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Herceptin® in the adjuvant setting
Herceptin® in the adjuvant setting: rationale
HER2 overexpression is an early event in breast cancerdevelopment and is associated with aggressive disease
Herceptin® offers
A new mechanism of antitumour activity
Proven clinical benefits in the metastatic setting,including increased survival when used in combination with chemotherapy
Greater benefit when used earlier in metastatic disease
A favourable safety profile and good tolerability
Four major ongoing Herceptin® adjuvant trials
The extensive Herceptin® adjuvant trial programme will
– investigate complementary strategies
– establish the efficacy and role of Herceptin® in the adjuvant setting
– establish the safety profile of Herceptin®
– determine the optimal duration of adjuvant Herceptin® therapy
Herceptin in the adjuvant setting: major trials
Four main trials are currently investigatingHerceptin® in the adjuvant setting
HERA (Herceptin® Adjuvant) Trial NSABP (National Surgical Adjuvant Breast Project)
trial B31 Intergroup trial N9831 BCIRG (Breast Cancer International Research Group)
trial 006
HERA TRIAL: study design
Herceptin®
q3w x 1 yearHerceptin®
q3w x 2 years Observation*
Stratification
Randomisation
Primary management (surgery, [neo]adjuvant chemotherapy
± adjuvant radiotherapy)
*Observation group to receive the same follow-up as the Herceptin® treatment groups
HERA TRIAL: primary objectives
Compare disease-free survival (DFS) in patients with HER2-overexpressing breast cancer who received Herceptin® versus those who did not receive Herceptin®
– in patients treated for 1 year
– and those treated for 2 years
HERA TRIAL: secondary objectives
Overall survival, relapse-free survival and distant DFS
– 1 year of Herceptin® versus observation
– 2 years of Herceptin® versus observation
Safety and tolerability – Herceptin® versus observation
Incidence of cardiac dysfunction – Herceptin® versus observation
Treatment duration (efficacy and safety) – 1 year versus 2 years of Herceptin®
HERA TRIAL: substudies
To study PK of Herceptin®:
– in the adjuvant setting
– after 1 year versus 2 years of treatment
– with 3-weekly regimen
Correlate levels ofnatriuretic peptides and other markers
with LVEF/CHFand outcomes
Pharmacokinetic (PK) substudy
Cardiac marker substudy
TransHERAsubstudy
To establisha tissue bank
to enabletranslational
research
HERA TRIAL: study size and duration
Number of centres: ~600
Sample size: 3,192 (1,064 per arm)
Target population: women with HER2-positive primary breast cancer (IHC 3+ or FISH positive)
Study duration
– recruitment 48 months
– follow-up until 10 years after last patient enrolled
HERA TRIAL: planned duration
2003 2004 2005 2006 20072002 20162008
Interimsafety
analysesEnrolmentcomplete
Main efficacy analysis
Enrolment starts
Interimefficacy analysis
10-yearfollow-up complete
Enrolment Follow-up
HERA TRIAL: key inclusion criteria
Invasive, non-metastatic, operable primary breast cancer –histologically confirmed and adequately excised
Axillary node positive, or node negative with tumour size >1cm
Known hormone receptor status (ER/PgR or ER alone)
Completed 4 cycles of approved (neo)adjuvant chemotherapy
Baseline LVEF >55% (echocardiography or MUGA scan)
Completed radiotherapy if indicated
Centrally confirmed HER2 overexpression (IHC 3+ or FISH positive) in invasive component of primary tumour
HERA TRIAL: key exclusioncriteria
Clinical T4 tumour, including inflammatory breast cancer
Cumulative dose of doxorubicin >360mg/m2 or epirubicin >720mg/m2
(Neo)adjuvant chemotherapy with peripheral blood/bone marrow stem cell support
Supraclavicular lymph node involvement
Any prior malignant neoplasms (including primary invasive breast cancer), except– curatively treated basal/squamous cell carcinoma of skin– curatively treated in-situ cervical carcinoma
