center

Philadelphia, PA

ASCO 2005 Breast Cancer Update

Abstract #/ Session Title/ Subject

512 E2197: Adjuvant AT vs. AC

513 ECTO: A->CMF vs AT->CMF

MoAB Ed N9831/ NSABP B31 Joint Analysis – Adjuvant Trastuzumab

MoAB Ed N9831 – Adjuvant Trastuzumab

MoAB Ed HERA: Adjuvant Trastuzumab

MoAB Ed E2100: T +/- bevacizumab MBC

E2197: Phase III AT vs. AC in the Adjuvant Treatment of Node Positive and High Risk Node

Negative Breast Cancer

Goldstein LJ, O’Neill A, Sparano JA, Perez EA, Shulman LN, Martino S, Davidson NE.

E2197 RationalePhase II Studies Anthracyline + Taxane

Study A/Por D mg/m2 RR % CHF %

Gianni/ 60/P200 80-90 20Dombernowsky

Sledge E1193 50/P150 47 9.8

Sparano E4195 60/P200 57 6

Sparano E1196 60/D60 57 6

Cresta 60/D60 63 10

Misset 50/D75 81 0

E2197 RationalePhase III Studies:Anthracyline + Docetaxel

Phase III Studies:

MBC AT (50/75) AC (60/600)

RR% 60 47 p=.012

TTPwk 37.1 31.9 p=.015

CHF % 2 4

FN% 33 10

No difference OS Nabholtz JCO 2003

TAC vs. FAC MBC Mackey ASCO 2002

Increase RR with TAC; no difference in TTP or OS

TAC vs. FAC Adjuvant: Nabholtz ASCO 2002

TAC increase DFS/ OS

E2197: Schema

T1-3 N0-1 M0

No then T> 1.0cm

Tamoxifen 20mg daily x 5 yearspost chemotherapy for ER and/or PR positive tumor

Adriamycin 60mg/m2

Docetaxel (T) 60mg/m2

Adriamycin 60mg/m2

Cyclophosphamide 600mg/m2

Stratified:•Nodal Status•HR Status (ER+PR+,ER+PR-,ER-PR+,ER- PR-,ER/PR unknown)•Menopausal Status

RANDOMIZE

IV q 3wk x 4

IV q 3wk x 4Cipro 500mg po. bid D8 x 10d

*G-CSF -per ASCO guidelines

E2197: Objectives

• To determine whether AT will improve DFS and OS

• To compare toxicity of AT vs. AC

No difference in LVEF between AT and AC reported ASCO 2003.

E2197: Study Design

• Primary endpoint: DFS-recurrences, new breast primaries, or death without recurrence whichever comes first.

• Design: 83% power to detect a 25% reduction of the DFS failure hazard rate(5% absolute improvement in 5 yr DFS from 78% to 83% by using AT)

• Sample size: 2778 including an estimated 10% ineligible

• Primary Analysis: Intent-to-treat analysis on eligible patients.

E2197:Results

• Opened 7/30/98; closed 1/21/00

• 2952 entered through the collaborative effort of ECOG, CALGB, NCCTG, SWOG and EPP.

• 3% Ineligibility rate

• 2885 eligible and analyzable

E2197: Patient Characteristics

• Balanced for age, HR, menopause, nodes, surgery, grade and size

• Age range 24-85 yo, Median age 51

• 64% ER +

• 65% LN-

• Grade: 10% low, 38% int., 46% high

• Size: 0.1 – 12.5 cm; Median – 2.0 cm

E2197: Toxicity Summary

AT AC

Feb/Infxn/N 28% 10%

AML/MDS 7 7

Lethal Events

Related 4

Unrelated 2 2

E2197 Cardiac Safety

AT AC

Grade 3 4 5 3 4

CHF 15 2 1 10

Total 18 10

% .01 .006

No statistically significant difference

E2197: DFS• Fall 2004 DMC (409/ 420 DFS failures)• O’Brien-Fleming boundary had not been

crossed, there was not enough evidence to suggest a significant difference

• April 2005 - Median follow-up = 59 months • 432/ 2885 (15%) recurred, developed

second breast cancer or died.

E2197: DFS/OSHazard Ratio

HR > 1 favors AT

HR (adjusted)

DFS 1.03 (0.86-1.25), p=0.70

OS 1.09 (0.85-1.40), p=0.49

As of 4/4/05, 242 deaths

Per

cen

t

0

10

20

30

40

50

60

70

80

90

100

Months

0 12 24 36 48 60 72

ATAC

1444 2131441 219

N Events87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)87 (1)

4-Yr % (S.E.)

E2197 Disease-Free Survival

Per

cen

t

0

10

20

30

40

50

60

70

80

90

100

Months

0 12 24 36 48 60 72

ATAC

1444 1171441 125

N Events94 (1)94 (1)94 (1)94 (1)94 (1)94 (1)94 (1)94 (1)94 (1)94 (1)94 (1)94 (1)94 (1)94 (1)93 (1)93 (1)93 (1)93 (1)93 (1)93 (1)93 (1)93 (1)93 (1)93 (1)93 (1)93 (1)93 (1)93 (1)93 (1)93 (1)93 (1)93 (1)

4-Yr % (S.E.)

E2197 Overall Survival

E2197: DFSSubgroup Analysis

No significant effect within any of the following subgroups :

•Nodes

•Size

•Age

•Menopausal Status

•Grade

•Type of Surgery

•Race

Per

ce

nt

0

10

20

30

40

50

60

70

80

90

100

Months

0 12 24 36 48 60 72

ATAC

454 85463 109

N Events83 (2)83 (2)83 (2)79 (2)79 (2)79 (2)79 (2)79 (2)79 (2)79 (2)79 (2)

4-Yr % (S.E.)

