Transcript No Slide Title
ASCO, Scientific Session, May 16, 2005
FIRST RESULTS OF THE HERA TRIAL
A randomized three-arm multi-centre comparison of: • 1 year Herceptin® • 2 years Herceptin® • or no Herceptin® in women with HER-2 positive primary breast cancer who have completed adjuvant chemotherapy
Martine J. Piccart-Gebhart, MD, PhD on behalf of: The Breast International Group (BIG), NON-BIG participating groups, Independent sites, F. Hoffmann – La Roche Ltd.
ACCRUAL: 5090 WOMEN 478 centers from 39 countries (2002-2005) CANADA NORDIC COUNTRIES 71.5% EU CENTRAL & 5.5% SOUTH AMERICA EASTERN EUROPE:
11% SOUTH AFRICA JAPAN
12% ASIA PACIFIC AUSTRALIA – NEW ZEALAND
HERA TRIAL DESIGN
Women with HER2 POSITIVE invasive breast cancer IHC3+ or FISH+ centrally confirmed Surgery + (neo)adjuvant chemotherapy (CT)
radiotherapy Stratification Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age, region Randomization Trastuzumab 8 mg/kg
6 mg/kg 3 weekly x 2 years Trastuzumab 8 mg/kg
6 mg/kg 3 weekly x 1 year Observation
KEY INCLUSION CRITERIA • • • • • Centrally confirmed HER-2 overexpression or amplification Node-positive or (sentinel) node-negative with T1c Completed 4 cycles of approved (neo)adjuvant chemotherapy regimen Baseline LVEF 55% (Echo or MUGA) Known hormone receptor status
ENDPOINTS AND ANALYSIS PLAN
EFFICACY Target accrual: 4482 HR = 0.77 (power 80% 2 sided
= 0.025) for each pairwise test (1y vs nil or 2y vs nil) SAFETY
• •
Tolerability Incidence of cardiac dysfunction.
Primary endpoint: DFS Secondary endpoints: RFS, DDFS, OS, 2 years vs 1 year trastuzumab One interim efficacy analysis (n = 475 events) One primary core analysis (n = 951 events) Three interim analysis of cardiac endpoints after n = 300 n = 600 n = 900 pts Stopping rule:
4% absolute increase in primary cardiac events
HERA FLOW CHART 5090 Women enrolled 2y trastuzumab N=1694 N=26 5081 with available data 1 year median follow-up 1y trastuzumab N=1694 Observation N=1693 N=20 N=3 N= 1677 1y trastuzumab N=1736 Observation Efficacy Analysis N=3387 Safety Analysis N=3413
PATIENT/TUMOR CHARACTERISTICS
Observation (n = 1693) < 35 y 35- 49 y 50 - 59 y
60 y missing 43.7
32.7
Age (%) 1 year trastuzumab (n = 1694) 16.2
7.3 7.6
0.2
16.2
0.2
31.8
44.3
Adjuvant chemotherapy (%) 68.3
No anthracyclines, no taxane Anthracyclines Anthracyclines + taxanes missing 6.1
6.2
25.5
0.1
0.2
26.0
67.9
PATIENT/TUMOR CHARACTERISTICS
Menopausal status at randomization (%) Observation (N=1693) 47.1
37.2
1 year trastuzumab (N=1694) 15.4
Prem 16.1
Uncertain Postmenopausal 37.9
50.0
PATIENT/TUMOR CHARACTERISTICS
Observation (N=1693) 1 year trastuzumab (N=1694) Any (neoadjuvant) Node neg.