HERA TRIAL: unique features
Investigating the role of Herceptin® independently from chemotherapy regimen
Investigating 2 years of Herceptin® treatment
3-weekly schedule from the start
– more convenient
– gives similar exposure to Herceptin® as weekly administration of lower doses
New model of partnership between academia and pharmaceutical industry
NSABP trial B-31: study design
*Tamoxifen for ER+ or PgR+; tamoxifen optional for ER– and PgR– patients 50 years old
Operable breast cancerHER2-positive tumour
Pathologically positive axillary nodes
Randomisation
AC x 4*
Paclitaxel x 4
AC x 4*
Paclitaxel x 4 + Herceptin®
NSABP trial B31: treatment plan
Doxorubicin 60mg/m2
Cyclophosphamide 600mg/m2
Paclitaxel 175mg/m2 q3w
Herceptin® – loading dose 4mg/kg on week 1– maintenance dose 2mg/kg x 51 weeks
AC
NSABP trial B31: primary objectives
Stage I: (n=1,000)
– evaluation of cardiac safety
Stage II: (n=1,700; total=2,700)
– evaluation of efficacy
• survival: primary endpoint
• disease-free survival (DFS): secondary endpoint
NSABP trial B31: secondary objectives
Prognostic and predictive value of phosphorylated HER2 receptor
Prognostic and predictive value of shed extracellular domain (ECD)
Concordance between different HER2 assays, i.e. IHC versus FISH
Change in HER2-phosphorylated receptor, ECD level or HER2 overexpression upon relapse
NSABP trial B31: key inclusion criteria
Histologically/cytologically proven invasive adenocarcinoma of the breast
At least one positive axillary node Axillary dissection AND either total mastectomy OR
lumpectomy HER2 overexpression (IHC 3+ or FISH positive) Known hormone receptor status (ER/PgR) No more than 84 days since prior surgery for breast cancer No prior chemotherapy, radiotherapy or hormonal therapy
for breast cancer Normal cardiac, renal and hepatic function
NSABP trial B31: patient accrual
1,200
1,000
800
600
400
200
00 4 8 12 16 20 24
Months
Nu
mb
er o
f p
atie
nts
Actual
Projected
NSABP trial B31: overall toxicity
50
40
30
20
10
0
Per
cen
tag
e o
f p
atie
nts
2 3 4 5
Grade of overall toxicity
P (n=251)P + H (n=245)
NSABP trial B31: toxicity (paclitaxel versus paclitaxel plus Herceptin®)
Neutropenicinfection
Febrileneutropenia
0 1 2
Percentage of patients
Grade 3
Grade 4
P
P + H
P
NSABP trial B31: toxicity (paclitaxel versus paclitaxel plus Herceptin®)
Sensoryneuropathy
Arthralgia
Myalgia
Fatigue
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
P
P + H
P
P + H
P
P + H
P
P + H
Grade 2
Grade 3
Percentage of patients
Intergroup trial N9831: study design
Operable breast cancerHER2-positive tumour
Node positive
Randomisation
AC q3w x 4
Paclitaxel x 12
AC q3w x 4
Paclitaxel x 12+ Herceptin
® x 12
Herceptin® x 40
AC q3w x 4
Paclitaxel x 12 + Herceptin
® x 52
Intergroup trial N9831: treatment plan Herceptin®
– 4mg/kg loading dose (90 minutes i.v. infusion) followed by 4mg/kg weekly (90 minutes i.v. infusion or 30 minutes i.v. infusion based on toxicity)
Doxorubicin 60mg/m2 every 3 weeks
Cyclophosphamide 600mg/m2 every 3 weeks
Paclitaxel 80mg/m2 weekly
Intergroup trial N9831: objectives
Primary– disease-free survival – cardiotoxicity
Secondary– overall survival – evaluation of whether sHER1 or sHER2 levels
at baseline are prognostic for disease-free and overall survival
– concordance of IHC (HercepTest®) with FISH (VysisTM); disease-free survival; and overall survival
Intergroup trial N9831: inclusion criteria Operable, histologically confirmed adenocarcinoma of
the breast Node-positive disease Hormonal status known (ER/PgR) HER2 overexpression (IHC 3+ or FISH positive) No prior chemotherapy
– hormonal therapy allowed for up to 4 weeks but discontinued prior to enrolment
No more than 84 days from mastectomy or axillary node dissection