E2197 Disease-Free Survival:ER-/PR-

Per

ce

nt

0

10

20

30

40

50

60

70

80

90

100

Months

0 12 24 36 48 60 72

ATAC

52 1438 3

N Events77 (6)95 (4)

4-Yr % (S.E.)

E2197 Disease-Free Survival:ER-/PR+P

erc

en

t

0

10

20

30

40

50

60

70

80

90

100

Months

0 12 24 36 48 60 72

ATAC

162 22164 34

N Events90 (2)83 (3)81 (3)81 (3)

4-Yr % (S.E.)

E2197 Disease-Free Survival:ER+/PR-

Per

ce

nt

0

10

20

30

40

50

60

70

80

90

100

Months

0 12 24 36 48 60 72

ATAC

767 91770 73

N Events90 (1)90 (1)90 (1)90 (1)90 (1)90 (1)90 (1)92 (1)92 (1)92 (1)92 (1)92 (1)92 (1)92 (1)

4-Yr % (S.E.)

E2197 Disease-Free Survival:ER+/PR+

Disease Free Survival

0.1 0.2 0.5 1 2 5

ER+/PR+ 0.79 (0.58, 1.10)

ER+/PR- 1.64 (0.96, 2.80)

ER-/PR+ 0.30 (0.10, 0.95)

ER-/PR- 1.30 (0.96, 1.70)

Favors AC Favors AT

E2197 Conclusions• These results show a better than expected

outcome for both regimens.87%(obs) vs 78% (expected for AC) DFS at 4 yrs.

• At 59 mo median follow-up, there is no difference in DFS or OS between AT and AC.

• Prespecified stratifications at randomization: LN, menopause, ER/PR – no significant difference between the 2 treatment arms.

• In PR negative tumors, a potential benefit to AT may be suggested.

E2197: Issues for DiscussionWould longer f/u change these results? Unlikely

Observed DFS = 87% at 4 yrs. Expected DFS = 78% at 4yrs.

Aromatase Inhibitor Affect:60% on Tam; Median 41 mo; AI info collected; future analysis

Subset analysis of prespecified ER/PR stratifications:Hypothesize that the biology of the primary tumor predicts outcome and benefit to specific therapies.Central review of ER/PR/Her 2 pending

Genomic Health/ Sanofi-Aventis Analysis:OncotypeGenomic profiling Use as training set for validation with E1199Pharmacogenomics

PACCT- 1 Trial

Thank You

Patients

Data managers/ CRA’s

CALGB, NCCTG, SWOG, EPP

Anne O’Neill, Deborah Namande, Eric Ross

European Cooperative Trial in Operable Breast Cancer(ECTO):

Improved freedom from progression from adding

paclitaxel(T) to doxorubicin(A) followed by CMF

Luca Gianni

Abstract 513

ECTO: Schema

Tumors > 2 cm randomized to :

A. SURG ->A 75 mg/m2 x 4 -> CMF x 4

B. SURG ->AT 60/ 200 x 4 -> CMF x 4

C. AT 60/ 200 x 4 -> CMF x 4 -> SURG

Tam for HR +

Analysis: FFP A vs B

B vs C

ECTO at 5 years Analysis A vs. B

Pts. Events HR p

A-CMF 453 91 .66 0.01*

AT-CMF 451 63

Analysis B vs. C

S-AT-CMF 451 63 1.22 0.24

AT-CMF-S 451 78

Data super imposable so far, no significant difference, however pCR had improved FFP.

ECTO: Main Treatment Outcomes

A(%) B(%) C(%)

Total FFP

pCR 89

no pCR 75

N - 81 89 86

N + 1-3 79 86 71

N +>3 58 65 59

OS 82 91 90

No significant difference in OS.

No significant difference in cardiac toxicity

Combined Analysis ofNSABP-B31/NCCTG-N9831

Doxorubicin and Cyclophosphamide Followed by Paclitaxel with or without Trastuzumab as Adjuvant Therapy for Patients with

HER-2 Positive Operable Breast Cancer

Romond EH, Perez EA, Bryant J, Suman V, Geyer CE,Davidson N, Tan-Chiu E, Martino S, Swain SM, Kaufman

P, Fehrenbacher L, Pisansky T, Vogel V, Kutteh LA, Yothers G, Visscher D, Brown AM, Jenkins R, Seay TE,

Mamounas E, Abrams J, Wolmark N

NSABP B-31

NCCTG N9831

Arm 1Arm 2

Arm A

Arm B

Arm C

= doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4= paclitaxel (T) 175 mg/m2 q 3 wk x 4= paclitaxel (T) 80 mg/m2/wk x 12

= trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

Control: ACT

Investigational: ACT+H

Patient Eligibility• HER-2 positive by FISH or +++ by IHC verified

centrally (N9831) or by approved reference lab (B-31)

• Normal left ventricular ejection fraction

• No past or active cardiac disease including:• History of myocardial infarction• History of congestive heart failure• Angina pectoris requiring medication• Arrhythmia requiring medication• Clinically significant valvular disease• Uncontrolled hypertension• LVH• Cardiomegaly on CXR

B-31 Arm 2 / N9831 Arm C AC Paclitaxel + Trastuzumab

B-31 Arm 1 / N9831 Arm A AC Paclitaxel

0mo.

18mos.

6mos.

9mos.

3mos.

0mo.

18mos.

6mos.

9mos.

3mos.

LVEF Evaluation ScheduleLVEF Evaluation Schedule

Within Normal Limits

1- 5 % below LLN

6 % below LLN

Cont.

Hold *

Hold *

Relationship of LVEF to LLN

Absolute Decreaseof < 10%

Absolute Decrease of 10 - 15%

Absolute Decrease of 16%

Hold *

Hold *

Hold *

Cont.

Cont.

