HERCEPTIN Herceptin [trastuzumab] Foundation of care in women with HER2-positive breast cancer...
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HERCEPTIN
Herceptin [trastuzumab]Foundation of care in women with HER2-positive breast cancer Update
2010
Herceptin Small Tumor
Efficacy is consistent across tumor size and nodal status
Herceptin KIT MBC
Efficacy is consistent across tumor size and nodal status
Herceptin®(trastuzumab)
Foundation of care in women with HER2-positive breast cancer Update 2010
This document contains information outside of the indications of Herceptin
HER2: role in breast cancer
Human epidermal growth factor receptor 2 (HER2) is a transmembrane protein and part of the HER family of 4 growth factor receptors (HER1/EGFR to HER4)
Overexpression of HER2 and / or amplification of the HER2 gene occurs in up to 15% of breast cancers
HER2 positivity is associated with • aggressive disease
• a high risk of relapse
• poor survival
Marla 2008Slamon 1989Slamon 1987
Penault-Llorca 2005
HER2 = Important therapeutic target
Spector 2009
5 mechanisms of action
t +Action 1 + + +t t t tAction 2 Action 3 Action 4 Action 5
Herceptin inhibits proliferation and induces apoptosis of HER2+ tumor cells
Spector 2009
EBC: Early Breast CancerMBC: Metastatic Breast Cancer
Herceptin : Expertise in all stages of Breast Cancer
Rela
pse
HERA
NSABP-B31
NCCTG N9831
BCIRG 006
FinHer
PACS-04
AdjuvantSurg
ery
TECHNONOAH
GeparQuintoNeoAltto
NeoSphere
Neoadjuvant
EBC
1st line
HO648g
M77001
BCIRG 007
CHAT
TAnDEM
RHEA
2nd+ lines
GBG-26
EGF 104900
Numerous Phase II studies
MBC
Pro
gre
ssio
n
Why do we give neoadjuvant therapy to patients with HER2-positive breast cancer?
• Decrease primary tumor size• Surgical removal of previously
inoperable tumor1
• Increase chance of breast-conserving surgery2,3
• Assess chemoresponsiveness of tumor4-6
• Predict outcome by assessment of tumor response5,7
• Decrease residual cancer burden8
• Improve long-term outcome4,8
• Reduce micrometastases4
1. van der Hage et al. 2007; 2. Fisher et al. 19983. van der Hage et al. 2001; 4. Connolly and Stearns 2010
5. von Minckwitz et al. 2008; 6. Kaufmnann et al. 20077. von Minckwitz et al. 2010; 8. Symanns et al. 2007
Assessing response: pathological complete response as surrogate for survival (NSABP-B27)
• 2411 patients with primary operable breast cancer
• Primary endpoint: OS and DFS
• pCR was a significant predictor of OS, regardless of treatment (hazard ratio = 0.33; 95% CI: 0.23–0.47; P<0.0001)
Years after surgery7
Ove
rall
Surv
ival
(%) 100
40
pCR (n=410)
non-pCR (n=1889)
Bear et al. 2006
60
80
6543210
H + T q3w x 4 cycles
H q3w x 4 cycles+ CMF q4w x 3 cycles
H continued q3wto Week 52
Surgery followed by radiotherapy
NOAH: Study design
HER2-positive(IHC 3+ or FISH+)
HER2-negative(IHC 0/1+)
ATq3w x 3 cycles
Tq3w x 4 cycles
CMFq4w x 3 cycles
ATq3w x 3 cycles
Tq3w x 4 cycles
CMFq4w x 3 cycles
n=118 n=117 n=99
Surgery followed by radiotherapy
H + ATq3w x 3 cycles
Surgery followed by radiotherapy
Median follow-up = 3 years
H, trastuzumab (8 mg/kg loading dose then 6 mg/kg); AT, doxorubicin (60 mg/m2), paclitaxel (150 mg/m2); q3w, every 3 weeks; T, paclitaxel (175 mg/m2); q4w, every 4 weeksCMF: Cyclophosphamide (600mg/m2), Methotrexate (40mg/m2), Fluorouracil (600mg/m2) Gianni 2010
NOAH: Herceptin almost doubles pCR rates
Median follow-up = 3 yearspCR = pathological Complete Response
0
10
20
30
40
50
WithoutHerceptin
WithHerceptin
Pati
ents
wit
h p
CR
, %
p=0.0007
43%
n=117n=118
22%
43%
Gianni 2010
NOAH: Herceptin extends event-free survival
Median follow-up = 3 yearsa Unadjusted for stratification variablesCTx: chemotherapy
1.00
0.75
0.50
0.25
0.000 6 12 18 24 30 36 42
Pro
babili
ty, event-
free s
urv
ival
Months
56 71 0.59 0.38-0.90 0.013
CTxHerceptin + CTx
118
117
n3-year
EFS (%) HR 95% CI p valuea
51 36
Events
Gianni 2010
NOAH : Herceptin is well tolerated with acceptable cardiac safety
Arthralgia
Diarrhea
Febrile neutropenia
Infection
LVEF decline
Myalgia
Neuropathy peripheral
Neutropenia
Pneumonia
Stomatitis
WithoutHerceptin
n=113
3
4
2
0
0
1
2
4
0
4
WithHerceptin
n=115
0
1
2
0
2
1
1
3
1
1
Selected grade ¾adverse events (%)
Gianni 2010
TECHNO Trial : PCR after NeoAdjuvant Chemotherapy predicts survival
Geparquinto : pCR with Herceptin is statistically better than with lapatinib.
60%
50%
40%
30%
20%
10%
0
50.4%
EC + Doc + lapatinib
EC + Doc + Herceptin
P<0.05
35.2%
Untch M, et al. SABCS 2010;#S3-1
(no invasive/ non-invasive residual in breast & nodes )
NeoSphere : pCR
Gianni L, et al. SABCS 2010;#S3-2
60%
50%
40%
30%
20%
10%
0
45.8
Herceptin + Doecetaxel
Herceptin + Pertuzumab +
Docetaxel
29,0
16.8%
Herceptin + Pertuzumab
% R
esp
onse
24.0%
Pertuzumab+ Docetaxel
NeoAltto StudyPathological Complete Response
Baselga J, et al. SABCS 2010;#S3-3
60%
50%
40%
30%
20%
10%
0
29.5%
lapatinib Herceptin
24.7
51.3%
Herceptin + lapatinib
% R
esp
onse
Herceptin : Expertise in all stages of Breast Cancer
Rela
pse
HERA
NSABP-B31
NCCTG N9831
BCIRG 006
FinHer
PACS-04
AdjuvantSurg
ery
NOAH
MDACC
GeparQuattro
Numerous Phase II studies
Neoadjuvant
EBC
1st line
HO648g
M77001
BCIRG 007
CHAT
TAnDEM
RHEA
2nd+ lines
GBG-26
EGF 104900
Numerous Phase II studies
MBC
Pro
gre
ssio
n
EBC: Early Breast CancerMBC: Metastatic Breast Cancer
Key trastuzumab studies in HER2-positive EBC
1. Gianni L, et al. 2011; 2. Slamon D, et al. 2009; 3. Perez EA, et al. 2011
Study N Treatment arms Follow-up(yrs)
HERA1 5102CT* ± RT observationCT* ± RT trastuzumab 1 year CT* ± RT trastuzumab 2 years
4
BCIRG0062 3222
AC docetaxelAC docetaxel+trastuzumab trastuzumabDocetaxel+carboplatin+trastuzumab trastuzumab
5
NCCTG N98313 2614
AC paclitaxelAC paclitaxel trastuzumabAC paclitaxel+trastuzumab trastuzumab
4
NSABP B-313 2043 AC paclitaxel
AC paclitaxel+trastuzumab trastuzumab 4
*Chemotherapy selected from a list of approved regimens consisting of ≥4 cycles
Extensive clinical programme involving >12,000 patients
Conclusions
• HERA
• Joint Analysis
• BCIRG-006
Pivotal adjuvant trials all now published
HERA (BO16348)
HERceptin Adjuvant (HERA): A randomised three-arm multicentre comparison of 1 year and 2 years of trastuzumab versus no trastuzumab in
women with HER2-positive primary breast cancer who have completed adjuvant chemotherapy
Surgery + (neo)adjuvant CTx ± RT
Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55%
2 years Herceptin8 mg/kg 6 mg/kg3-weekly schedule
1 year Herceptin8 mg/kg 6 mg/kg3-weekly schedule
Women with locally determined HER2-positive invasive early breast cancer
HERA study design
After ASCO 2005, option of crossover
to Herceptin
