Transcript Christian Jackisch

Christian Jackisch
Head of the Department of Gynaecology at Klinikum Offenbach
Senior Lecturer at Philipps University of Marburg, Germany
 Chairman of the Breast Centre at Klinikum
Offenbach
 Past deputy director of the Department of
Gynaecology at the University Hospital in
Marburg
 Long-standing member of national and
international steering committees for
breast and ovarian cancer trials
Klinikum Offenbach
 Member of the German Task Force
developing national guidelines for the
diagnosis and treatment of breast cancer
 Published more than 100 papers and book
chapters on obstetrics and gynaecology
Philipps University of Marburg
A decade of success: trastuzumab
in HER2-positive metastatic breast
cancer
Christian Jackisch
Klinikum Offenbach
Germany
Presentation objectives
 Discuss the central role of trastuzumab in the treatment of
HER2-positive MBC, in the context of other available
treatment options
– review the evidence base to support currently available
trastuzumab-based regimens
 Consider the potential benefits to our patients of the
introduction of new trastuzumab-based regimens
– evaluate the latest evidence for selected novel
therapeutic approaches
 Introduce pertuzumab as the first in a new class of
anti-HER2 therapy
HER2 = human epidermal growth factor receptor 2
MBC = metastatic breast cancer
HER2-positive disease
HER2 expression in breast cancer
HER2 amplification leads
 HER2 is a transmembrane protein and
part
to HER2
over-of the HER family of
growth factor receptors
expression
 Gene or DNA amplification and protein overexpression are
indicators of HER2 status
Normal
HER2 overexpression
HER2
leads to
expression
tumour proliferation
Binding of trastuzumab
to HER2
 HER2 protein levels on the surface of HER2-positive tumour cells
are several orders of magnitude greater than on adjacent normal
breast epithelium1
1Lewis
GD, et al. Cancer Immunol Immunother 1993;37:255–63
Role of HER2 in breast cancer
 20–30% of patients with breast cancer have
HER2-positive disease1,2
 HER2-positive status is associated with poor
prognosis, including reduced relapse-free and overall
survival (OS)3,4
– suggests key role for HER2 in pathogenesis
 HER2 status is also an important predictor of
response to chemotherapy and hormonal therapy5,6
1Owens
MA, et al. Clin Breast Cancer 2004;5:63–9; 2Ross JS, et al. Mol Cell Proteomics
2004;3:379–98; 3Hynes NE, Stern DF. Biochim Biophys Acta 1994;1198:165–84
4Menard S, et al. Oncology 2001;61(Suppl. 2):67–72; 5Lohrisch C, et al.
Clin Breast Cancer 2001;2:129–35; 6Piccart M, et al. Oncol 2001; 61(Suppl. 2)73–82
Trastuzumab: anti-HER2 epitope
monoclonal antibody
 Recombinant humanised monoclonal antibody directed against
the extracellular domain of HER2
Extracellular domain
(632 amino acids)
Ligand-binding site
Plasma
membrane
Transmembrane domain
(22 amino acids)
Intracellular domain
(580 amino acids)
Tyrosine kinase activity
Cytoplasm
Trastuzumab: four mechanisms of action
Activation of ADCC
Prevention of p95HER2 formation
Inhibition of cell proliferation
Inhibition of angiogenesis
ADCC = antibody-dependent cellular cytotoxicity
Accurate HER2 testing is vital for
appropriate patient selection
Patient tumour
sample
FISH/CISH
IHC
0
2+
3+
FISH/CISH
Trastuzumab
therapy
1+
–
–
+
Trastuzumab
therapy
+
Trastuzumab
therapy
IHC = immunohistochemistry
FISH = fluorescence in-situ hybridisation
CISH = chromogenic in-situ hybridisation
Bilous M, et al. Mod Pathol 2003;16:173–82
A decade of success: tailored treatment
for HER2-positive MBC
Hormonal therapy ±
trastuzumab
ER-positive; low risk
HER2-positive
MBC
ER-negative
ER-positive;
high risk
ER-negative
ER-positive; high risk
No prior taxanes
Prior taxanes
Trastuzumab +
taxanes
Trastuzumab +
other CT
Trastuzumab monotherapy
ER = oestrogen receptor; CT = chemotherapy
Data from monotherapy trials show that
trastuzumab is active in HER2-positive MBC
 114 first-line patients randomised to trastuzumab at standard or
high dose (8mg/kg followed by 4mg/kg weekly)
Patients
RR (%) (95% CI)
All