Cont.*

* Repeat LVEF assessment after 4 weeks - If criteria for continuation met – resume trastuzumab - If 2 consecutive holds, or total of 3 holds occur – discontinue trastuzumab

Asymptomatic PatientsRules for Trastuzumab Continuation

Based on Serial LVEFs

2.1

7.2

2.9

7.7

0

5

10

15

20

25

1st Quarter 2nd Quarter 3rd Quarter 4th Quarter

B-31: Trastuzumab Discontinuation Due to Asymptomatic or Symptomatic Cardiac Dysfunction by Quarter

Patient and Tumor Characteristics (%)AC Paclitaxel AC Paclitaxel

+ Trastuzumab

872B-31

807N9831

864B-31

808N9831

Age<5050-59≥60

523415

513415

513216

503218

No. Pos Nodes01-34-910+

0572914

13482515

0572914

11502514

Hormone ReceptorsER+ER-PR+PR-

53474158

52464157

51483960

51483960

Tumor Size≤2.0 cm.2.1-4.0 cm.>4.0 cm.

414314

404613

374417

384714

Statistical Analysis

• Median follow-up: 2.0 years (2.4 years on B-31/1.5 years on N9831)

• Primary endpoint: DFS– analyzed by intent-to-treat

• Secondary endpoints: OS and Time to 1st Distant Recurrence

• Definitive analysis after 710 DFS events

• First interim analysis after 355 DFS events

• Stop trials only if equivalence is rejected at p=0.0005 (2p=0.001)

Disease-Free Survival

87%87% 85%85%

67%

75%

N EventsACT 1679 261ACTH 1672 134

%

HR=0.48, 2P=3x10-12

ACACTHTH

ACT

Years From Randomization B31/N9831

Hazard Ratio0.2 0.4 0.6 0.8 1.0 1.2 1.4

Forest Plot For Disease-Free Survival

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

0 1 2 3 4 550

60

70

80

90

100

0 1 2 3 4 5

50

60

70

80

90

100

Disease-Free Survival

B-31 N9831

ACTH 864 83ACT 872 171 ACT 807 90

ACTH 808 51

N Events N Events

HR=0.45, 2P=1x10-9 HR=0.55, 2P=0.0005

ACACTHTH ACACTHTH

ACTACT

74%

87%85%

66%

78%

87% 86%

68%

Years From Randomization

%

Time to First Distant Recurrence

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

B31/N9831Years From Randomization

90%90% 90%90%

81%

74%%

Hazard of Distant Recurrence

0 1 2 3 4

0

20

40

60

80

100

120R

ate

per

100

0 W

om

en /

Yr

Years From Randomization

ACACTHTH

ACT

B31/N9831

B-31/N9831 Survival

ACACTHTH94%94%

91%91%

87%

92%ACT

N DeathsACT 1679 92ACTH 1672 62

HR=0.67, 2P=0.015

Years From Randomization B31/N9831

3574.00.63.0

5324.00.62.5

7194.00.42.0

9243.90.41.5

11683.50.41.0

14122.50.30.5

No. A

t Risk

Cum

Inc A

rm2 (%

)

Cum

Inc A

rm 1 (%

)

Yrs P

ost Day 1 C

yc5

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

B-31: Cumulative Incidence ofCardiac Events in the Evaluable Cohort

HR=7.2

4.0%

0.6%

Arm 2: AC→T HN=846, 30 CHFs,No Cardiac Deaths

Arm 1: AC→T N=811, 3 CHFs, 1 Cardiac Death

LV

EF

(%

)

Age

B-31: Post-AC LVEF and Age Are Independent Predictors of Trastuzumab-Associated CHF

P(Age)=0.04P(LVEF)<0.0001

Conclusions1. For high risk HER-2 positive breast cancer,

trastuzumab given concurrently with paclitaxel following AC chemotherapy, reduces the risk of a first breast cancer event at 3 years by 52%.

2. The relative risk reduction benefit was present and of similar magnitude in all subsets of patients analyzed. There is not, however, statistical power to establish efficacy in the node negative subset.

3. The addition of trastuzumab reduced the probability of distant recurrence by 53% at 3 years, and the hazard of developing distant metastases appears, thus far, to decrease over time.

Conclusions

4. Results at a median follow-up of 2 years show a statistically significant survival advantage with a relative risk reduction of 33%.

5. The combination of trastuzumab and chemotherapy has a notable risk of cardiac toxicity. Careful monitoring of cardiac function is of vital importance if trastuzumab is to be used in the adjuvant setting.

NCCTG N9831May 2005 Update

NCCTG N9831May 2005 Update

Perez EA, Suman VJ, Davidson N, Martino S, Kaufman P, on Behalf of

NCCTG, ECOG, SWOG, CALGB

Perez E. Protocol NCCTG-N9831. H=trastuzumab (4mg/kg loading dose, followed by 2mg/kg); doxorubicin dose 60mg/m2; cyclophosphamide, 600mg/m2; paclitaxel, 80mg/m2

q3w=every 3 weeks; qw=weekly

NCCTG N9831 Schema

RRAANNDDOOMMIIZZEE

Radiation and/or hormonal therapy as indicatedRadiation and/or hormonal therapy as indicated

Paclitaxel qw x 12Paclitaxel qw x 12Arm A:Arm A: AC q3w x 4AC q3w x 4

Paclitaxel qw x 12Paclitaxel qw x 12Arm B: Arm B: AC q3w x 4AC q3w x 4 H qw x 52H qw x 52