Randomisation
Observation
≥
CTx: chemotherapyRT: radiotherapy Gianni 2009
HERA: Key inclusion criteria
• Histologically confirmed, completely excised, invasive breast cancer
• Centrally confirmed HER2 overexpression (IHC 3+) or amplification (FISH+)
• Node-positive or (sentinel) node-negative with >T1c
• Completed >4 cycles of approved adjuvant or neoadjuvant CT
• Baseline LVEF >55% (ECHO or MUGA scan) after completion of (neo)adjuvant CT and RT
• Known hormone receptor status
Piccart-Gebhart MJ, et al. 2005
HERA: Endpoints
Primary endpoint
• DFS
• Trastuzumab 1 year vs observation
• Trastuzumab 2 years vs observation
Secondary endpoints
• OS, TTR, TTDR, cardiac safety
• Trastuzumab 1 year vs observation
• Trastuzumab 2 years vs observation
• Trastuzumab 1 year vs trastuzumab 2 years
Gianni L, et al. 2011; Smith I, et al. 2007; Piccart-Gebhart MJ, et al. 2005
HERA: Cardiac safety endpoints
• Assessment of specific cardiac events• Severe CHF
• Symptomatic CHF
• Significant LVEF drop
• Confirmed significant LVEF drop
• Three interim analyses of cardiac endpoints after n=300, n=600 and n=900 patients treated/followed for 6 months
• Stopping guideline: ≥4% absolute increase in pre-defined cardiac events
Suter TM, et al. 2007
HERA: Study timeline
2005 2009 2010 2011
DFS data:• ASCO• NEJM1
*Event-driven analysis: 725 OS events required1. Piccart-Gebhart MJ, et al. 2005; 2. Smith I, et al. 2007;3. Gianni L, et al. 2011
2008
1st interimanalysis(n=475
DFS events)
2-year follow-up(n=539
DFS events)
2006
OS data:ASCO
4-year follow-up(n=827
DFS events)
4-year data:St Gallen
4-year data:Lancet Oncol3
OS data:Lancet2
2007 Q3/4 2012
Anticipatedrelease of
2-year data*
HERA: Patient characteristics (1)
Gianni L, et al. 2011
Patients, %
Observation(n=1698)
Trastuzumab 1 year(n=1703)
Age, years
<35 7 8
35−49 44 44
50−59 32 32
≥60 16 16
Prior (neo)adjuvant CT
No anthracyclines 6 6
Anthracyclines, no taxanes 68 68
Anthracyclines + taxanes 26 26
HERA: Patient characteristics (2)
*Status at randomisation
Patients, %
Observation(n=1698)
Trastuzumab 1 year(n=1703)
Menopausal status*
Premenopausal 14 15
Postmenopausal 45 45
Uncertain 41 40
Hormone receptor status
Negative 50 50
Positive 50 50
Nodal status
Neoadjuvant CT 10 11
Negative 33 32
13 29 29
≥4 28 28
Gianni L, et al. 2011
Interim analysis and IDMC recommendations
As specified in the protocol, an interim analysis of 1-year vs 2-year Herceptin was performed in Q3 2008
The IDMC reviewed the interim analysis on 20 October 2008 and recommended that:
• no information on the 1-year vs 2-year Herceptin be released
• updated information on the 1-year Herceptin vs observation be presented and published
IDMC: Independent Data Monitoring Committee Gianni 2009
Surgery + (neo)adjuvant CTx ± RT
Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55%
2 years Herceptin
8 mg/kg 6 mg/kg3-weekly schedule
1 year Herceptin
8 mg/kg 6 mg/kg3-weekly schedule
Women with locally determined HER2-positive invasive early breast cancer
HERA study design
After ASCO 2005, option of crossover
to Herceptin
Randomisation
Observation
CTx: chemotherapyRT: radiotherapy Gianni 2009
Sustained DFS Benefit
1414 1297
854 712
1352 1240
1280 1180
1020 992
1703 1698
1619 1564
1552 1440
1485 1363
No. at risk
100
80
60
40
20
0
0 6 12 18 24 30 4836 42
Months from randomisation
Events
369458
4-yearDFS
78.672.2
HR
0.76
1-year Herceptin
Observation+6.4%
Pati
ents
(%
)
95%Cl
0.66, 0.87
p value
<0.0001
+6.3%+8.4%
p<0.0001p<0.0001 p<0.0001
Gianni 2009Piccart 2005Smith 2007
HERA: DFS at all timepoints
1 year1
Medianfollow-up
2 years2
4 years3
Number of DFS events Trastuzumab
vs observation
127 vs 220P<0.0001
218 vs 321P<0.0001
369 vs 458P<0.0001
0 1 2Favourstrastuzumab
Favours notrastuzumab
HR (95% CI)
DFS benefit
1. Piccart-Gebhart MJ, et al. 2005; 2. Smith I, et al. 2007; 3. Gianni L, et al. 2011
Consistent DFS benefit for trastuzumab vs observation
HERA: Exploratory analysisof DFS by subgroup (1)
Smith I, et al. 2007
Consistent DFS benefit for trastuzumab across subgroups
Subgroup (number of patients)
Nodal status
Number of eventstrastuzumab vs
observationHR (95% CI)
Age at randomisation<35 years (253) 19 vs 31 0.57 (0.32‒1.01)35‒49 years (1508) 89 vs 150 0.54 (0.42‒0.70)
50‒59 years (1096) 71 vs 97 0.71 (0.52‒0.97)
≥60 years (544) 39 vs 43 0.91 (0.59‒1.41)
Menopausal status at randomisationPremenopausal (491) 43 vs 49 0.80 (0.53‒1.21)
Uncertain (1373) 70 vs 135 0.48 (0.36‒0.64)
Postmenopausal (1535) 105 vs 137 0.75 (0.58‒0.97)
Not assessed (372) 39 vs 50 0.66 (0.43‒1.00)
Negative (1099) 34 vs 58 0.59 (0.39‒0.91)
1‒3 positive nodes (976) 50 vs 80 0.61 (0.43‒0.87)≥4 positive nodes (953) 95 vs 132 0.64 (0.49‒0.83)
All patients (3401) 218 vs 321 0.64 (0.54‒0.76)
0.0 0.5 1.0 1.5HR
HERA: Exploratory analysisof DFS by subgroup (2)
Smith I, et al. 2007
Consistent DFS benefit for trastuzumab across subgroups
Subgroup (number of patients)
Pathological tumour size
Hormone receptor status
Previous radiotherapy
Type of (neo)adjuvant chemo
Number of eventstrastuzumab vs
observationHR (95% CI)
Any (neoadjuvant chemo) (372) 39 vs 50 0.66 (0.43‒1.00)0‒2 cm (1351) 61 vs 95 0.65 (0.47‒0.90)>2‒5 cm (1482) 97 vs 150 0.55 (0.43‒0.71)>5 cm (171) 20 vs 25 1.14 (0.63‒2.06)
ER-negative/PgR-negative (1627) 126 vs 190 0.63 (0.50‒0.78)ER-negative/PgR-positive (172) 12 vs 12 0.77 (0.34‒1.74)ER-positive/PgR-negative (460) 26 vs 39 0.82 (0.50‒1.34)ER-positive/PgR-positive (984) 46 vs 61 0.63 (0.43‒0.93)
Yes (2606) 183 vs 265 0.64 (0.53‒0.77)No (795) 35 vs 56 0.64 (0.42‒0.98)
No anthracyclines (202) 12 vs 15 0.76 (0.35‒1.62)Anthracyclines, no taxanes (2310) 132 vs 221 0.57 (0.46‒0.71)Anthracyclines and taxanes (889) 74 vs 85 0.80 (0.59‒1.10)
All patients (3401) 218 vs 321 0.64 (0.54‒0.76)
0.0 0.5 1.0 1.5
HR
0.6
0.5
0.4
0.3
0.2
0.0
0
1698 1557 1359 1040 722 432 194
0.1
Switched totrastuzumab
No.at risk
Pro
bab
ilit
y o
f cro
ssover
to t
rastu
zum
ab
885/1354 eligible patients (65%) crossed over to
trastuzumab
HERA: Patient crossoverto trastuzumab
6 12 18 24 30 36 42 48
1965
Time from randomisation (months)
Gianni L, et al. 2011
Proportion of patients crossing over increased over time
HERA: DFS at 4 years, censored for crossover
100
80
60
40
20
00 6 12 18 24 30 4836 42
Months from randomisation
4-yearDFS
78.671.7
HR
0.69
95% CI
0.59–0.79
P value
<0.0001
Trastuzumab 1 year
Observation*6.9%
17031698
16191557
15521364
14851089
1414836
1352620
854234
1280448
1020324
No. at risk
Alive a
nd
dis
ease f
ree (
%)
*Excludes data from patients randomised to observation who crossed over to trastuzumab (n=885)Gianni L, et al. 2011
