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Tamoxifen in MBC
1973
Ward. Br Med J 1973; 1: 13-14
Ward
60-77%Stable disease or response
Tamoxifen monotherapy
CMF in MBC
33%
3 months
Overall response rate
Median survival
1976
Canellos
Canellos et al. Cancer 1976; 38: 1882-1886
CMF vs L-phenylalanine mustard
C, cyclophosphamide;M, methotrexate;F, 5-fluorouracil
Paclitaxel in MBC
First publication: Nabholtz et al. Proc Am Soc Clin Oncol 1993; 12: abs 42
1993
CA139-048
29%
4.2 months
Paclitaxel monotherapy high vs low dose
Latest data (175 mg/m2 dose)
Nabholtz et al. J Clin Oncol 1996; 14: 1858-1867
Overall response rate
Time to progression
Aromatase inhibitors in MBC
4.2 months Median survival
First publication: Jonat et al. Proc Am Soc Clin Oncol 1995; 14: abs 130
Buzdar et al. Cancer 1998; 83: 1142-1152
Latest data
1995
Arimidex Study Group trials 3 and 4Anastrozole vs megestrol acetate
Docetaxel in MBC
14.5% Overall response rate
First publication: Chan et al. Proc Am Soc Clin Oncol 1997; 16: abs 540
1997
TAX 303Docetaxel vs doxorubicin
Nabholtz et al. J Clin Oncol 1999; 17: 1413-1424
2.7 months Median survival
Latest data
Docetaxel vs mitomycin C + vinblastineTAX 304
First publication: Nabholtz et al. Proc Am Soc Clin Oncol 1997; 16: abs 519
Latest data
Chan et al. J Clin Oncol 1999; 17: 2341-2354
Herceptin in MBC
First publication: Slamon et al. Proc Am Soc Clin Oncol 1998; 17: 98a, abs 377
1998
H0648gHerceptin + chemotherapy vs chemotherapy
7 months Median survival
Smith. Anticancer Drugs 2001; 12 (Suppl 4): S3-S10
Herceptin + paclitaxel vs paclitaxel (HER2 IHC 3+ )Latest data
32% Overall response rate
Adjuvant CMF
21%
Risk of recurrence
Bonadonna et al. BMJ 2005; 330: 217
1976
The CMF programmeCMF vs observation
C, cyclophosphamide;M, methotrexate;F, 5-fluorouracil
First publication: Bonadonna et al. N Engl J Med 1976; 294: 405-410
Latest data
29%
Risk of death
1976
Adjuvant tamoxifen
36%
29%
Risk of recurrence
Risk of death
First publication: Lancet 1983; 1: 257-261
Br J Cancer 1988; 57: 608-611
Latest data
1983
NATO trialTamoxifen vs observation
Adjuvant anthracyclines
Risk of recurrence
First publication: Levine et al. J Clin Oncol 1998; 16: 2651-2658
Latest data
Levine et al. J Clin Oncol 2005; 23: 5166-5170
1998
NCIC MA.5CEF vs CMF
24%
C, cyclophosphamide; E, epirubicin;F, fluorouracil; M, methotrexate
Adjuvant taxanes
18%
Risk of recurrence
Risk of death
1998
First publication: Henderson et al. Proc Am Soc Clin Oncol 1998; 17: 101a, abs 390A
CALGB 9344AC→P vs AC
17%
A, doxorubicin;C, cyclophosphamide;P, paclitaxel
Latest data
Henderson et al. J Clin Oncol 2003; 21: 976-983
Adjuvant aromatase inhibitors
13% Risk of recurrence
First publication: Baum et al. Breast Cancer Res Treat 2001; 69: 210, abs 8
2001
ATACAnastrozole vs tamoxifen
Howell et al. Lancet 2005; 365: 60-62
Latest data
Adjuvant Herceptin
36%
34%
Risk of recurrence
Risk of death
First presentation: Piccart-Gebhart et al. ASCO 2005
Smith et al. Lancet 2007; 369: 29-36
Latest data
3 further large studies have also demonstrated similar significant reductions in risk of relapse and risk of death
Romond et al. N Engl J Med 2005; 353: 1673-1684; Slamon et al. SABCS 2006; abs 52
2005
HERA1-year Herceptin vs observation after chemotherapy
Herceptin landmarks
Defined as key studies in the evolution of Herceptin therapy