AC q3w x 4Paclitaxel qw x 12 Paclitaxel qw x 12

++H qw x 12H qw x 12

Arm C:Arm C: H qw x 40H qw x 40

Statistical PlanAddition of H to AC T

• Two pairwise comparisons

• Goal

– To detect a 33% increase in median DFSfrom 6.3 to 8.4 years

• Final analysis

– At 663 events for A vs C comparison

– At 789 events for A vs B comparison

Control: AC TSequentialAC T H

Concurrent AC T + H H

Control: AC T

T=paclitaxel; DFS=disease free survival

vs

vs

Statistical Plan Timing of H Initiation

• Pairwise comparison

• Goal

– To detect a 29% increase in median DFSfrom 7.3 to 9.4 years

• Final analysis

– At 590 events for B vs C comparison

SequentialAC T H

Concurrent AC T + H H

vs

Cardiac Testing

Time (months)

LVEF measurement

6 9 18–210 3

Arm B: AC x 4 Paclitaxel H

Arm A: AC x 4 Paclitaxel

Arm C: AC x 4 Paclitaxel + H H

LVEF=left ventricular ejection fraction; LLN=lower limit of normal

Pre-AC Post-AC

No H if symptoms or LVEF ↓ >15% or ↓ to <LLN

RRAANNDDOOMIMIZZEE

Impact of Joint Analysis on N9831 April 2005

• Joint analysis with B-31: Concurrent approach

• DMC asked for an unplanned interim analysis comparing Arm B (sequential) vs Arm C (concurrent) to assist in patient management

DMC=data monitoring committee

AC AC T + H T + H HH significantly improves significantly improves disease-free and overall survival vs disease-free and overall survival vs controlcontrol: : AC AC T T

Patient/Event Status at Time of Joint Analysis April 2005

• Patients

– Enrollment goals met (n: >3300)

700 patients on chemotherapy

• 2701 patients entered prior to 1/1/2005

– Median follow up: 1.5 years

• Total disease-free survival events

– A and B: 220 (of 789 needed)

– B and C: 147 (of 590 needed)

Pairwise Comparison

Number of events

Log rank p-value*

HR* (95% CI)

AC → T vs AC → T + H → H

395 3x10–12 0.48 (0.39-0.60)

Pairwise Comparison

Number of events

Log rank p-value*

HR* (95% CI)

AC → T vs AC → T → H

(n=1964)**

220 0.2936 0.87 (0.67-1.13)

AC → T → H vs AC → T + H → H (n=1682)**

137

0.0114 0.64 (0.46-0.91)

Results Disease-Free Survival

*Stratified – nodal status and receptor status**for patients randomized before 1/1/2005

*Stratified – nodal status and receptor status

Joint Analysis

N9831 Analysis

A B

BC

Disease-Free Survival: A vs BN9831

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4

YearsNumber of patients followedA 979 629 353 168 15B 985 637 403 169 20

AC AC →→ T TEvents=117Events=117

Hazard ratio=0.87Hazard ratio=0.87Stratified logrank Stratified logrank 2P2P=0.2936=0.2936

AC AC →→ T T →→ H HEvents=103Events=103

%

Disease-Free Survival: B vs CN9831

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4

YearsNumber of patients followedB 842 501 285 162 20C 840 520 285 178 17

AC AC →→ T T →→ H H Events=84Events=84

AC AC →→ T + H T + H →→ H HEvents=53Events=53

%

Hazard ratio=0.64Hazard ratio=0.64Stratified logrank Stratified logrank 2P2P=0.0114=0.0114

Pairwise Comparison

Number of events

Log rank p-value*

HR* (95% CI)

AC → T vs AC → T + H → H

154 0.015 0.67 (0.48-0.93)

Pairwise Comparison

Number of events

Log rank p-value*

HR* (95% CI)

AC → T vs AC → T → H

79 0.4752 0.85 (0.55-1.33)

AC → T → H vs AC → T + H → H

56

0.2696 0.74 (0.43-1.26)

Overall Survival

*Stratified – nodal status and receptor status

*Stratified – nodal status and receptor status

Joint Analysis Results

N9831 Analysis Results

AB

BC

Other Relevant Factorsfor Patient Management

• HER2 testing

• Cardiac tolerability comparisons based on planned analyses

HER2 Testing in N9831• Modest level of concordance between local and

central laboratories for both IHC and FISH

– With HercepTest™: 81% (78-83%)

– With FISH: 87% (84-90%)

• High level of agreement between central and reference laboratory results for HER2

– 94.5% for IHC (0, 1+, 2+)

– 95.1% for FISH (not amplified)

• Accurate HER2 testing is critical given the degree of trastuzumab benefit as a component of adjuvant therapy

Updated from Perez EA, et al. ASCO 2004 (abstract 567)

Cardiac Monitoring Plan

• Monthly formal review of LVEF, clinical data

• Interim analyses after 100, 300, and 500 patients per arm

– completed AC and followed at least 6 months

• ~ 9 months from registration

Perez EA, et al. ASCO 2005 (abstract 556)

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

• 9 month analysis; 500 per arm with nl LVEF or LVEF decrease 15% from baseline (after AC)

– 0.0% (95% CI,0.0-0.7%) for control

– 2.2% (95% CI,1.1-3.8%) for control vs sequential

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

Effect of the Introduction of H on Cardiac Tolerability

Perez EA, et al. ASCO 2005 (abstract 556)

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

Effect of Introduction of H on Disease Recurrence

Conclusions• 52% decreased recurrence with concurrent

vs control treatment (P=3X10-12) (joint analysis finding)

• 13% decreased recurrence with sequential vs control treatment (P=0.2936)

• 36% decreased recurrence with concurrent vs sequential treatment (P=0.0114)

• More follow up is needed to determine whether this trend continues

NCCTG N9831Next Steps

• Pre-specified interim analyses at 50%, 67%, and 75% of events still planned

• Continued exploration of predictive factors for cardiac toxicity

• Continued patient follow up

A randomized three-arm multi-centre comparison of:A randomized three-arm multi-centre comparison of:• 1 year Herceptin®1 year Herceptin®• 2 years Herceptin®2 years Herceptin®• or no Herceptin®or no Herceptin®

in women with HER-2 positive primary breast cancer in women with HER-2 positive primary breast cancer who have completed adjuvant chemotherapywho have completed adjuvant chemotherapy

Martine J. Piccart-Gebhart, MD, PhD on behalf of: Martine J. Piccart-Gebhart, MD, PhD on behalf of: The Breast International Group (BIG), NON-BIG participating The Breast International Group (BIG), NON-BIG participating

groups, Independent sites, F. Hoffmann – La Roche Ltd.groups, Independent sites, F. Hoffmann – La Roche Ltd.