Censored analysis reinforces long-term DFS benefits
0 6 12 18 24 30 4836 42Months from randomisation
4-yearDFS
89.381.5
HR
0.53
95% CI
0.44–0.65
P value
<0.0001
7.8%
Trastuzumab 1 year
Observation*
100
80
60
40
20
0
17031698
16601635
16401524
16151287
15771047
1524827
953331
1447636
1149479
No. at risk
HERA: OS at 4 years, censoredfor crossover
Alive (
%)
Censored analysis suggests OS benefit of trastuzumab for 1 year
*Excludes data from patients randomised to observation who crossed over to trastuzumab (n=885)Gianni L, et al. 2011
HERA: Impact of crossover on DFS
Gianni L, et al. 2009
Improvement in DFS even for late introduction of trastuzumab
100
80
60
40
20
0
0
Alive a
nd
dis
ease f
ree (
%)
6 12 18 24 30 36 42 48Months from randomisation
885 885 884 878 870 851 822 690 480
Selective crossover to trastuzumab
469 468 455 438 408 388 358 302 232
No crossover
No. at risk
HERA: Adverse events and cardiac endpoints
*Crossover patients were censored from the date of starting trastuzumab; †Not including cardiac death‡20 New York Heart Association II and 13 New York Heart Association III and IV§ Asymptomatic or mildly symptomatic
Adverse event, n (%)Observation*
(n=1719)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 adverse events 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)
Trastuzumab discontinued due tocardiac problems
87 (5)
Any type of cardiac endpoint 14 (1) 75 (5)
Gianni L, et al. 2011
Low incidence of cardiac adverse events with trastuzumab
HERA: Adverse event profilein crossover patients
*After 15 May 2005; †After crossover to trastuzumab; ‡Myocardial infarction and pulmonary embolism § Haemorrhagic stroke; **Not including cardiac death; ††Symptomatic or mildly symptomatic‡‡For 3 patients, LVEF drop happened soon after the release of trial results
Adverse event, n (%)No selective
crossover* (n=469)
Selective crossover†
(n=865)
Patients with ≥1 Grade 3/4 AE 19 (4) 80 (9)
Patients with ≥1 SAE 19 (4) 79 (9)
Fatal adverse events 2‡ (0) 1§ (0)
Treatment withdrawals 103 (12)
Cardiac endpoints
Cardiac death 0 0
Symptomatic CHF (II, III and IV) ** 1 (0) 9 (1)
Confirmed significant LVEF drop†† 5‡‡ (1) 26 (3)
Trastuzumab discontinued due to cardiac problems
43 (5)
Any type of cardiac endpoint 5 (1) 26 (3)
Gianni L, et al. 2011
Crossover to trastuzumab does not affect tolerability
HERA: Risk of cardiac death, or severe or symptomatic CHF
Procter M, et al. 2010
Low incidence of cardiac events at long-term follow-up
0 6 12 18 24 30 36 42 48
0.05
0.10
0.15
Pro
bab
ilit
y o
f a c
ard
iac e
ven
t
Time (months)
ObservationTrastuzumab for 1 year
0
NCCTG N9831 and NSABP B-31
NCCTG N9831: Phase III trial of doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel with or without 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 trastuzumab (ACTH) in node-positive breast cancer patients who
have tumours that overexpress HER2
NCCTG N9831: Study design
Romond EH, et al. 2005
HER2-positiveEBC
N=2614
RANDOMISATION
AC (q3w x 4)
AC (q3w x 4)
AC (q3w x 4)
Paclitaxel(qw x 12)
Paclitaxel(qw x 12)
Trastuzumab(qw x 52)
Paclitaxel (qw x 12) + trastuzumab (qw x 52)
Arm A
Arm B
Arm C
Note: Sequential arm (B) was excluded from the joint analysis with NSABP B-31
n=819
n=981
n=814
AC = doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4; Paclitaxel 80 mg/m2/wk × 12)Trastuzumab 4 mg/kg loading dose then 2 mg/kg qw × 52
NSABP B-31: Study design
Romond EH, et al. 2005
HER2-positiveEBC
N=2043
RANDOMISATION
AC (q3w x 4)
AC (q3w x 4)
Paclitaxel(q3w x 4 or
qw x 12)
Paclitaxel(q3w x 4 or qw x 12) + trastuzumab (qw x 52)
Group 1
Group 2
n=1024
n=1019
AC = doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4Paclitaxel 175 mg/m2 q3w × 4 or 80 mg/m2 qw × 12Trastuzumab 4 mg/kg loading dose then 2 mg/kg qw × 52
Combined analysis: Rationale
• Treatment arms broadly comparable• 52 weeks of trastuzumab added to anthracycline → paclitaxel
• Trastuzumab administered concurrently with paclitaxel for 12 weeks, then 40 weeks alone
• RT or hormonal therapy initiated after completionof 12-week regimen of trastuzumab + paclitaxel
• Joint efficacy analysis• Primary endpoint: DFS
• Secondary endpoint: OS
Perez EA, et al. 2007
= 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 (trastuzumab 4 mg/kg loading dose then 2 mg/kg qw × 52)
Combined analysis: Study design
Perez EA, et al. 2011
Control group (n=2017): ACT
NCCTG N9831 Arm A (n=971)
NSABP B-31 Group 1 (n=1046)
Trastuzumab group (n=2028): ACTH
NCCTG N9831 Arm C (n=973)
NSABP B-31 Group 2 (n=1055) TH
ACT
TH
ACT
AC
AC
Concurrent administration of trastuzumab with paclitaxel
Combined analysis: Key inclusion criteria
• Resected invasive HER2-positive breast cancer• NCCTG N9831: Node-positive; amended to allow high-risk
node-negative disease
• >1.0 cm if ER-negative or >2.0 cm if ER-positive
• NSABP B-31: Node-positive
• Adequate haematological, hepatic and renal function
• No significant sensory or motor neuropathy
• No significant past or active cardiac disease
• LVEF ≥ radiology facility’s lower limit of normal
Perez EA, et al. 2011
Combined analysis: Endpoints and analyses
• Primary• DFS
• Local/regional/distant recurrence
• Contralateral breast disease (including DCIS)
• 2nd primary invasive cancers
• Death due to any cause
• Secondary• OS
• TTDR
1. Romond EH, et al. 2005; 2. Perez EA, et al. 2007; 3. Perez EA, et al. 2011
1st interim efficacyanalysis after
355 DFS events1
2nd interim efficacyanalysis after
619 DFS events2
3rd interim efficacyanalysis after
779 DFS events3
NCCTG N9831 NSABP B-31
Patients, %ACT
n=971ACTHn=973
ACTn=1046
ACTHn=1055
Age, years <40
40495059≥6069
16.833.433.816.1
15.433.831.918.9
16.333.633.916.3
16.334.832.516.4
Tumour size, cm≤2.0 2.15.0≥5.0Not stated
40.452.47.10.1
38.053.68.40
40.350.47.61.7
38.050.110.61.3
Nodal involvement01349≥10
15.447.024.313.3
13.748.924.712.7
057.529.113.5
057.928.613.5
Tumour grade123Not stated
27.471.41.2
28.070.31.6
32.565.32.2
29.668.61.8
ER+ PgR+
51.439.4
49.737.9
52.340.3
52.038.9
Combined analysis: Patient characteristics (1)
Perez EA, et al. 2011
Combined analysis: Patient characteristics (2)
Perez EA, et al. 2011
NCCTG N9831 NSABP B-31
Patients, %ACT
n=971ACTHn=973
ACTn=1046
ACTHn=1055
Extent of surgeryMastectomyBreast conserving
60.539.4
62.038.0
60.038.9
60.738.7
PaclitaxelWeeklyEvery 3 weeks
100.00.0
100.00.0
16.183.9
16.183.9
RT Yes No Unknown
65.025.39.7
67.326.36.4
76.524.50.0
76.924.10.0
Hormonal therapy (First) Yes No Unknown
51.347.51.2
51.048.30.7
55.944.10.0
56.044.00.0
Combined analysis: DFS at 4 years of follow-up
Follow-up (years)
Alive a
nd
dis
ease-f
ree (
%)