The data shown are from the most mature analyses available from these trials
Preclinical evidence for targeting HER2
Anti-HER2 monoclonal antibodies revert transformed cells to non-transformed phenotype
Drebin et al. Cell 1985; 41: 697-706
1985
HER2 amplified in 15 to 30% of breast cancers
Link between HER2 expression and breast cancer progression established
Slamon et al. Science 1987; 235: 177-182
1987
Herceptin + chemotherapy in MBC
First publication: Slamon et al. Proc Am Soc Clin Oncol 1998; 17: 98a, abs 377
1998
H0648gHerceptin + chemotherapy vs chemotherapy
7 months Median survival
Smith. Anticancer Drugs 2001; 12 (Suppl 4): S3-S10
Herceptin + paclitaxel vs paclitaxel (HER2 IHC 3+ )Latest data
32% Overall response rate
First-line Herceptin monotherapy in MBC
2000
First publication: Vogel et al. Proc Am Soc Clin Oncol 2000; 19: 71a, abs 376
Vogel et al. Oncology 2001; 61 (Suppl 2): 37-42
Latest data
26% Overall response rate
24 months Median survival
H0650g
Herceptin + docetaxel in MBC
First publication: Extra et al. Breast Cancer Res Treat 2003; 82: 47, abs 217
2003
M77001Herceptin + docetaxel vs docetaxel
8.5 months Median survival
Marty et al. J Clin Oncol 2005; 23: 4265-4274
Latest data
27% Overall response rate
Herceptin + anastrozole in MBC
2.4 months Progression-free survival
Kaufman et al. Ann Oncol 2006; 17 (Suppl 9): LBA2
2006
TAnDEM
14.8% Clinical benefit rate
Herceptin + anastrozole vs anastrozole
Adjuvant Herceptin
36%
34%
Risk of recurrence
Risk of death
First presentation: Piccart-Gebhart et al. ASCO 2005
Smith et al. Lancet 2007; 369: 29-36
Latest data
3 further large studies have also demonstrated similar significant reductions in risk of relapse and risk of death
Romond et al. N Engl J Med 2005; 353: 1673-1684;Slamon et al. SABCS 2006; abs 52
2005
HERA1-year Herceptin vs observation after chemotherapy
Treatment guidelines for HER2-positive EBC
1. Goldhirsch et al 2011; 2. Aebi et al 2011; 3. www.nccn.org
Adjuvant therapy Recommended patient groups Administration
St. Gallen1
1 year of Herceptin®
(trastuzumab)
• HER2-positive tumours ≥1 cm
• HER2-positive node-negative tumours 0.51.0 cm (pT1b)
• Excludes: HER2-positive node-negative tumours 0.10.5 cm (pT1a)
• Preferred: concurrent use of Herceptin®
(trastuzumab) with chemotherapy
• Acceptable: chemotherapy followed by Herceptin® (trastuzumab) sequentially
ESMO2
1 year of Herceptin®
(trastuzumab)
• HER2-positive tumours ≥1 cm
• Use of Herceptin® (trastuzumab) should be discussed with patients with small node-negative HER2-positive breast cancers
• Herceptin® (trastuzumab) may be started in parallel with a taxane
• Herceptin® (trastuzumab) should not be given concurrently with an anthracycline outside the context of a clinical trial
NCCN3
1 year of Herceptin®
(trastuzumab)
• Category 1 recommendation: patients with HER2-positive tumours >1 cm
• Category 2A recommendation: patients with HER2-positive node-negative tumours 0.6‒1.0 cm
• HER2-positive node-negative pT1a or pT1b tumours: use of Herceptin® (trastuzumab) to be based on individual benefit:risk
• Preferred: doxorubicin and cyclophosphamide followed by concurrent administration of Herceptin® (trastuzumab) with taxane
• Preferred: docetaxel, carboplatin and Herceptin® (trastuzumab), other regimen see at NCCN
• Acceptable: chemotherapy followed by Herceptin® (trastuzumab) sequentially