FIRST RESULTS OF THE FIRST RESULTS OF THE HERA TRIALHERA TRIAL

ASCO, Scientific Session, May 16, 2005ASCO, Scientific Session, May 16, 2005

EU

71.5%

EASTERN EASTERN EUROPE: EUROPE:

11%11%

JAPAN JAPAN

12%12%

ASIA ASIA PACIFICPACIFIC

CENTRAL &

SOUTH AMERICA

5.5%5.5%

ACCRUAL: 5090 WOMEN ACCRUAL: 5090 WOMEN 478 centers from 39 countries (2002-2005)478 centers from 39 countries (2002-2005)

CANADACANADA

NORDIC NORDIC COUNTRIESCOUNTRIES

SOUTH SOUTH AFRICAAFRICA

AUSTRALIA – AUSTRALIA – NEW ZEALANDNEW ZEALAND

HERA TRIAL DESIGN HERA TRIAL DESIGN

Women with HER2 POSITIVE invasive Women with HER2 POSITIVE invasive breast cancer IHC3+ or FISH+ centrally confirmedbreast cancer IHC3+ or FISH+ centrally confirmed

Surgery + (neo)adjuvant chemotherapy (CT) Surgery + (neo)adjuvant chemotherapy (CT) radiotherapy radiotherapy

StratificationStratificationStratificationStratificationNodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy,

age, regionage, region

RandomizationRandomizationRandomizationRandomization

TrastuzumabTrastuzumab8 mg/kg 8 mg/kg 6 mg/kg 6 mg/kg3 weekly x 2 years3 weekly x 2 years

TrastuzumabTrastuzumab8 mg/kg 8 mg/kg 6 mg/kg 6 mg/kg3 weekly x 1 year3 weekly x 1 year

ObservationObservation

KEY INCLUSION CRITERIAKEY INCLUSION CRITERIA

• Centrally confirmed HER-2 overexpression Centrally confirmed HER-2 overexpression or amplificationor amplification

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

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

• Baseline LVEF Baseline LVEF 55% (Echo or MUGA) 55% (Echo or MUGA)• Known hormone receptor statusKnown hormone receptor status

Primary endpoint: Primary endpoint: DFSDFS

Secondary endpoints: RFS, DDFS, OS, Secondary endpoints: RFS, DDFS, OS, 2 years vs 1 year trastuzumab2 years vs 1 year trastuzumab

EFFICACYEFFICACY

ENDPOINTS AND ANALYSIS PLANENDPOINTS AND ANALYSIS PLAN

Target accrual: 4482Target accrual: 4482HR = 0.77 (power 80% 2 sided HR = 0.77 (power 80% 2 sided = 0.025) = 0.025)

for each pairwise test (1y vs nil or 2y vs nil)for each pairwise test (1y vs nil or 2y vs nil)

Target accrual: 4482Target accrual: 4482HR = 0.77 (power 80% 2 sided HR = 0.77 (power 80% 2 sided = 0.025) = 0.025)

for each pairwise test (1y vs nil or 2y vs nil)for each pairwise test (1y vs nil or 2y vs nil)

One interim efficacy analysis (n = 475 events)One interim efficacy analysis (n = 475 events)One primary core analysis (n = 951 events)One primary core analysis (n = 951 events)

SAFETYSAFETY

• TolerabilityTolerability• Incidence of cardiac Incidence of cardiac

dysfunction.dysfunction.

Three interim analysis of Three interim analysis of cardiac endpoints aftercardiac endpoints aftern = 300n = 300 n = 600n = 600 n = 900 n = 900 ptspts

Stopping rule: Stopping rule: 4% 4% absolute increase in primary absolute increase in primary

cardiac eventscardiac events

HERA FLOW CHARTHERA FLOW CHART

5090 Women enrolled5090 Women enrolled

5081 with available data5081 with available data1 year median follow-up1 year median follow-up

2y trastuzumab2y trastuzumabN=1694N=1694

Efficacy Efficacy AnalysisAnalysisN=3387N=3387

N= 1677N= 16771y trastuzumab1y trastuzumab

N=1736N=1736ObservationObservation

Safety Safety AnalysisAnalysisN=3413N=3413

N=3N=3N=20N=20N=26N=26

ObservationObservationN=1693N=1693

1y trastuzumab1y trastuzumabN=1694N=1694

PATIENT/TUMOR CHARACTERISTICSPATIENT/TUMOR CHARACTERISTICS

Age (%)Age (%)

< 35 y< 35 y

35- 49 y35- 49 y50 - 59 y50 - 59 y 60 y60 ymissingmissing

Observation (n = 1693) 1 year trastuzumab (n = 1694)

Adjuvant chemotherapy (%)Adjuvant chemotherapy (%)

Anthracyclines + taxanesAnthracyclines + taxanes

No anthracyclines,No anthracyclines,no taxaneno taxane

AnthracyclinesAnthracyclines

missingmissing

7.3 7.6

31.844.343.7

16.20.2

32.7

0.216.2

6.26.1

26.025.50.1 0.2

68.3 67.9

Menopausal status at randomization (%)Menopausal status at randomization (%)

Observation (N=1693)Observation (N=1693) 1 year trastuzumab (N=1694)1 year trastuzumab (N=1694)