3957021132188149589113001952 No.
at risk17561652
Stratified HR at 4 years = 0.52 (95% CI: 0.45‒0.60); P<0.001Factors: nodes, hormone receptor status, paclitaxel schedule, study
73.7%
86.8%
79.0%
85.7%
92.4%88.0%
ACT
ACTH
0
20
40
60
80
100
0 1 2 3 4 5Perez EA, et al. 2011
Significant DFS benefit of trastuzumab at all timepoints
Alive (
%)
Stratified HR at 4 years = 0.61 (95% CI: 0.50‒0.75); P<0.001Factors: nodes, hormone receptor status, paclitaxel schedule, study
85.6%96.1%
92.7%
93.0%95.1%97.7%
Combined analysis: OS at 4 years of follow-up
ACT
ACTH
Perez EA, et al. 2011 Follow-up (years)
0
20
40
60
80
100
0 1 2 3 4 5
5038861375196055497614201991 No.
at risk18751816
Significant OS benefit of trastuzumab at long-term follow-up
Combined analysis: Independent adjudication of cardiac events
Russell SD, et al. 2010
Confirmed cardiacevents, n (%)
ACT(n=1755)
ACTH(n=1799)
Total events 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 trastuzumabis very low at 2.0%, and most patients recover with treatment
NCCTG N9831: DFS with sequential trastuzumab
0
20
40
60
80
100
0 1 2 3 4Years from
randomisation735728
675643
624581
586529
95% CI
0.55−0.82
AC→T→H
AC→T
n
1097
1087
Events
164
222
5513447
71.9%79.7%
80.1%85.2%
No.at risk
Perez EA, et al. 2009
Alive a
nd
dis
ease-f
ree (
%)
DFS benefit observed with sequential treatment
HR
0.67
P value
0.0005
10971087
NCCTG N9831: DFS for sequential vs concurrent trastuzumab
0
20
40
60
80
100
Alive a
nd
dis
ease-f
ree (
%)
0 1 2 3 4
Years fromrandomisation
837830
788766
740705
676641
5456418
No.at risk
*Significant P value pre-defined as P=0.00116
84.2%89.1%
79.8%85.7%
Perez EA, et al. 2009
Non-significant* DFS benefit for concurrent treatment
AC→TH
AC→T→H
95% CI
0.60−0.94
n
949
954
Events
138
174
HR
0.75
P value*
0.0190
949954
NCCTG N9831 and NSABP B31: Conclusions
• In this analysis of more than 4000 patients, 1 year of trastuzumab provided a consistent long-term survival advantage after 4 years of follow-up• 48% relative reduction in DFS event rate
• 39% relative reduction in death rate
• Trastuzumab was associated with a low incidence of cardiac events, with no evidence of an increase over time
Trastuzumab for 1 year provides long-term benefits during concurrent or sequential administration with paclitaxel
Perez EA, et al. 2011
BCIRG 006
Multicentre Phase III randomised trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC→T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) and with docetaxel, carboplatin and trastuzumab (TCH) in the treatment of node-positive
and high-risk node-negative adjuvant patients
6 x T + C
AC→T
AC→TH
TCH
1 year of 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 trastuzumab
BCIRG 006: Study design
4 x AC 4 x T
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: 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 D, et al. 2011
→
BCIRG 006: Key inclusion criteria
• Histologically confirmed breast cancer
• Definitive surgical treatment within 60 days of registration
• Stage T 1‒3, N0 or N1, M0
• 1/6 resected nodes positive for tumour
or
• 0/6 resected nodes positive for tumour and negative sentinel node biopsy AND at least one of the following risk factors
• Tumour size >2 cm
• ER and PgR negative
• Histologic and/or nuclear grade 23
• Age <35 years
• HER2-positive by FISH
• Age 1870 years
• Karnofsky performance status >80%
• No prior systemic therapy or RT for breast cancer
Slamon D, et al. 2011
BCIRG 006: Endpoints and analyses
• Primary
• DFS
• Local/regional/distant recurrence
• 2nd primary invasivecancers
• Death due to any cause
• Secondary
• OS
• Safety
• Pathological and molecular markers for predicting efficacy
1. Slamon D, et al. 2005; 2. Slamon D, et al. 2006; 3. Slamon D, 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
BCIRG 006: Patient characteristics (1)
Slamon D, et al. 2011
Patients, % AC→T(n=1073)
AC→TH(n=1074)
TCH(n=1075)
Age <50 years 52 52 54
Karnofsky performance status of 100 80 79 80
Mastectomy 59 63 60
RT 67 67 68
Hormonal therapy 49 50 50
BCIRG 006: Patient characteristics (2)
Patients, % AC→T(n=1073)
AC→TH(n=1074)
TCH(n=1075)
Number of positive nodes
0 29 28 29
13 38 38 39
410 22 24 23
>10 11 9 10
Tumour size, cm
≤2 41 38 40
>2 and ≤5 53 55 53
>5 6 7 6
ER+ and/or PgR+ 54 54 54
Slamon D, et al. 2011
BCIRG 006: Patient crossover
• After the trastuzumab efficacy results were announced in April 2005, patients were permitted to cross over to receive trastuzumab
• 23/1073 patients (2.1%) randomised to AC→T crossed over to receive trastuzumab
• 1050/1073 patients (97.9%) remained in the AC→T arm for subsequent DFS, OS and safety comparisons
Slamon D, et al. 2011
DFS: Median follow-up 5,4 years
1
0.9
0.8
0.7
0.6
0.5
0.4
0 12 24 36 48 60 72Time (months)
% a
live a
nd
Dis
ease-F
ree
AC-T100
AC-T100Herceptin
T75CbHerceptin
1073
1074
1075
Patients
257
185
214
Events
1 (reference)
0.64 (0.53 - 0.78)
0.75 (0.63 - 0.90)
HR (95% C.I.)
84%
81%
75%
<0.001
0.04
p
BCIRG006
Slamon 2009A: doxorubicin, 60 mg/m2; C: cyclophosphamide, 600 mg/m2; T100: docetaxel, 100 mg/m2 ; T75: docetaxel, 75 mg/m2 ; Cb: carboplatin AUC 6
Significant DFS benefit with trastuzumab in both regimens
BCIRG 006: OS at 5 years of follow-up
20
40
60
80
100
0 1 2 3 4 650
Alive (
%)
Years from randomisation
Slamon D, et al. 2011
ACTHTCHACT
ACTHTCH ACT
n107410751073
Events94113141
HR0.630.77
1 (ref)
95% CI0.48‒0.810.60‒0.99
−
P value<0.0010.038
−
Significant OS benefit with trastuzumab at long-term follow-up
BCIRG 006: Summary of efficacy endpoints at 5 year follow-up
185 vs 257 0.64 (0.530.78)
No. eventsTrastuzumab
vs observation
HR (95% CI)
214 vs 257 0.75 (0.630.90)
0.0 0.5 1.0 1.5
DFS
OS
AC→TH
TCH
AC→TH
TCH
94 vs 141 0.63 (0.480.81)
113 vs 141 0.77 (0.600.99)
HR (95% CI)
Slamon D, et al. 2011
Favours trastuzumab
Favours observation
Consistent efficacy benefit of trastuzumab withanthracycline-based and non-anthracycline-based regimens
BCIRG 006: Grade 3/4 non-haematological adverse events
*Statistically significantly fewer events
Events, % AC→Tn=1050
AC→THn=1068
TCHn=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
Slamon D, et al. 2011
Low incidence of Grade 3/4 non-haematological AEs across treatment groups at 5 years of follow-up
BCIRG 006: Grade 3/4 haematological adverse events
Events, % AC→Tn=1050
AC→THn=1068
TCHn=1056
Neutropenia 63.3 71.5 65.9*
Leucopenia 51.8 60.3 48.2*
Febrile neutropenia 9.3 10.9 9.6
Neutropenic infection 11.1 11.9 11.2
Anaemia 2.4 3.1* 5.8
Thrombocytopenia 1.6 2.1* 6.1
Slamon D, et al. 2011
*Statistically significantly fewer events
Similar incidence of Grade 3/4 haematological AEsacross treatment groups at 5 years of follow-up
BCIRG 006: Cardiac deaths and CHF (independently adjudicated)
Slamon D, et al. 2009; Slamon D, et al. 2011
Stable CHF rates at long-term follow-up
Events, n
AC→Tn=1050
AC→THn=1068
TCHn=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
P=0.0121 P<0.001
BCIRG 006: Mean LVEF (all observations)
Slamon D, et al. 2011
LVEF >50% maintained long term in both Herceptin armswith good recovery of function in TCH arm
59
62
63
65
66