Herceptin® (trastuzumab) recommended across international guidelines
Key Herceptin® (trastuzumab) studies in HER2-positive EBC
CT, chemotherapy (*selected from a list of approved regimens consisting of ≥4 cycles); RT, radiotherapy
1. Gianni et al 2011; 2. Slamon et al 2011; 3. Perez et al 2011
Study N Treatment armsFollow-up
(years)
HERA1 5102CT* ± RT observationCT* ± RT Herceptin® (trastuzumab) 1 year CT* ± RT Herceptin® (trastuzumab) 2 years
4
BCIRG0062 3222
AC docetaxelAC docetaxel+Herceptin® (trastuzumab) Herceptin®
(trastuzumab) Docetaxel+carboplatin+Herceptin® (trastuzumab) Herceptin® (trastuzumab)
5
NCCTG N98313 3505
AC paclitaxelAC paclitaxel Herceptin® (trastuzumab) AC paclitaxel+Herceptin® (trastuzumab) Herceptin®
(trastuzumab)
4
NSABP B-313 2101
AC paclitaxelAC paclitaxel+Herceptin® (trastuzumab) Herceptin®
(trastuzumab) 4
Extensive clinical programme involving >12,000 patients
HERA (BO16348)
HERceptin Adjuvant (HERA): a randomised three-arm multicentre comparison of 1
year and 2 years of Herceptin® (trastuzumab) versus
no Herceptin® (trastuzumab) in women with HER2-positive primary breast cancer
who have completed adjuvant chemotherapy
HERA: study design
*Stratification factors: nodal status, adjuvantCT regimen, hormone receptor status andendocrine therapy, age, region
Piccart-Gebhart et al 2005: Smith et al 2007; Gianni et al 2011
RANDOMISATION
Observation(n=1698)
1 year of Herceptin®
(trastuzumab) 8 mg/kg6 mg/kg3-weekly schedule
(n=1703)
2 years of Herceptin®
(trastuzumab) 8 mg/kg6 mg/kg3-weekly schedule
(n=1701)
CROSSOVER
(n=885)
HER2-positiveinvasive EBC
(N=5102)*
Surgery + (neo)adjuvant
CT±RT
HERA: endpoints I
• Primary endpoint– Disease-free survival (DFS)
• Herceptin® (trastuzumab) 1 year vs observation• Herceptin® (trastuzumab) 2 years vs observation
• Secondary endpoints include:– Overall survival (OS) and cardiac safety
• Herceptin® (trastuzumab) 1 year vs observation• Herceptin® (trastuzumab) 2 years vs observation
– DFS, OS, RFS, DDFS, TTR, TTDR, cardiac safety, overall safety• Herceptin® for 1 year vs Herceptin® for 2 years
– Safety and tolerability of Herceptin®
– Cardiac dysfunction of Herceptin® vs observation
Piccart-Gebhart et al 2005: Smith et al 2007; Gianni et al 2011
HERA: disease-free survival at all time points
CI, confidence interval; HR, hazard ratio
1. Piccart-Gebhart et al 2005; 2. Smith et al 2007; 3. Gianni et al 2011
1 year1
Medianfollow-up
2 years2
4 years3
Number of DFS eventsHerceptin® (trastuzumab)
vs observation
127 vs 220p<0.0001
218 vs 321p<0.0001
369 vs 458p<0.0001
0 1 2Favours
Herceptin®
(trastuzumab)
Favours noHerceptin®
(trastuzumab)
HR (95% CI)
DFS benefit
Consistent disease-free survival benefit for Herceptin® (trastuzumab) vs observation
HERA: overall survival at all time points
1. Piccart-Gebhart et al 2005; 2. Smith et al 2007; 3. Gianni et al 2011
29 vs 37p=0.26
20051
1 year
59 vs 90p=0.0115
182 vs 213p=0.1087
20062
2 years
20083
4 years
Overall survival benefit for Herceptin® (trastuzumab) loses significance at 4 years due to extensive crossover
0 1 2Favours
Herceptin®
(trastuzumab) Favours
observation
HR (95% CI)
OS benefitMedian
follow-up No. of deaths
Herceptin® (trastuzumab)vs observation
HERA: adverse events and cardiac endpoints
