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