0 604858
2412
64
61
60
Time (months)
LVEF p
oin
ts (
%)
AC→T(n=1014)
AC→TH(n=1042)
TCH(n=1030)
36
BCIRG 006: Conclusions
• Trastuzumab for 1 year provides significant clinical benefits which are maintained over 5 years of follow-up
• Significant DFS and OS benefits maintained over the long-term
• Concurrent administration of trastuzumab with docetaxel was effective and well tolerated
• Consistent benefit of trastuzumab when used with either anthracycline-based or non-anthracycline-based chemotherapy
• Both combinations were well tolerated
• Lower incidence of adverse events (including cardiovascular) with non-anthracycline-based chemotherapy
Slamon D, et al. 2011
Cardiac safety profile with trastuzumab is maintained with long-term follow-up
Time (years)
10
0
8
6
4
2
0
1 2 3 4 5Rastogi 2007
Perez 2008Slamon 2009Gianni 2009
Procter 2010
Cum
ula
tive inci
dence
Congest
ive h
eart
failu
re
(Gr3
/4)
and c
ard
iac
death
(%
) Anthracycline-containing
Anthracycline-free
B-31 AC THerceptin (n=947)
N9831 AC THerceptin (n=570)
BCIRG 006 AC THerceptin (n=1068)
N9831 AC T Herceptin (n=710)
HERA CTx Herceptin (n=1682)
BCIRG 006 TCbHerceptin (n=1056)
3.8%3.3%2.8%
2%
0.8%0.4%
A: doxorubicin, 60 mg/m2; C: cyclophosphamide, 600 mg/m2; T100: docetaxel, 100 mg/m2 ; T75: docetaxel, 75 mg/m2 ; Cb: carboplatin AUC 6
1-year Herceptin increasesDisease Free Survival
N9831
HERA
N9831/B31
BCIRG006
2184
3401
3401
3387
3968
2147
DFS benefit
0.67
0.76
0.64
0.54
0.48
0.64
0.0005
<0.0001
<0.0001
<0.0001
<0.00001
<0.001
Median
Follow-up
(years)
5.5
4
2
1
2.9
5.41
HR
2Favours
no Herceptin
Trials n
AC T H
CTx H
AC TH H
AC TH H
Treatment P
0 Favours
Herceptin
Risk of Relapse is reduced by up to 52%Perez 2008; Gianni 2009; Smith 2007;
Piccart 2005; Perez 2007; Slamon 2009
1-year Herceptin extends OverallSurvival in Early Breast Cancer
N9831
HERA
N9831/B31
BCIRG006
2184
3401
3401
3968
2147
OS benefit
0.281
0.1087
0.0115
0.0007
<0.001
Median
Follow-up
(years)
5.5
4
2
2.9
5.4
1
HR
Risk of Death is reduced by up to 37%
Trials n
AC T H
CTx H
AC TH H
AC TH H
Treatment P
2Favours
no Herceptin
0.86
0.85
0.66
0.65
0.63
Confounded by crossover
Confounded by crossover
0 Favours
Herceptin
Perez 2009 ; Gianni 2009; Smith 2007;Piccart 2005; Perez 2007; Slamon 2009
Adjuvant Herceptin is changing the epidemiology of the disease
20.000
18.000
16.000
14.000
12.000
10.000
8.000
6.000
4.000
2.000
0
2000 2005 2010 2015 2020
27.727
Num
ber
of
pati
ents
wit
h
MB
C in 5
EU
countr
ies
Projected MBC patients
Impact of Herceptin
Weisgerber-Kriegl 2008
Herceptin therapy is unilaterally recommended for HER2-positive disease
NCCNconsider Herceptin for
Node- & 0.6-1cmHormone receptor-
ESMOuse Herceptin for
St Gallenuse Herceptin for
≥ 1cm
OR
Node+
NCCN 2010; Kataja 2009; Goldhirsch 2009
≥ 1cm
OR
Node+
use Herceptin for
Node- & 0.6-1cmHormone receptor-
(if grade>1 & unfavorable features)
>1cm
Node+
OR
OR
Conclusions
• 1-year adjuvant Herceptin extends Overall Survival
• Herceptin delivers high cure rates for womenwith HER2-positive early breast cancer
• Herceptin is well tolerated with acceptable cardiac safety
• Herceptin is the foundation of care in women with HER2-positive early breast cancer
De Vita 2006Smith 2007
Romond 2005Marty 2005
Spector 2009Procter 2010
Herceptin : Expertise in all stages of Breast Cancer
Rela
pse
HERA
NSABP-B31
NCCTG N9831
BCIRG 006
FinHer
PACS-04
AdjuvantSurg
ery
NOAH
MDACC
GeparQuattro
Numerous Phase II studies
Neoadjuvant
EBC
1st line
HO648g
M77001
BCIRG 007
CHAT
TAnDEM
RHEA
2nd+ lines
GBG-26
EGF 104900
Numerous Phase II studies
MBC
Pro
gre
ssio
n
EBC: Early Breast CancerMBC: Metastatic Breast Cancer
Study design
Anthracycline+
Cyclophosphamide
n=138
Anthracycline+
Cyclophosphamide+
Herceptin
n=143
Paclitaxel175mg/m2
n=96
Paclitaxel175mg/m2
+Herceptin
2 mg/kg/week(4mg/kg loading dose)
n=92
HER2-positive MBC
(IHC 2+ or IHC 3+)
No prior chemotherapy for
MBC
H0648g
Slamon 2001
Study design
a Additional cycles of docetaxel administered at investigator’s discretion. Patients progressing on docetaxel alone could cross over to receive Herceptin
b 2 patients did not receive study medicationFISH, fluorescence in situ hybridisation; LVEF, left ventricular ejection fraction
Docetaxel 100 mg/m2
q3w x 6 cycles +Herceptin 4 mg/kg loading dose,
then 2 mg/kg qw until disease progression
n=92b
HER2-positive MBC (IHC 3+ and / or FISH+)
No prior chemotherapy for MBCBaseline LVEF>50%
n=188
Docetaxel 100 mg/m2
q3w x 6 cycles
n=94a
M77001
Marty 2005
Study design
Anastrozole1mg/day
+Herceptin
2 mg/kg/week(4mg/kg loading
dose)n=103
Postmenopaused women
with HER2-positive
(ICH 3+ or FISH+)
& hormone receptor-positive
(ERpositive and/or PgR
positive) MBC
Anastrozole1mg/day
n=104
Kaufman 2009
TAnDEM
1st line Herceptin increasesProgression Free Survival
Month
s
14
12
10
8
6
4
2
0
11.7 months(TTP)
6.9 months(TTP)
4.8 months(PFS)+5.6 months
p=0.0001
+3.9 monthsp<0.001 +2.4 months
p=0.0016
pacl
itaxe
lpa
clita
xel
+
Her
cept
in
doce
taxe
ldo
ceta
xel
+
Her
cept
in
anas
troz
ole
anas
troz
ole
+ H
erce
ptin
n=188H0648g
n=186M77001
n=207TAnDEM
Slamon 2001Marty 2005
Kaufman 2009
1st line Herceptin extends Overall Survival
* Subgroup analysis limited to 188 patients (total population = 469)** 70% of patients in the anastrozole alone arm crossed over to receive Herceptin after progression on anastrozole alone
Month
s35
30
25
20
15
10
5
0
31.2 months
22.1 months
28.5 months
+8.5 monthsp=0.0325
+3.7 monthsp=0.17%*
+4.6 monthsp=0.325**
n=188H0648g
n=186M77001
n=207TAnDEM
pacl
itaxe
lpa
clita
xel
+
Her
cept
in
doce
taxe
ldo
ceta
xel
+
Her
cept
in
anas
troz
ole
anas
troz
ole
+ H
erce
ptin
Slamon 2001Marty 2005
Kaufman 2009
Herceptin in MBC considerably improves the prognosis of HER2-positive disease
HER2 positive, Herceptin (n=191)
HER2 negative (n=1782)
HER2 positive, no Herceptin (n=118)
100
80
60
40
20
00 12 24 36 48 60
Months from diagnosis
Pro
babili
ty o
f su
rviv
al (%
)
Dawood 2010
Herceptin : Expertise in all stages of Breast Cancer
Rela
pse
HERA
NSABP-B31
NCCTG N9831
BCIRG 006
FinHer
PACS-04
AdjuvantSurg
ery
NOAH
MDACC
GeparQuattro
Numerous Phase II studies
Neoadjuvant
EBC
1st line
HO648g
M77001
BCIRG 007
CHAT
TAnDEM
RHEA
2nd+ lines
GBG-26
EGF 104900
Numerous Phase II studies
MBC
Pro
gre
ssio
n
EBC: early breast cancer MBC: metastatic breast cancer
Progression under Herceptin-based 1st line therapya (monotherapy or with taxane- or with non taxane-chemotherapy)
GBG-26 is the 1st randomised Phase III study to investigate continuation of Herceptin beyond progression
Xeloda 1,250 mg/m2
bid d1-14 q21d +
continuation of Herceptin 6 mg/kg q3w
n=78
Xeloda 1,250 mg/m2 bid d1-14 q21d
n=78
RANDOMIZATION
a Includes 3 patients who received adjuvant Herceptin + taxane von Minckwitz 2009
Continuation of Herceptin improves response rate
CR: Complete ResponsePR: Partial ResponseCBR: CR+PR or SD > 24 weeks
Herceptin + Xeloda (n=75)
Xeloda (n=68)
48
Pati
ents
(%
)
0
10
20
30
40
50
60
70
80
CR + PR CBR
Median follow-up 15.6 months
p=0.01
27
75
54
p=0.007
von Minckwitz 2009
Continuation of Herceptin prolongs median Time to Progression
