A randomized three-arm multi-centre A randomized three-arm multi-centre comparison of: 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 in women with HER-2 positive primary breast cancer who have completed breast cancer who have completed adjuvant chemotherapy adjuvant chemotherapy Martine J. Piccart-Gebhart, MD, PhD Martine J. Piccart-Gebhart, MD, PhD on behalf of: on behalf of: The Breast International Group (BIG), NON-BIG The Breast International Group (BIG), NON-BIG participating groups, Independent sites, F. participating groups, Independent sites, F. Hoffmann – La Roche Ltd. Hoffmann – La Roche Ltd. FIRST RESULTS OF THE FIRST RESULTS OF THE HERA TRIAL HERA TRIAL ASCO, Scientific Session, May 16, 2005 ASCO, Scientific Session, May 16, 2005
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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®
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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,
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
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.