*Crossover patients were censored from the date of starting Herceptin® (trastuzumab); †Not including cardiac death‡20 New York Heart Association II and 13 New York Heart Association III and IV§ Asymptomatic or mildly symptomatic Gianni et al 2011
Adverse event (AE), n (%)Observation*
(n=1719)
Herceptin®
(trastuzumab) 1 year (n=1677)
Patients with ≥1 Grade 3/4 AE 131 (8) 239 (14)
Patients with ≥1 SAE 129 (8) 199 (12)
Fatal AEs 6 (0) 12 (1)
Treatment withdrawals – 176 (11)
Cardiac endpoints
Cardiac death 1 (0) 0
Symptomatic CHF (II, III and IV)† 2 (0) 33 (2)‡
Confirmed significant LVEF drop§ 13 (1) 62 (4)
Herceptin® (trastuzumab) discontinued due to
cardiac problems– 87 (5)
Any type of cardiac endpoint 14 (1) 75 (5)
Low incidence of cardiac adverse events with Herceptin® (trastuzumab)
BCIRG 006
Multicentre Phase III randomised trial comparing doxorubicin and cyclophosphamide followed by
docetaxel (ACT) with doxorubicin and cyclophosphamide followed by docetaxel and Herceptin® (trastuzumab) (ACTH) and with
docetaxel, carboplatin and Herceptin®
(trastuzumab) (TCH) in the treatment of node-positive and high-risk node-negative adjuvant
patients
6 x T + C
ACT
AC TH
TCH
1 year of Herceptin® (trastuzumab)
HER2-positive
Node-positive or high-risk
node-negative EBC
N=3222
Stratified by nodes and hormone-receptor status
4 x AC 4 x T
1 year of Herceptin® (trastuzumab)
BCIRG 006: study design
AC: Doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 q3w x 4T: Docetaxel 100 mg/m2 q3w x 4 (75 mg/m2 q3w x 6 when combined with carboplatin)C: Carboplatin AUC 6 q3w x 6 H: Herceptin® (trastuzumab) was administered weekly during chemotherapy (4 mg/kg loading dose, then
2 mg/kg qw), followed by 6 mg/kg q3w as monotherapy for a total treatment duration of 12 months
Slamon et al 2011
4 x AC 4 x T
BCIRG 006: end points and analyses
• Primary– Disease-free survival (DFS)
• Local/regional/distant recurrence
• 2nd primary invasivecancers
• Death due to any cause
• Secondary– Overall survival (OS)– Safety– Pathological and molecular
markers for predicting efficacy
1. Slamon et al 2005; 2. Slamon et al 2006; 3. Slamon et al 2011
1st interim efficacyanalysis after
322 DFS events (23 months)1
2nd interim efficacyanalysis after
462 DFS events (36 months)2
3rd interim efficacyanalysis after
656 DFS events (65 months)3
Aliv
e a
nd
dis
eas
e-f
ree
(%
)
BCIRG 006: disease-free survival at 5 years of follow-up
Slamon et al 2011
Years from randomisation
ACTH 84%TCH 81% ACT 75%
Significant disease-free survival benefit with Herceptin® (trastuzumab) in both regimens
0 1 2 3 4 65
20
40
60
80
100
0
n Events HR 95% CI p value
ACTH 1074 185 0.64 0.53‒0.78 <0.001
TCH 1075 214 0.75 0.63‒0.90 0.04
ACT 1073 257 1 (ref) − −
ACTH 92%TC H 91%ACT 87%
Years from randomisation
BCIRG 006: overall survival at 5 years of follow-up
Slamon et al 2011
Significant overall survival benefit with Herceptin® (trastuzumab) at long-term follow-up
n Events HR 95% CI p value
ACTH 1074 94 0.63 0.48‒0.81 <0.001
TCH 1075 113 0.77 0.60‒0.99 0.0038
ACT 1073 141 1 (ref) − −
BCIRG 006: summary of efficacy endpoints at 5-year follow-up
Slamon et al 2011
185 vs 257 0.64 (0.530.78)
No. eventsHerceptin®
(trastuzumab) vs observation
HR (95% CI)
214 vs 257 0.75 (0.630.90)
0.0 0.5 1.0 1.5
DFS
OS
ACTH
TCH
ACTH
TCH
94 vs 141 0.63 (0.480.81)
113 vs 141 0.77 (0.600.99)
HR (95% CI)
FavoursHerceptin® (trastuzumab)
Favoursobservation