400
0.0
0.2
1.0
0.8
0.6
0.4
10 20 30
8.25.6
Pro
babili
ty HR=0.69 (p=0.034)
Xeloda (n=78)Herceptin + Xeloda (n=78)
Time from 1st progression (months)Median follow-up 15.6 months
von Minckwitz 2009
Continuation of Herceptin extendsOverall Survival
HR=0.76 (p=0.26)
20.4
400
0.0
0.2
1.0
0.8
0.6
0.4
10 20 30
25.5
Xeloda (n=78)Herceptin + Xeloda (n=78)
Pro
babili
ty
Time from 1st progression (months)Median follow-up 15.6 months
von Minckwitz 2009
Continuation of Herceptin beyond progression was not associated with increased toxicity
* includes hand-foot syndrome
AnemiaCardiovascular disorderDiarrheaDyspneaEdema FatigueFebrile neutropeniaFeverInfectionMucositisNail changesNeutropeniaSensory neuropathySkin changes*ThrombocytopeniaVomiting
Herceptin + XelodaXelodaGrade ¾ adverse events (%)
05.2
15.62.60
3.92.61.32.61.33.95.32.6
32.50
1.3
2.782.7
18.96.81.45.400
8.12.70
4.45.4
24.31.394.1
von Minckwitz 2009
EGF104900 study: Lapatinib ± Herceptin in progressing MBC
Crossover if Progressive Disease
HER2-positive MBC(FISH+ or IHC 3+)
n=296
Lapatinib 1500 mg qd
n=148
Lapatinib 1000 mg qd+ Herceptin 4 2 mg/kg qw
n=148
Blackwell 2009Blackwell 2010
Heavily pretreated population
Lapatinib
n=148
Lapatinib + Herceptin
n=148
Median prior chemotherapy regimens
% patients ≥ 6 prior regimens
Median prior Herceptin regimens for MBC
4
28
3
5
34
3
Study Arms
ITT Population
Blackwell 2009Blackwell 2010
Herceptin + lapatinib is superior to lapatinib alone
PFS, progression-free survivalOS, overall survival
Lapatinib + Herceptin n = 146
Lapatinib n = 145
ORR, overall response rateCBR, clinical benefit rate
12.4
(%)
(weeks
)
p=0.46
p=0.01
p=0.008
p=0.026
0
5
10
15
20
25
30
ORR CBR0
10
20
30
40
50
60
PFS OS
6.9
10.312.4
24.7
8.112.0
40.9
60.2
Blackwell 2009Blackwell 2010
Study Arms
ITT Population
Cardiac & safety events
Total # patients with event1
Grade 3/4
Serious events2
Event related to study drug(s)
Fatal3
1 Two patients experienced 2 events (other event was Grade 1/2) 2 Serious events defined as LV dysfunction ≥ Grade 3 or LVEF decrease ≥ 20% relative to baseline + below institutions LLN3 Cardiac failure; cause of death: pulmonary thromboembolism
Lapatinib
n=146
Lapatinib + Herceptin
n=149
3
1
3
2
0
111
3
10
10
1
Blackwell 2009Blackwell 2010
Adverse events All grades (% patients)
Anorexia
Cough
Dermatitis acneiform
Diarrhea
Dyspnea
Fatigue
Headache
Nausea
Rash
Vomiting
Lapatinib
n=146
10
10
10
48
10
19
9
28
29
18
Lapatinib + Herceptin
n=149
11
5
5
60
12
21
10
28
22
14
adverse event(incidence ≥ 10%)
Blackwell 2009Blackwell 2010
Herceptin given in 2nd line or beyondincreases Progression Free Survival
* HR = 0.69; 95% Cl, 0.48 to 0.97; p = 0.0338** HR = 0.73; 95% Cl, 0.57 to 0.93; p = 0.008
8.2 months(TTP)
+2.6 monthsp=0.0338*
2.7 months(PFS)
+0.9 monthsp=0.008**
0
Month
s
Xelo
daXe
loda
+ H
erce
ptin
n=156GBG-26
1
2
3
4
5
6
7
8
9
lapa
tnib
lapa
tinib
+ H
erce
ptin
n=291EGF104900
Von Minckwitz 2009Blackwell 2009Blackwell 2010
Herceptin given in 2nd line or beyondextends Overall Survival
* HR = 0.76; two-sided; p = 0.257** HR = 0.74; 95% Cl, 0.57 to 0.97; p = 0.026
Month
s
25.5 months
+5.1 monthsp=0.257* 14 months
+4.5 monthsp=0.026**
0
5
10
15
20
25
30
Xelo
daXe
loda
+ H
erce
ptin
n=156GBG-26
lapa
tnib
lapa
tinib
+ H
erce
ptin
n=296EGF104900
Von Minckwitz 2009Blackwell 2009Blackwell 2010
Conclusions
• Herceptin improves Overall Survival in 1st line MBC
• Benefit of continuing Herceptin beyond progression has been confirmed in phase III trial
• Herceptin is well tolerated with an acceptable cardiac safety profile
• Herceptin is the foundation of any treatment regimen in HER2-positive breast cancer
Slamon 2001Marty 2005
Kaufman 2009von Minckwitz 2009
Blackwell 2009Blackwell 2010
Update on CNS metastases in HER2-positive breast cancer
Prevention
Delay
Overall Survival increase
Quality of Life
Herceptin given in 1st Line MBC delays the occurrence of CNS metastases
13.1
2.1
p=0.0008
19
7
P<0.001
02
4
6
8
10
12
14
16
18
20
Not treatedwith Herceptin
n=80
Treatedwith Herceptinn=100
Not treatedwith Herceptin
n=11
Treatedwith Herceptinn=38
Media
n t
ime t
o C
NS m
eta
stase
s (m
onth
s)
Dawood 2008Park 2009
Herceptin delays the progression of CNS metastases
2.9
p=0.006
7.8
01
2
3
4
5
6
7
8
9
10
Not treatedwith Herceptin
n=11
Treatedwith Herceptin
after BMn=29
Media
n T
TP o
f in
tracr
ania
l tu
mors
(m
onth
s)
Park 2009
Brain radiotherapy makes blood-brain barrier more permeable
Herc
epti
n in
cere
bro
spin
al fluid
(ng/m
L)
0
100
200
300
400
Beforeradiotherapy
226ng/ml
Afterradiotherapy
After radiotherapy for brain metastases,Herceptin levels in brain (n = 6)
Stemmler 2007
Disruption of the blood-brain barrier occurs at thesite of brain metastases
MRI
HER2-positive brain lesion revealed by 89 Zr-Herceptin PET imaging and confirmed by MRI
PET
Dijkers 2010
Herceptin: the only anti-HER2 treatment improving Overall Survival of patients with CNS metastases
11.9 months
Month
s (0
S)
+Her
cept
in*
Churchn=26
25
20
15
10
5
0
+Her
cept
in**
+Her
cept
in**
*
+Her
cept
in*
Bartschn=38
Dawoodn=254
Parkn=40
+8.9 monthsp=0.05
21 months
11.6 months13.6 months
+12 monthsp<0.001
+5.5 monthsp=0.03
+8.1 monthsp<0.001
* After BM
** After WBRT
*** Before or at time of BM diagnosis
Church 2008Bartsch 2007Dawood 2008
Park 2009
Anti-HER2 targeted therapy:the future…
Pertuzumab and trastuzumab bind to different regions on HER2 and have synergistic activity
● Preferentially inhibits ligand-independent HER2 signalling
● Prevents shedding of HER2 ECD● Flags cells for destruction by the
immune system
● Inhibits HER2 forming dimer pairs● Suppresses multiple HER signalling
pathways, leading to a more comprehensive blockade of HER signalling
● Flags cells for destruction by the immune system
Subdomain IV of HER2
HER2 receptor
Trastuzumab Pertuzumab
Dimerisation domain
of HER2
Baselga 2009
BO17929: a Phase II trial of pertuzumab + trastuzumab in HER2-positive MBC patients progressing during trastuzumab-based therapy
Pertuzumab + trastuzumab
Coh
ort
s
1 a
nd
2
HER2-positive MBC progressing on trastuzumab +
chemotherapy (n=29)
16 patients receivedpertuzumab
+ trastuzumab
Coh
ort
3 Pertuzumab
PD
HER2-positive MBC progressing on trastuzumab
+ chemotherapy (Cohort 1, n=24;Cohort 2, n=42)
Primary objective: efficacy (ORR and/or SD> 6 months)
Secondary objectives:• safety profile of the combination, duration of response, time to response, TTP,
PFS (evaluate safety of combined antibody treatment)• efficacy (response rate + stabilisation of disease = CBR)
Heavily pretreated population• median 3 prior lines of therapy in the metastatic setting
MBC: Metastatic Breast CancerCBR: Clinical Benefit Rate
Baselga 2010Baselga 2009
Pertuzumab / trastuzumab combination therapy more active than treatment with either agent alone
a: only 27 patients evaluable: 1 patient did not progress on pertuzumab monotherapy before moving onto combination therapy and 1 patient’s tumour was unassessable after cycle 2b: n=14 as at data cut-off, 1 patient had not reached overall best response end point (8 cycles of assessment during this phase) and 1 patient died before efficacy assessmentP, pertuzumab monotherapy; P + T, pertuzumab / trastuzumab combination therapy;CR: Complete Response; PR: Partial Response; ORR: Overall Response Rate; SD: Stable Disease; PD: Progressive Disease