1-3 + nodes
4 + nodes missing 32.9
28.9
27.9
Nodal Status (%) 10.2
0.1
11.1
0.2
28.5
28.3
32.1
HR negative HR positive Hormone Receptor (%) 49.9
50.0
50.9
ADJUVANT ENDOCRINE THERAPY Observation LHRH ± TAM TAM
AI 11% AI 9% 16% TAM 64% 1 year trastuzumab LHRH ± TAM TAM
AI AI 8% 8% 17% TAM 66%
OVERVIEW OF ADVERSE EVENTS
Patients with at least one grade 3 or 4 AE Patients with at least one SAE Fatal AE Treatment withdrawals Observation (N=1736) N % 75 81 3 (a) 4.3
4.7
1 year trastuzumab (N=1677) N % 132 7.9
117 7.0
143 (c) 6 (b) 8.5
a) Cardiac failure, suicide, unknown b) Cerebral hemorrhage, cerebrovascular accident, sudden death, appendicitis, two unknown c) Reason: safety in 6%, refusal in 2.5%
SAFETY ANALYSIS POPULATION Cardiotoxicity
Observation N=1736 Decrease by 10 EF points and LVEF < 50% Same LVEF criteria and symptomatic CHF NYHA class III/IV, confirmed by cardiologist 2.2 % 0 % (95% CI: 0.00-0.21) 1 year trastuzumab N=1677 7.1 % 0.5% (95% CI: 0.25-1.02) Cardiac death
0.1% 0%
DISEASE-FREE SURVIVAL
% alive and disease free 100 90 80 70 60 50 40 30 20 10 0 No. at risk 2 DFS yr 5 Months from 15 randomization
DISEASE-FREE SURVIVAL Type of First Event
Observation n= 220 events 1 year trastuzumab n= 127 events Distant event 70% Loco regional event Contralateral breast Ca n=154 Second non breast malignancy 23% 3% 3% n= 85 67% n=50 n=7 n=27 n=6 21% 5% n=6 n=3 2% Death as first event 1% n=3 n=6 5%
DFS BENEFIT IN SUBGROUPS HR: 1 year trastuzumab vs observation Nodal status Any, neo-adjuvant chemotherapy 0 pos, no neo-adjuvant chemotherapy 1-3 pos, no neo-adjuvant chemotherapy
4 pos, no neo-adjuvant chemotherapy Anthracycline, no taxane Anthracycline + taxane Receptor status/endocrine therapy Pos + no endocrine therapy Pos + endocrine therapy Age group <35 yrs 35-49 yrs 50-59 yrs
60 yrs Asia Pacific, Japan Eastern Europe Central + South America Favors trastuzumab Favors observation 358 1100 972 953 203 2307 467 1234 1490 1091 405 364 Hazard ratio 0.53
0.52
0.51
0.53
0.64
0.43
0.49
0.68
0.52
0.53
0.42
0.31
SECONDARY EFFICACY ENDPOINTS Intent-to-treat Analysis RFS DDFS OS 0.76
0.50
No of events 209 113 95% CI p value (logrank) 2y outcome (%) 0.40-0.63
< 0.0001
78.6 vs 87.2
0.51
179 98 37 29 0.40-0.66
< 0.0001
81.8 vs 89.7
0.47-1.23
<0.26
95.0 vs 96.0
Observation 1 year trastuzumab
CONCLUSIONS At one year median follow-up:
•
Trastuzumab given every 3 weeks for one year following adjuvant chemotherapy significantly prolongs DFS and RFS for women with HER-2 positive early breast cancer
•
Trastuzumab significantly reduces the risk of distant metastases
•
Trastuzumab’s clinical benefits are independent of patients’ baseline characteristics (nodal status, hormone receptor status, ...) and of type of adjuvant chemotherapy received
CONCLUSIONS
•
Trastuzumab therapy is associated with a low incidence of severe symptomatic congestive heart failure; longer follow-up is needed to better quantify this risk
•
All patients continue to be followed for long-term safety: patients in the observation arm will be offered trastuzumab (guidelines in preparation)
•
Results regarding optimal trastuzumab duration (1 versus 2 years) should be available by 2008
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 006
Adjuvant Breast Cancer Node Positive and High Risk Node Negative
4 x AC 60/600 mg/m 2 4 x Docetaxel 100 mg/m 2
AC
T
HER2 +
FISH
N=3150 480 centres
AC
TH
1 Year Trastuzumab 6 x Docetaxel and Platinum salts 75 mg/m 2 75 mg/m 2 or AUC 6
TCH
1 Year Trastuzumab
BCIRG 006 LVEF Decline by NYHA Class >10 < LLN AC-T 9 AC-TH 34 TCH 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.