Consistent efficacy benefit of Herceptin® (trastuzumab) withanthracycline-based and non-anthracycline-based regimens
BCIRG 006: Grade 3/4 non-haematological adverse events
*Statistically significantly fewer events
Events, %ACT
(n=1050)ACTH
(n=1068)TCH
(n=1056)
Arthralgia 3.2 3.3 1.4*
Myalgia 5.2 5.2 1.8*
Fatigue 7.0 7.2 7.2
Hand-foot syndrome 1.9 1.9 0.0*
Stomatitis 3.5 2.9 1.4*
Diarrhoea 3.0 5.6 5.4
Nausea 5.9 5.7 4.8
Vomiting 6.2 6.7 3.5*
Irregular menses 27.0 24.3 26.5
Low incidence of Grade 3/4 non-haematological AEsacross treatment groups at 5 years of follow-up
Slamon et al 2011
BCIRG 006: Grade 3/4 haematological adverse events
*Statistically significantly fewer events Slamon et al 2011
Similar incidence of Grade 3/4 haematological AEsacross treatment groups at 5 years of follow-up
Events, %ACT
(n=1050)ACTH
(n=1068)TCH
(n=1056)
Neutropenia 63.3 71.5 65.9*
Leucopaenia 51.8 60.3 48.2*
Febrile neutropenia 9.3 10.9 9.6
Neutropaenic infection 11.1 11.9 11.2
Anaemia 2.4 3.1* 5.8
Thrombocytopenia 1.6 2.1* 6.1
BCIRG 006: cardiac deaths and congestive heart failure (independently adjudicated)
Slamon et al 2009; Slamon et al 2011
p=0.0121 p<0.001
Stable CHF rates at long-term follow-up
Events, nACT
(n=1050)ACTH
(n=1068)TCH
(n=1056)
Cardiac-related death
First analysis (23 months) 0 0 0
Second analysis (36 months) 0 0 0
Third analysis (65 months) 0 0 0
Cardiac left ventricular function (CHF) Grade 3/4
First analysis (23 months) 3 17 4
Second analysis (36 months) 4 20 4
Third analysis (65 months) 7 21 4
NCCTG N9831 and NSABP B-31: combined analysis
NCCTG N9831: Phase III trial of doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel with or without Herceptin® (trastuzumab) as adjuvant treatment
for women with HER2 overexpressing node-positive or high-risk node-negative breast cancer
NSABP B-31: A randomised trial comparing the safety and efficacy of adriamycin and cyclophosphamide followed by
paclitaxel (ACT) to that of adriamycin and cyclophosphamide followed by paclitaxel plus Herceptin®
(trastuzumab) (ACTH) in node-positive breast cancer patients who
have tumours that overexpress HER2
= AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4)
= T (paclitaxel 80 mg/m2/wk × 12)
= T (paclitaxel 175 mg/m2 q3w × 4 or 80 mg/m2 qw × 12)
= H (Herceptin® (trastuzumab) 4 mg/kg loading dose then 2 mg/kg qw × 52)
Combined analysis: study design
Perez et al 2011
Control group (n=2017): ACT
NCCTG N9831 Arm A (n=971)
NSABP B-31 Group 1 (n=1046)
Herceptin® (trastuzumab) group (n=2028): ACTH
NCCTG N9831 Arm C (n=973)
NSABP B-31 Group 2 (n=1055) T
H
ACT
T
H
ACT
AC
AC
Concurrent administration of Herceptin® (trastuzumab) with paclitaxel
Combined analysis: end points and analyses
• Primary– Disease-free survival
(DFS)• Local/regional/distant
recurrence• Contralateral breast
disease (including DCIS)• 2nd primary invasive
cancers• Death due to any cause
• Secondary– Overall survival (OS)– Time to distant
recurrence (TTDR)
1. Romond et al 2005; 2. Perez et al 2007; 3. Perez et al 2011
1st interim efficacyanalysis after
355 DFS events1
2nd interim efficacyanalysis after
619 DFS events2
3rd interim efficacyanalysis after
779 DFS events3
DCIS, ductal carcinoma in situ
Further analysis
• 102 women (5%) assigned to treatment arm did not receive trastuzumab because of cardiac symptoms or decrease in LV function. These patients were included in treatment arm in the ITT analysis.