50.0

37.9

16.115.4

37.2

47.1 Postmenopausal

Uncertain

PremPrem

PATIENT/TUMOR CHARACTERISTICSPATIENT/TUMOR CHARACTERISTICS

Observation (N=1693)Observation (N=1693) 1 year trastuzumab (N=1694)1 year trastuzumab (N=1694)

28.532.1

11.1

28.328.9

32.910.2

27.9

Node neg.Node neg.1-3 + nodes1-3 + nodes 4 + nodes4 + nodes

0.20.20.10.1missingmissing

Nodal Status (%)Nodal Status (%)

Hormone Receptor (%)Hormone Receptor (%)

49.9

50.0

49.0HR negativeHR negative

HR positiveHR positive

Any (neoadjuvant)Any (neoadjuvant)

50.9

49.0

PATIENT/TUMOR CHARACTERISTICSPATIENT/TUMOR CHARACTERISTICS

ADJUVANT ENDOCRINE THERAPYADJUVANT ENDOCRINE THERAPY

ObservationObservation 1 year trastuzumab1 year trastuzumab

TAMTAM

64%64%AIAI

TAMTAMAIAI

9%9%

11%11%

LHRH ± TAMLHRH ± TAM

16%16%

TAMTAM

66%66%8%8%

8%8%

17%17%

AIAI

TAMTAMAIAI

LHRH ± TAMLHRH ± TAM

OVERVIEW OF ADVERSE EVENTSOVERVIEW OF ADVERSE EVENTS

7.97.91321324.34.37575Patients with at least Patients with at least one grade 3 or 4 AEone grade 3 or 4 AE

8.58.5143 143 (c)(c)Treatment withdrawals Treatment withdrawals

6 6 (b)(b)3 3 (a)(a)Fatal AEFatal AE

7.07.01171174.74.78181Patients with at least Patients with at least one SAEone SAE

%%NN%%NN

1 year trastuzumab1 year trastuzumab

(N=1677)(N=1677)

ObservationObservation

(N=1736)(N=1736)

a)a) Cardiac failure, suicide, unknownCardiac failure, suicide, unknownb)b) Cerebral hemorrhage, cerebrovascular accident, sudden death, appendicitis, two unknownCerebral hemorrhage, cerebrovascular accident, sudden death, appendicitis, two unknownc)c) Reason: safety in 6%, refusal in 2.5%Reason: safety in 6%, refusal in 2.5%

SAFETY ANALYSIS POPULATIONSAFETY ANALYSIS POPULATIONCardiotoxicityCardiotoxicity

0.5%0.5%

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

0 %0 %

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

Same LVEF criteriaSame LVEF criteriaandand symptomatic CHF symptomatic CHF NYHA class III/IV, NYHA class III/IV, confirmed by confirmed by cardiologist cardiologist

Cardiac deathCardiac death

7.1 %7.1 %2.2 %2.2 %Decrease by Decrease by 10 EF points 10 EF points and LVEF < 50% and LVEF < 50%

1 year trastuzumab1 year trastuzumab

N=1677N=1677

ObservationObservation

N=1736N=1736

0.1% 0%

DISEASE-FREE SURVIVALDISEASE-FREE SURVIVAL

% alive % alive and and

disease disease freefree

Months fromMonths from randomizationrandomization00 55 1010 1515 2020 2525

16931693 14281428 994994 580580 280280 8787

16941694 14721472 10671067 629629 303303 102102

EventsEvents22--yryr

DFSDFS %% 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

1 year trastuzumab1 year trastuzumab

ObservationObservation

10010090908080707060605050404030302020101000

No. No. at riskat risk

Months fromMonths from randomizationrandomization00 55 1010 1515 2020 2525

16931693 14281428 994994 580580 280280 8787

16941694 14721472 10671067 629629 303303 102102

EventsEvents22--yryr

DFSDFS %% 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

1 year trastuzumab1 year trastuzumab

ObservationObservation

10010090908080707060605050404030302020101000

No. No. at riskat risk

3%3% n=6n=6 n=3n=3 2%2%

n=6n=6 5%5%

DISEASE-FREE SURVIVALDISEASE-FREE SURVIVALType of First EventType of First Event

Observation Observation n= 220 eventsn= 220 events

1 year trastuzumab1 year trastuzumabn= 127 eventsn= 127 events

n=154n=154 n= 85n= 85 67%67%

23%23% n=50n=50

3%3% n=7n=7

1%1% n=3n=3

n=6n=6 5%5%

Distant eventDistant event

Loco regional eventLoco regional event

Contralateral breast CaContralateral breast Ca

Death as first eventDeath as first event

Second non breast malignancySecond non breast malignancy

70%70%

n=27n=27 21% 21%

DFS BENEFIT IN SUBGROUPSDFS BENEFIT IN SUBGROUPSHR: 1 year trastuzumab vs observationHR: 1 year trastuzumab vs observation

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 yrsAge group

35-49 yrs50-59 yrs

60 yrs

Europe, Nordic, Canada, SA, Aus, NZRegion

Asia Pacific, JapanEastern Europe

Central + South America

972953

0.510.53

1674 0.514671234

0.490.68

251 0.4714901091

0.520.53

549 0.70

2430 0.58405364

0.420.31

188 0.90

Favorstrastuzumab

Favorsobservation

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 yrsAge group

35-49 yrs50-59 yrs

60 yrs

Europe, Nordic, Canada, SA, Aus, NZRegion

Asia Pacific, JapanEastern Europe

Central + South America

972953

0.510.53

1674 0.514671234

0.490.68

251 0.4714901091

0.520.53

549 0.70

2430 0.58405364

0.420.31

188 0.90

Favorstrastuzumab

Favorsobservation

SECONDARY EFFICACY ENDPOINTSSECONDARY EFFICACY ENDPOINTSIntent-to-treat AnalysisIntent-to-treat Analysis