CR, %
PR, %
ORR, %
SD ≥ 6 months, %
CBR, %
(CR + PR + SD ≥ 6
months)
PD, %
Cohorts 1 and 2
(P + T) n=66
7.6
16.7
24.2
25.8
50.0
50.0
Cohort 3 (P)
n=27a
0.0
3.4
3.4
6.9
10.3
not available
Cohort 3 (P P + T)
n=14b
0.0
21.4
21.4
21.4
42.8
57.1
Baselga 2010Baselga 2009
Pertuzumab / trastuzumab combination safety profile comparable to pertuzumab monotherapy
AEs: Adverse Events
AEs
Asthenia
Back pain
Chills
Diarrhoea
Fatigue
Nausea
Rash
Vomiting
Weight decrease
BO17929 Cohort 3 Pertuzumab monotherapy
n=29
BO17929 Cohort 3 Pertuzumab + trastuzumab
n=16Any grade, %
17
17
0
48
17
34
10
24
0
Grade 3/4, %
0
0
0
3
3
0
0
0
0
Any grade, %
13
13
19
31
25
31
19
25
19
Grade 3/4, %
0
6
0
6
6
0
0
0
0
Baselga 2009
BO17929: pertuzumab + trastuzumab has a similar cardiac safety profile to trastuzumab
• No significant changes in LVEF over the treatment period
Only 3 patients in the trial had a decrease in LVEF of ≥10% points and <50% absolute value but all were asymptomatic
• No additional cardiac safety signals were observed
LVEF: Left Ventricular Ejection FractionBaselga 2010Baselga 2009
CLEOPATRA: a Phase III trial of trastuzumab + pertuzumab in the 1st line setting
An international, Phase III, randomised, double-blind, placebo-controlled study (~250 sites worldwide)• End points
• PFS and OS• (cardiac) Safety
1:1 HER2-positiveMBC (n=800a)
Docetaxel + trastuzumab + pertuzumab
Docetaxel + trastuzumab + placebo
1:1
www.clinicaltrials.gov
PHEREXA: a Phase II trial of trastuzumab + capecitabine with or without pertuzumab
aRecruitment started Jan 2010
An international, Phase II, randomised study in patients with HER2-positive MBC that has progressed after 1st line of trastuzumab-based therapy in the metastatic setting
1:1 HER2-positiveMBC (n=450a)
Trastuzumab + capecitabine+ pertuzumab
Trastuzumab + capecitabine
1:1
www.clinicaltrials.gov
T-DM1: 1st-in-class HER2 antibody-drug conjugate (ADC)
Monoclonal antibody: trastuzumab
Target expression: HER2
Highly potent chemotherapy(maytansine derivative)
Cytotoxic agent: DM1
Systemically stableBreaks down in target cancer cell
LinkerT-DM1
Baselga 2009
T-DM1 selectively delivers a highly toxic payload to HER2-positive tumour cells
T-DM1 binds to the HER2 protein on cancer cells
Baselga 2009
T-DM1 selectively delivers a highly toxic payload to HER2-positive tumour cells
Receptor-T-DM1 complex is internalised into HER2-positive cancer cell
Baselga 2009
T-DM1 selectively delivers a highly toxic payload to HER2-positive tumour cells
Potent antimicrotubule agent is released once inside the HER2-positivetumour cell
Baselga 2009
Single-agent T-DM1 Phase II studies in pretreated HER2-positive MBC
Phase II (TDM4258g)
n=112
• Single-arm study of single-agent T-DM1 (3.6 mg/kg iv q3w) • HER2-positive MBC patients who have progressed on HER2 therapy • Previously received trastuzumab and ≥ 1 line of chemotherapy for MBC
Phase II (TDM4374g)
n=110
• Single-arm study of single-agent T-DM1 (3.6 mg/kg i.v. q3w) for HER2-positive MBC patients who have been pretreated with lapatinib, trastuzumab, capecitabine, anthracyclines and taxanes
• Two HER2-directed regimens in the metastatic setting• PD on last regimen received
Vogel 2009Krop 2009Krop 2009
TDM4258g: encouraging efficacy demonstrated for single-agent T-DM1
Population
All efficacy evaluable patients
112
38.4
25.0
4.9
n
ORR, %
Investigator assessed
Independent review
PFS, months
After 9.5 months’ follow-
up
Lapatinib pretreated
patients
67
35.8
23.9
na
Patients with centrally confirmed
HER2-positive disease
75
48
32.0
na
Heavily pretreated population• median 3 prior chemotherapy agents in the metastatic setting
na: not available Vogel 2009
TDM4374g: a Phase II trial of T-DM1 in HER2-positive MBC patients progressing during HER2-targeted therapy
T-DM13.6 mg/kg
q3w
• Patients with HER2-positive MBC (n=110)• Prior exposure to anthracycline, taxane, capecitabine,
lapatinib and trastuzumab (median 7 prior agents of therapy in the metastatic setting)
• PD on last regimen received
Krop 2009
Substantial clinical benefit seen with T-DM1 in a heavily pretreated population
aIncluding unconfirmed PRsCI, confidence interval; n/a, not assessed
Independent reviewn=110
32.7(24.1, 42.1)
032.746.418.21.80.9
44.5 (35.1, 54.3)7.3 (0-11.7)
Investigator assessedn=110
30.0(22.0, 39.4)
1.828.252.713.60.92.7
40.0 (31.1, 49.3)
n/a
Tumour response
ORR, %(95% CI) CR PR SDa
PD Unevaluable Missing CBR, % (95% CI)Median PFS, months (range)
Krop 2009
T-DM1 is well tolerated with no new safety signals observed
AST: aspartate aminotransferase
Only 6 (5.5%) patients discontinued due to AEs
AST increased
Constipation
Dry mouth
Fatigue
Headache
Nausea
Pyrexia
Thrombocytopenia
Grade 1, %
11
17
17
30
17
26
13
11
Grade 2, %
11
3
4
26
3
10
8
13
Grade 3, %
3
1
0
3
0
1
1
4
Grade 4, %
0
0
0
0
0
0
0
2
All grades, %
25
21
20
59
20
37
22
29
Krop 2009
T-DM1: potential future clinical benefit for heavily pretreated patients with HER2-positive MBC
T-DM1 has shown robust single-agent activity in heavily pretreated patient groups
•substantial clinical benefit observed in patients with PD during prior HER2-targeted therapy
T-DM1 is well tolerated with no dose-limiting cardiac events observed
Further investigation of T-DM1 is ongoing
Krop 2009
EMILIA: ongoing Phase III study of T-DM1 vs capecitabine + lapatinib in the 2nd-line setting
HER2-positive incurable locally advanced breast cancer or MBC
Prior trastuzumab and taxanen=580
T-DM1 3.6 mg/kg q3w
Capecitabine + lapatinib
n=221 as of 16 March 2010
1:1
www.clinicaltrials.gov
TDM4450g: ongoing Phase II study of T-DM1 vs trastuzumab + docetaxel in 1st-line HER2-positive MBC
HER2-positive locally advanced or MBCNo prior chemotherapy for metastatic disease
n=120
T-DM1 Trastuzumab + docetaxel
● Study start date July 2008● Fully recruited www.clinicaltrials.gov
TDM4788g / BO22589: Phase III study of T-DM1 + pertuzumab vs trastuzumab + docetaxel in 1st-line HER2-positive MBC
HER2-positive locally advanced or MBCNo prior chemotherapy for metastatic disease
n=1092
T-DM1 + placebo Trastuzumab + docetaxel
T-DM1 + pertuzumab
www.clinicaltrials.gov
Summary: pertuzumab and T-DM1 are promising new therapeutic agents for HER2-positive MBCPertuzumab
• 1st HER2 dimerisation inhibitor
• Has demonstrated encouraging clinical efficacy and tolerability in combination with trastuzumab
• Offers a more comprehensive approach to blocking HER2-driven signalling than trastuzumab alone
T-DM1
• 1st HER2-directed ADC delivering cytotoxic drug specifically to HER2-positive tumour cells while retaining the biological activity of trastuzumab
• Has demonstrated encouraging clinical efficacy and tolerability in heavily pretreated patients
Clinical trials of both agents are ongoing, including pertuzumab and T-DM1 in combination
Outlook
• Small or Node negative HER2 positive tumors : should you botHER?