• 413 women (20.4%) assigned to control arm received Trastuzumab after the first interim analysis reported positive findings in 2005. These patients were included in control arm in the ITT analysis.
Combined analysis: independent adjudication of cardiac events
Russell et al 2010AC, doxorubicin + cyclophosphamide; CHF, congestive heart failure; H, Herceptin® (trastuzumab); T, docetaxel.* Confirmed by ACREC Committee
Patients ACT(n=1755)
ACTH(n=1799)
Confirmed cardiacevents*, n (%)
8 (0.5) 36 (2.0)
Symptomatic CHF 7 (0.4) 34 (1.9)
Probable cardiac death 1 (0.1) 2 (0.1)
Hospitalised 5 (0.3) 11 (0.6)
Recovery 7 36
Incidence of symptomatic cardiac events with Herceptin® (trastuzumab)is very low at 2.0%, and most patients recover with treatment
NCCTG N9831: disease-free survival for sequential Herceptin® (trastuzumab)
*log-rank Perez et al 2011
ACTH
ACT71.8%
80.1%
Years fromrandomisation
Aliv
e a
nd
dis
eas
e-f
ree
(%
)
0
20
40
60
80
100
0 1 2 3 4 5 6735728
675643
624582
588530
539470
No.at risk
10971087
389330
Disease-free survival benefit observed with sequential treatment
n Events HR 95% CI p value*
1097 165 0.69 0.57−0.85 <0.001
1087 225
Years fromrandomisation
Aliv
e a
nd
dis
eas
e-f
ree
(%
)
0
20
40
60
80
100
0 1 2 3 4 5 6837830
790766
742707
691654
576519
No.at risk
949954
334288
NCCTG N9831: disease-free survival for sequential vs concurrent Herceptin® (trastuzumab)
*Significant p value pre-defined as p=0.00116 Perez et al 2011
Non-significant* disease-free survival benefit for concurrent treatment
84.4%
80.1%
ACTH
ACTH
n Events HR 95% CI p value*
949 139 0.77 0.53−1.11 0.022
954 174
Consistent disease-free survival benefit for Herceptin®
(trastuzumab) 1 year
1. Piccart-Gebhart et al 2005; 2. Smith et al 2007; 3.Gianni et al 20114. Slamon et al 2011; 5. Romond et al 2005; 6. Perez et al 2011
1 0.543387
HERA13 2 0.643401
4 0.763401
FavoursHerceptin® (trastuzumab)
Favoursobservation
10 2
BCIRG 0064
ACTHH vs ACTTCH vs ACT
50.75
0.643222
Study HRFollow-up (years)
N
Combined analysis5,6
NCCTG N9831/NSABP B-31)
2 0.483351
4 0.524045
HR (95% CI)
0.77
0.63
3401
3401
5 3222
10 2
Consistent overall survival benefit with adjuvant Herceptin® (trastuzumab)
1. Smith et al 2007; 2. Gianni et al 20113. Slamon et al 2011; 4. Perez et al 2011
2 0.66
4 0.85
4 4045 0.61
HR (95% CI)
Study HRFollow-up (years)
N
HERA1,2
BCIRG 0063
ACTHH vs ACTTCH vs ACT
Combined analysis4
NCCTG N9831/NSABP B-31)ACTHH
FavoursHerceptin® (trastuzumab)
Favoursobservation
Low incidence of cardiac events across studies
*Cardiac events: CHF or cardiac death1. Rastogi et al 2007; 2. Perez et al 2008
3. Slamon et al 2011; 4. Procter et al 2010
NCCTG N9831 ACTH (n=570)2
BCIRG 006 ACTH (n=1068)3
BCIRG 006 TCH (n=1056)3
NCCTG N9831 ACTH (n=710)2
HERA CTH (n=1682)4
NSABP B-31 ACTH (n=947)1
3.3%
2%
0.4%
2.8%
0.8%
Time (years)
Cu
mu
lati
ve in
cid
en
ce (
%)
3.8%
0
2
4
6
8
10
0 1 2 3 4 5
Cumulative incidence of cardiac events* with 1 yearof Herceptin® (trastuzumab)remains low with long-term follow-up
Conclusions
• Disease-free survival and overall survival benefits with Herceptin® (trastuzumab) are maintained at long-term follow-up– Herceptin® (trastuzumab) may be administered