RFSRFS DDFSDDFS OSOS

0.500.50 0.510.51

0.760.76

95% CI95% CIpp value (logrank) value (logrank)2y outcome (%)2y outcome (%)

0.40-0.630.40-0.63< 0.0001< 0.0001

78.6 vs 87.278.6 vs 87.2

0.40-0.660.40-0.66< 0.0001< 0.0001

81.8 vs 89.781.8 vs 89.7

0.47-1.230.47-1.23<0.26<0.26

95.0 vs 96.095.0 vs 96.0ObservationObservation1 year trastuzumab1 year trastuzumab

No of No of eventsevents

209209 113113 179179 9898 3737 2929

CONCLUSIONSCONCLUSIONS

At one year median follow-up:At one year median follow-up:

• Trastuzumab given every 3 weeks for one year following Trastuzumab given every 3 weeks for one year following adjuvant chemotherapy significantly prolongs DFS and RFS adjuvant chemotherapy significantly prolongs DFS and RFS for women with HER-2 positive early breast cancerfor women with HER-2 positive early breast cancer

• Trastuzumab significantly reduces the risk of distant Trastuzumab significantly reduces the risk of distant metastasesmetastases

• Trastuzumab’s clinical benefits are independent of Trastuzumab’s clinical benefits are independent of patients’ baseline characteristics (nodal status, hormone patients’ baseline characteristics (nodal status, hormone receptor status, ...) and of receptor status, ...) and of type of adjuvant chemotherapy type of adjuvant chemotherapy receivedreceived

• Trastuzumab therapy is associated with a low incidence of Trastuzumab therapy is associated with a low incidence of severe symptomatic congestive heart failure; longer severe symptomatic congestive heart failure; longer

follow-up is needed to better quantify this riskfollow-up is needed to better quantify this risk

• All patients continue to be followed for long-term safety: All patients continue to be followed for long-term safety: patients in the observation arm will be offered trastuzumab patients in the observation arm will be offered trastuzumab (guidelines in preparation)(guidelines in preparation)

• Results regarding optimal trastuzumab duration (1 versus 2 Results regarding optimal trastuzumab duration (1 versus 2 years) should be available by 2008years) should be available by 2008

CONCLUSIONSCONCLUSIONS

HERA Study Design Elements

•Randomized following ctx

•DFS was primary endpoint

•Most patients did not receive taxane

•In contrast to the Joint analysis, HERA included a large percentage of node negative pts(About 1/3).

•Very short median follow-up

Adjuvant Trastuzumab Summary and Conclusions

•Does adjuvant trastuzumab improve DFS? YES!

•Should we give trastuzumab with or following CTX?

•What is the appropraite duration of trastuzumab?

•What is the price of trastuzumab?

Should we give Trastuzumab before or after CTX?

•Preclinical data suggest that trastuzumab may amplify ctx’s pro-apoptotic effects.

•Synergistic activity in preclinical models for some ctx

•Cardiotoxicity concerns when trastuzumab is given in proximity to anthracyclines.

What is the appropriate duration of Trastuzumab?

•Unknown (HERA 1 vs. 2 yr pending)

•Current data supports one year of therapy

•Current data supports initiation of therapy for up to 6 months following completion of chemotherapy or radiation therapy

•Could we get by with less trastuzumab?

( ie. only with chemo?)

What is the price of Trastuzumab?

Cardiac Toxicity(CHF) can be consequence of using trastuzumab

Rate = 3.3-4.3% AC-TH vs. 0-0.5% AC-T (B31/ N9831)

Rate = 0.5-2.2% post ctx (HERA/N9831)

Degree of reversibility uncertain and requires further follow-up

Long term effects unknown

While benefit far outweighs the risks, the price is real and should be discussed with patients

BCIRG 006Adjuvant Breast Cancer

Node Positive and High Risk Node Negative

HER2 +FISH

4 x AC60/600 mg/m2

4 x Docetaxel100 mg/m2

6 x Docetaxel and Platinum salts75 mg/m2 75 mg/m2 or AUC 6

1 Year Trastuzumab

N=3150480

centres

1 Year Trastuzumab

ACT

ACTH

TCH

BCIRG 006 LVEF Decline by NYHA Class

AC-T AC-TH TCH

>10 < LLN 9 34 7

>15%< LLN 6 25 4

Grade 3-4 CHF 1 18 1

Implication: Trastuzumab by itself is not cardiotoxic; it becomes so when it keeps company with doxorubicin.

Intergroup Guidelines for N9831

•For women receiving trastuzumab, continue until 1 year is completed.

•For women randomized to 1 yr TH, continue as planned

•For women on Arm A: AC-T and are at most 6 months from completion of paclitaxel, begin weekly trastuzumab and continue until you have completed 1 yr of trastuzumab with cardiac testing.

Intergroup Guidelines for N9831

•For women on Arm A: AC-T and have not started paclitaxel, begin weekly trastuzumab with paclitaxel and continue until 1 yr of trastuzumab is completed, with cardiac testing.

•For women on Arm B: AC-T-H, and you have not begun trastuzumab, begin trastuzumab with paclitaxel and continue for 1 yr. with cardiac testing.

•If ctx completed > 6 mo. and have not received trastuzumab, discuss risks and benefits.