HER2-positive cancers have a distinct biology and an aggressive behaviour
• Do we have a cure?
18 Infusions of Herceptin deliver high cure rates for women with HER2-positive early breast cancer
• Is Herceptin efficient at all HER2 positive tumors?
Herceptin efficacy is consistent across tumor size and nodal status
• What do the international guidelines recommend?
St Gallen 2011 guidelines recommend : Herceptin when tumor size >0,5 cm
HER2-positive cancers have a distinct biology and an aggressive behaviour(1,5)
1 Oakman at al;Annals of oncology 21, 2010 (Supplement 7);vii112-vii119
2 Gonzalez-Angulo et al. J Clin Oncol 2009;27;5700-5706
3 Chia et al, Journal of Clinical Oncology, 2008, p5697-5704
4 Tovey et al, British Journal of Cancer, 2009,1-4
5 Banerjee et al, Lancet Oncol 2010; 11: 1193–99
Small HER2-positive tumors have a high risk of relapse(1)
0.2
0.4
0.6
0.8
1.0
0 1 2 3 4 50
Reccu
rren
ce-F
ree S
urv
ival
[pro
posit
ion
]
Time since diagnosis (years)
93,7%
HER2-negative
n=965T1a,bN0MO tumors
P<0,0001
HER2-negative
Small HER2-positive tumors have a high risk of relapse(1)
0.2
0.4
0.6
0.8
1.0
0 1 2 3 4 50
Reccu
rren
ce-F
ree S
urv
ival
[pro
posit
ion
]
Time since diagnosis (years)
93,7%
HER2-negative
n=965T1a,bN0MO tumors
P<0,0001
HER2-negative
77,1%
HER2-positive
HER2-positive
Small HER2-positive tumors have a high risk of relapse(1)
Finnish population based study(2)
20
40
60
80
100
0 1 2 3 4 50
Dis
tan
t D
isease-F
ree S
urv
ival
Years of folluw-up
CISH HER2-negative (n=167)
1-10 mmn Node negative
P<0,0001
HER2-negative
CISH HER2-positive (n=17)
HER2-positive
Joensuu(2)
Small tumors were defined in these studies as tumors of 1 cm or less(1,2)
Breast Cancer Classification(3)*
T1mi : Tumor ≤ 1 mm
T1a : Tumor >1mm but ≤ 5mm
T1b : Tumor >5mm but ≤ 10 mm
T1c : Tumor > 10 mm but ≤ 20 mm
T2 : Tumor > 20 mm but ≤ 50 mm
T3 : Tumor > 50 mm
T4 : Tumor of any size with direct extension to
the
chest wall and/or the skin
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 100
Bre
ast
Can
cer-
Sp
ecifi
c S
urv
ival
(pro
bab
ilit
y)
Time (years)
CISH HER2-negative (n=167)
n=1420
P<0,001
HER2-negative
Chia*(1)
Even for node negative patients, HER2 positivity doubles the 10-year risk of dying from breas cancer
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 100
Bre
ast
Can
cer-
Sp
ecifi
c S
urv
ival
(pro
bab
ilit
y)
Time (years)
HER2-negative
n=1420
P<0,001
HER2-negative
HER2-positive
HER2-positive
Chia*(1)
Even for node negative patients, HER2 positivity doubles the 10-year risk of dying from breas cancer
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 100
Bre
ast
Can
cer-
Sp
ecifi
c S
urv
ival
Follow-up (years)
HER2-negative (n=240)
P<0,001
HER2-negative
HER2-positive (n=22)
HER2-positive
Tovey(2)
Poor survival outcomes in HER2-positive breast cancer patients with low-grade, node-negative tumours(2)
1 3 5 7 9
Outlook
• Small or Node negative HER2 positive tumors : should you botHER?
HER2-positive cancers have a distinct biology and an aggressive behaviour
• Do we have a cure?
18 Infusions of Herceptin deliver high cure rates for women with HER2-positive early breast cancer
• Is Herceptin efficient at all HER2 positive tumors?
Herceptin efficacy is consistent across tumor size and nodal status
• What do the international guidelines recommend?
St Gallen 2011 guidelines recommend : Herceptin when tumor size >0,5 cm
40
50
60
70
80
90
0 1 2 3 4Time
(years)
ACTHACT
5
87%
92%
BCIRG 006
% A
live
ACT + Herceptin (n=1.074)
ACT (n=1.073)
HR=0,63 (95%CI,0.48_- 0.81)
P<0.001
100 ___
6
Herceptin significantly improves Overall Survival Relatives reduction in the risk of death of 37%
0
20
40
60
80
100
0 1 2 3 4
Follow-up
(years)
AC-TH
AC-T
5
Joint analysis of N9831 and NSABP B31 trials
Alive a
nd
dis
ease-f
ree (
%)
ACT-T+ Herceptin
AC-T
HR* adj=0,48 (95%CI,0.41_- 0.57)
P<0.001
6
Over 85% of women live without disease progression 4 years after the start of adjuvant treatment with Herceptin(3)
Number at risk
AC-TH (n=1.989)
AC-T (n=1.979)
*Nodes, receptor status, paclitaxel schedule, protocol
73.1%77.6%
86.4%
92.3%87.9%
85.9%
1.854
1.800
1.347
1.235
868
753
522
460
202
168
4
8
Outlook
• Small or Node negative HER2 positive tumors : should you botHER?
HER2-positive cancers have a distinct biology and an aggressive behaviour
• Do we have a cure?
18 Infusions of Herceptin deliver high cure rates for women with HER2-positive early breast cancer
• Is Herceptin efficient at all HER2 positive tumors?
Herceptin efficacy is consistent across tumor size and nodal status
• What do the international guidelines recommend?
St Gallen 2011 guidelines recommend : Herceptin when tumor size >0,5 cm
Combined analysis of N9831/B31 and N981 trials, 4 year FU(2)
Combined analysis of N9831/B31 and N981 trials, 4 year FU(2)
Disease Free Survival Rate
Adjuvant Herceptin decreases the recurrence or death rate* for patient with small tumors ≤1cm
Adjuvant Herceptin significantly improves DFS for patients with small tumors ≤1cm(1)
HERA: Disease Free Survival at 2 year median follow-up(2)
Herceptin overall survival benefit for node negative tumors is confirmed after a median follow-up of more than 5 years
Adjuvant Herceptin plus Chemotherapy results in consistent benefits for node-negative patients(1)
Outlook
• Small or Node negative HER2 positive tumors : should you botHER?
HER2-positive cancers have a distinct biology and an aggressive behaviour
• Do we have a cure?
18 Infusions of Herceptin deliver high cure rates for women with HER2-positive early breast cancer
• Is Herceptin efficient at all HER2 positive tumors?
Herceptin efficacy is consistent across tumor size and nodal status
• What do the international guidelines recommend?
St Gallen 2011 guidelines recommend : Herceptin when tumor size >0,5 cm