either concurrently or sequentially with chemotherapy, offering physicians different options to suit individual patient needs
• Herceptin® (trastuzumab) is well tolerated with a consistent safety and tolerability profile– Cumulative incidence of cardiac events remains
low after long-term follow-up
Gianni et al 2011; Perez et al 2011; Procter et al 2010; Russell et al 2010; Slamon et al 2011
Herceptin® (trastuzumab) for 1 year is the standard of carefor patients with HER2-positive EBC
PHARE* Trial results of subset
analysis comparing 6 to 12
months of trastuzumab in
adjuvant early breast cancerXavier Pivot, Gilles Romieu, Marc Debled, Jean-Yves Pierga, Pierre Kerbrat,
Thomas Bachelot, Alain Lortholary, Marc Espié, Pierre Fumoleau, Daniel Serin,Jean-Philippe Jacquin, Christelle Jouannaud, Maria Rios, Sophie Abadie-Lacourtoisie,Nicole Tubiana-Mathieu, Laurent Cany, Stéphanie Catala, David Khayat,Iris Pauporté, Andrew Kramar
*lighthouse in French
Protocol of
Herceptin®
Adjuvant with
Reduced
Exposure
NOAH (MO16432): Study design
H, trastuzumab (8 mg/kg loading dose then 6 mg/kg); AT, doxorubicin (60 mg/m2), paclitaxel (150 mg/m2); T, paclitaxel (175 mg/m2)aA separate treatment group of HER2-negative patients received chemotherapy onlybHormone receptor-positive patients received adjuvant tamoxifen Gianni et al 2010
ATq3w x 3 cycles
Tq3w x 4 cycles
CMFq4w x 3 cycles
CMFq4w x 3 cycles
HER2-positive LABC(IHC 3+ or FISH-positive)
HER2-negative LABC(IHC 0/1+)a
ATq3w x 3 cycles
Tq3w x 4 cycles
Surgery followed by radiotherapyb
H + ATq3w x 3 cycles
H + T q3w x 4 cycles
H q3w x 4 cycles+ CMF q4w x 3 cycles
H continued q3wto week 52
(n=117) (n=118) (n=99)
19 crossed over to H
An international, open-label, Phase III study of neo-adjuvant−adjuvant Herceptin® (trastuzumab) in patients with
locally advanced or inflammatory HER2-positive breast cancer
NOAH: Inclusion criteria• Histologically proven locally advanced breast
cancer (T3N1/T4) or any T plus N2/N3, or any T plus involvement of ipsilateralsupraclavicular nodes
• HER2-positive disease was defined as IHC 3+ overexpression or HER2 amplification by FISH according to a central laboratory
– For the observational arm, HER2-negative disease was defined as IHC 0 or 1+ on the basis of local laboratory testing
• Mandatory hormone receptor assessment
• LVEF ≥55%Gianni et al 2010
NOAH: Endpoints
Primary endpoint
• Event-free survival (EFS) defined as:– Time from randomisation to disease recurrence or progression (local,
regional, distant or contralateral), or
– Death from any cause
Secondary endpoints
• Total pathological complete response in breast and axillary nodes (tpCR)
• Pathological complete response in breast tissue (bpCR)
• Overall clinical response rates (ORR)
• Overall survival (OS)
• Safety and tolerability, including cardiac safety
Gianni et al 2010
NOAH: Baseline characteristics
Gianni et al 2010
HER2-positive patients
Herceptin® (trastuzumab) + chemotherapy
(n=117)
Chemotherapy(n = 118)
Stage group, %
T4, non-inflammatory 42 43
Inflammatory disease 27 26
N2 or ipsilateral nodes 31 31
Hormone receptor status, %
ER- and/or PgR-positive 36 36
Both negative 64 64