E2100A Randomized Phase III Trial of Paclitaxel

versus Paclitaxel plus Bevacizumab as First-Line Therapy for Locally Recurrent or

Metastatic Breast Cancer

KD Miller, M Wang, J Gralow, M Dickler, MA Cobleigh, EA Perez, TN Shenkier,

NE Davidson

Indiana University Cancer Center, Dana Farber Cancer Institute, Pudget Sound Oncology Consortium, Memorial Sloan Kettering Cancer Center, Rush-Presbyterian-St. Luke’s Medical

Center, Mayo Clinic, British Columbia Cancer Agency, Vancouver Cancer Center, Johns Hopkins Oncology Center

Rationale• Tumor growth is dependent on

angiogenesis• Bevacizumab is a humanized

monoclonal antibody directed against VEGF

• Recognizes all VEGF-A isoforms

• Active in patients with refractory MBC

• 9% response rate as monotherapy

• Increases ORR but not PFS in combination with capecitabine

• Greater activity expected in less heavily pre-treated patients

Stratify:• DFI < 24 mos. vs. > 24 mos.• < 3 vs. > 3 metastatic sites• Adjuvant chemotherapy yes vs. no• ER+ vs. ER- vs. ER unknown

RANDOMIZE

Paclitaxel + Bevacizumab

Paclitaxel

Study Design

28-day cycle:Paclitaxel 90 mg/m2 D1, 8 and

15Bevacizumab 10 mg/kg D1

and 15

Key Eligibility Criteria

• Locally recurrent or metastatic breast cancer– HER2+ only if prior treatment with

trastuzumab or contraindication• No prior chemo regimens for MBC

– Adjuvant taxane allowed if DFI > 12 months• ECOG PS 0 or 1• No anti-tumor therapy within 21 days• No CNS mets (head CT or MR required)• No significant proteinuria (> 500 mg/24 hr)• No therapeutic anticoagulation

Statistical Design - Efficacy

• Primary endpoint: Progression-Free Survival– 85% power for a 33% improvement

• 6 vs. 8 months

– One-sided type I error 2.5%– Requires 650 eligible patients

• Final analysis after 546 PFS events– Interim analyses after 270 and 425 events– Asymmetric boundaries to stop early either for

demonstrated benefit or for lack of benefit– O-Brien-Fleming boundaries and repeated

confidence interval analyses at each interim

Statistical Design - Safety

• Type I event: Grade 4 hemorrhage or HTN– Acceptable rate: 1%

• Type II event: Grade 3/4 thrombosis or embolism– Acceptable rate: 5%

Current Analysis

• Study activated Dec 21, 2001• Closed March 24, 2004

– 715 eligible patients

• First planned interim analysis• Data cut-off February 9, 2005• 355 events

– Progression – 291– Death without documented progression - 64

Patient Characteristics

Paclitaxel

(n=350)

Pac. + Bev.

(n=365)

Treated 346 365

Median age 55 (27-85) 56 (29-84)

DFI < 24 months 41% 41%

> 3 sites 29% 28%

Adjuvant chemo. 64% 65%

ER+ 63% 64%

All patients Measurable Disease

0

10

20

30

40

Paclitaxel

Ov

era

ll R

es

po

ns

e R

ate

Pac + Bev

Response

316 236330 250

34.3%

16.4%

28.2%

14.2%

P<0.0001P<0.0001

Progression Free Survival

HR = 0.498 (0.401-0.618)

Log Rank Test p<0.001

Months

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0PFS

Pro

port

ion

0 10 20 30

Pac. + Bev. 10.97 monthsPaclitaxel 6.11 months

Overall Survival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 10 20 30 40

Months

OS P

rop

ort

ion

Pac. + Bev.

Paclitaxel

HR = 0.674 (0.495-0.917)

Log Rank Test p=0.01

Bevacizumab ToxicityNCI-CTC Grade 3 and 4

Paclitaxel

(n=330)

Pac. + Bev.

(n=342)

%

Grade 3

Grade 4

Grade 3

Grade 4

HTN* 0 0 13 0.3

Thromboembolic 0.3 0.9 1.2 0

Bleeding 0 0 0.6 0.3

Proteinuria** 0 0 0.9 1.5NCI-CTC v3.0, worst per patient

*p<0.0001; **p=0.0004

Other ToxicitiesNCI-CTC Grade 3 and 4

Paclitaxel

(n=330)

Pac. + Bev.

(n=342)

%

Grade 3 Grade 4

Grade 3

Grade 4

Neuropathy* 13.6 0.6 19.9 0.6

Fatigue 2.7 0 4.7 0.3

Neutropenia 0 3 0.9 4.4

LVEF 0 0 0.3 0

NCI-CTC v3.0, worst per patient *p=0.01

Ongoing Correlative Studies

• Quality of Life (FACT-B)

• Circulating markers– Serum VCAM-1– Urine VEGF

• Analysis of primary tumor samples– VEGF expression

Conclusions and Future Directions

• Addition of bevacizumab to paclitaxel– Significantly prolongs progression free

survival– Increases objective response rate– Longer follow-up required to assess impact on

OS

• Further studies should – Explore the role of Bevacizumab in the

adjuvant setting– Develop methods to identify patients who are

most likely to benefit from VEGF-targeted therapies

Adjuvant Pilot TrialRationale

• Most successful use of anti-angiogenic therapy predicted to be in adjuvant setting– Require large trial for proof of concept

• Limitations of metastatic trials– Chronic therapy in only a few patients– Different tolerance for toxicity– Different metabolism (?)– Less concern for rare but potentially fatal

toxicities

E2104 Schema

REGISTER

Doxorubicin 60 mg/m2 plus Cyclophosphamide 600 mg/m2 Bevacizumab 10 mg/kgevery 14 days x 4

Arm A: ddBAC >BT >B

Arm B: ddAC >BT >B

Doxorubicin 60 mg/m2 plus Cyclophosphamide 600 mg/m2 every 14 days x 4

Paclitaxel 175 mg/m2 Bevacizumab 10 mg/kg every 14 days x 4

Paclitaxel 175 mg/m2 Bevacizumab 10 mg/kg every 14 days x 4

Bevacizumab 10 mg/kg every 14 days x 18

Bevacizumab 10 mg/kg every 14 days x 22

*Hormone therapy and radiation per standard care