LVEF normal
Intergroup trial N9831: exclusion criteria Locally advanced tumours Prior history of breast cancer Prior chemotherapy or radiotherapy for breast cancer Cardiac disease including:
– myocardial infarction– history of congestive heart failure– medication for arrythmia or angina pectoris
Prior anthracycline or taxane therapy for any malignancy
Intergroup trial N9831: cardiotoxicity
Arm 3 suspended due to a few cardiotoxic events
This arm was reopened following the first interim safety analysis in June 2002 and patient accrual continues
At first interim analysis cardiotoxicity remained within acceptable limits based on review Data Monitoring Committee
Intergroup trialN9831
NSABP trial B31
Arm 3: AC x 4 paclitaxel 80mg/m2
qw x 12 with weekly Herceptin® Arm 2: AC x 4 paclitaxel 175mg/m2
q3w x 4 with weekly Herceptin®
BCIRG trial 006: study design
AC x 4 Docetaxel + cisplatin or carboplatin x 6
+ Herceptin® weekly 3-weekly Herceptin® for 1 year from date
of first administration
Docetaxel x 4
Operable node-positive, HER2-positive (FISH) breast cancer
AC x 4
Docetaxel x 4 + Herceptin® weekly 3-weekly Herceptin® for 1 year from date
of first administration
Randomisation
BCIRG trial 006: treatment plan
Doxorubicin 60mg/m2
Cyclophosphamide 600mg/m2
Docetaxel 100mg/m2
Platinum salt
– carboplatin AUC 6
– cisplatin 75mg/m2
Herceptin®
– 6mg/kg every 3 weeks
BCIRG trial 006: objectives
Primary – disease-free survival
Secondary– overall survival– safety– cardiac toxicity– quality of life – prognostic value of HER2 overexpression
BCIRG trial 006: key inclusion criteria
Histologically proven breast cancer Definitive surgical treatment Node-positive/negative disease HER2 overexpression (FISH positive) Normal renal, hepatic and cardiac function No prior systemic therapy or radiotherapy for breast
cancer
Comparison of the four large Herceptin® adjuvant trials
Trial
Target accrual
Patient
selection
Accrual phase (years)
Follow-up phase (years)
Primary endpoint
NSABP B31 2,700 Node+, IHC 3+ or
FISH+
4.75 15 OS
Intergroup N9831
3,000 Node+, IHC 3+ or
FISH+
4.5 15 DFS
BCIRG 006 3,000 Node+ and – FISH+
NA NA DFS
HERA Trial 3,192 Node+ and – IHC 3+ or
FISH+
4 10 DFS
OS = overall survivalDFS = disease-free survival
Other Herceptin® adjuvant trials:ECOG trial E2198
234 anthracycline-naive patientsIHC 2+/3+
Paclitaxel + Herceptin®
AC observation
Paclitaxel + Herceptin®
Sledge G, et al. Breast Cancer Res Treat 2001;69:209 (Abstract 4)
AC Herceptin®
ECOG trial E2198: inclusion criteria
Histologically confirmed stage II or IIIa adenocarcinoma of the breast
HER2 overexpression (IHC 2+/3+) Axillary node dissection AND mastectomy or
lumpectomy within 12 weeks prior to enrolment No prior chemotherapy, hormonal therapy (at least
one year since tamoxifen therapy) or radiotherapy No history of cardiac disease
ECOG trial E2198: objectives
Evaluate the incidence of cardiotoxicity associated with paclitaxel plus Herceptin® in women with HER2-positive breast cancer
Assess the long-term safety of Herceptin® in this patient population
ECOG trial E2198: cardiotoxicity
Sledge G, et al. Breast Cancer Res Treat 2001;69:209 (Abstract 4)
LVEF >10%
LVEF < normal
LVEF grade 3/4
Post paclitaxel + Herceptin®
9.5 (18/189) 2.1 (4/189) –
Post AC 12.5 (16/128) 5.5 (7/128) 8
Other Herceptin® adjuvant trials:PACS 04
Second randomisation
n=2,600(HER2 positive/negative)
First randomisation
FEC100 x 6Epirubicin + docetaxel x 6
1-year Herceptin® monotherapy
Observation
n=520(HER2 positive)
Herceptin® in the adjuvant setting: conclusions
The extensive Herceptin® adjuvant trial programme will enable the role of Herceptin® in the adjuvant setting to be defined
Using Herceptin® in the adjuvant setting may lower the risk of treatment failure and improve survival in women with HER2-positive disease