Age group, %
<50 years 43 42
≥50 years 57 58
NOAH: EFS in the HER2-positive ITT
ITT, intent to treat Gianni et al 2010
With Herceptin® (trastuzumab)
Number at riskWith Herceptin®
(trastuzumab)Without Herceptin®
(trastuzumab)
Significant EFS benefit with the addition of Herceptin® (trastuzumab) to chemotherapy in HER2-positive patients
NOAH: EFS by subgroup in patients with HER2-positive disease
ER, oestrogen receptor; PR, progesterone receptor; cN, clinical nodal stage; bpCR, pathological complete response in breast tissue
HR (95% CI)
EFS benefit of Herceptin® (trastuzumab) is maintained across patient subgroups in HER2-positive patients
Gianni et al 2010
NOAH: Overall survival in the HER2-positive ITT population
ITT, intent to treat Gianni et al 2010
Trend towards overall survival benefit with the addition of Herceptin® (trastuzumab) to chemotherapy in HER2-positive patients
NOAH: pCR rates in the ITT population
ITT, intent to treatbpCR, pathological complete response in breast tissuetpCR, total pathological complete response (in breast and axillary nodes)* Absence of invasive tumour cells Gianni et al 2010
Significant improvement in pCR with addition of Herceptin® (trastuzumab) to chemotherapy in HER2-positive treatment groups
NOAH: Selected Grade 3/4 adverse events
H, Herceptin® (trastuzumab) Gianni et al 2010
HER2-positive HER2-negative
With H(n = 115)
Without H(n = 113)
Without H(n = 99)
n (%) n (%) n (%)
Febrile neutropenia 2 (2%) 2 (2%) 2 (2%)
Neutropenia 3 (3%) 5 (4%) 2 (2%)
Diarrhoea 1 (1%) 4 (4%) 1 (1%)
Stomatitis 1 (1%) 4 (4%) 3 (3%)
Infection 0 (0%) 0 (0%) 1 (1%)
Pneumonia 1 (1%) 0 (0%) 0 (0%)
Arthralgia 0 (0%) 3 (3%) 3 (3%)
Myalgia 1 (1%) 1 (1%) 1 (1%)
Peripheral neuropathy 1 (1%) 2 (2%) 0 (0%)
Low incidence of grade 3/4 adverse events with no difference between HER2-positive or negative patients
NOAH: LVEF during and after therapy
Gianni et al 2010
HER2-positive chemotherapyHER2-positive Herceptin®
(trastuzumab) + chemotherapy
20
40
60
80
LVEF
NOAH: Overview of safety and tolerability
• Herceptin® (trastuzumab) was well tolerated and adverse events were much the same in the three groups
• Safety and tolerability was consistent with the known profile of Herceptin® (trastuzumab)
• One patient in each arm had an adverse event that resulted in study drug discontinuation
• No increase in incidence of Grade 3 or 4 non-cardiac toxicities with the addition of Herceptin® (trastuzumab) to chemotherapy
• Low incidence of symptomatic cardiac dysfunction (1.7%), despite concurrent administration of Herceptin® (trastuzumab) with doxorubicin
Gianni et al 2010
NOAH: Conclusions
• Results from the NOAH study demonstrate the benefits of neo-adjuvant-adjuvant Herceptin®
(trastuzumab) as a treatment option for patients with HER2-positive LABC and with IBC– Neo-adjuvant Herceptin® (trastuzumab) with an
anthracycline- and taxane-containing chemotherapy significantly extends EFS in patients with HER2-positive disease
– The neo-adjuvant regimen with Herceptin® (trastuzumab) is well tolerated with acceptable cardiac safety
LABC, locally advanced breast cancerIBC, inflammatory breast cancerEFS, event-free survival Gianni et al 2010