26 (18–34)
IHC3-positive
35 (24–44)
IHC2-positive
0 (0–15)
FISH-positive
34 (26–56)
 Clinical benefit rate (CR + PR + SD >6m) = 48%;
IHC2-positive RR=0
RR = response rate
CI = confidence interval; CR = complete response;
PR = partial response SD = stable disease;
Vogel CL, et al. J Clin Oncol 2002;20:719–26
Trastuzumab plus taxanes
Trastuzumab plus taxanes: well-established
survival benefit of first-line therapy
H0648g
(HER2 IHC3-positive)
Outcome
T+P
(n=68)
P
(n=77)
ORR (%)
49.0
TTP (months)
OS (months)
M77001
(HER2 FISH-/IHC3-positive)
p value
T+D
(n=92)
D
(n=94)
p value
17.0
Not reported
61.0
34.0
0.0002
7.1
3.0
<0.05
11.7
6.1
0.0001
25.0
18.0
Not reported
31.2
22.7*
0.0325
*53 patients (57%) crossed over to receive trastuzumab after discontinuation of docetaxel;
OS in this group was 30.3 months, vs 16.6 months in patients who did not cross over
T = trastuzumab; P = paclitaxel
D = docetaxel; ORR = overall
response rate; TTP = time to progression
Baselga J. Oncology 2001;61(Suppl. 2):14–21
Herceptin® EU Summary of product characteristics
Marty M, et al. J Clin Oncol 2005;23:4265–74
Smith IE. Anticancer Drugs 2001;12(Suppl. 4):S3–10
Trastuzumab plus docetaxel:
long-term survival
50
Trastuzumab + docetaxel
Docetaxel
Patients (n)
40
79% of the patients in the docetaxelalone arm who survived ≥3 years had
crossed over to receive trastuzumab
30
20
10
0
>3
>4
Long-term survival (years)
>4.5
Marty M, et al. Breast Cancer Res Treat 2006;100(Suppl. 1):S102 (Abstract 2067)
Estimated probability
Evidence suggests trastuzumab
should be used upfront
1.0
Trastuzumab + docetaxel (n=92)
Docetaxel alone/cross over (n=53)
0.8
Docetaxel alone (n=41)
0.6
0.4
0.2
16.6
0
0
5
10
15
30.3
20
25
30
Months
31.2
35
40
45
50
Marty M, et al. J Clin Oncol 2005;23:4265–74
Trastuzumab plus taxanes
 Dramatic improvements in survival demonstrated with
trastuzumab in the first-line setting
– similar magnitudes of improvement have been reported only
rarely (in any therapeutic area)
– trastuzumab is the only HER2-targeted therapy shown to
improve survival in MBC patients with HER2-positive tumours
– benefits of trastuzumab were apparent regardless of age,
ER/PR status, or tumour burden
– cross-over patients in M77001 did benefit from later
trastuzumab, but survival times were shorter than with
first-line use
 Evidence indicates trastuzumab should be initiated as soon
as possible
PR = progesterone receptor
Case study
Locally-advanced breast cancer (LABC)
and MBC: what are your options?
13.10.00
Invasive ductal breast cancer confirmed by high speed biopsy
HER2-neu overexpression (IHC3-positive), ER-positive, PR-negative
LABC and MBC: what are your options?
13.10.00
Paclitaxel weekly: 80mg/m² q7d x 8 + trastuzumab: 4/2mg/kg q7d x 8
14.12.00
q7d = every 7 days
LABC and MBC: what are your options?
Still alive and doing fine
100.000
10.000
1000
Radiation
Bone scan
CA 125
Trastuzumab
Paclitaxel
TCT
ACT
CA 15-3
CEA
100
10
Trastuzumab q3w
Tamoxifen
Bisphosphonate (p.o.)
0
2002
2003
Year 3
2004
2005
2006
Year 5
Year 4
Year 6
Year 2
Year 1
q3w = every 3 weeks; p.o. = by mouth; CEA = carcinoembryonic antigen; CA = cancer antigen;
TCT = computed tomography of the thorax; ACT = computed tomography of the abdomen
Are other trastuzumab-based treatment
options needed for HER2-positive MBC?
 Unmet clinical need, i.e.
– patient has received prior taxanes
– patient is not responding to taxanes
 Other trastuzumab-based options include
– non-taxane chemotherapy
– triplet combinations
– endocrine therapy
Potential for new treatment options
based on trastuzumab
1. Trastuzumab plus non-taxane combinations
Trastuzumab plus vinorelbine:
phase II trials
100
First-line1–4
First-/second-line5,6
Second-line7–9
ORR (%)
80
60
40
20
0
30
25
25
30
25
25
25
25
35
Weekly vinorelbine schedule (mg/m2)
1Jahanzeb
M, et al. Oncologist 2002;7:410–17; 2Burstein HJ, et al. J Clin Oncol 2003;21:2889–95
3Bernado G, et al. J Clin Oncol 2004;22(Suppl. 23):59s (Abstract 731)
4Chan A, et al. Br J Cancer 2006;95:788–93; 5Bayo J, et al. J Clin Oncol 2004;22(Suppl. 23):67s (Abstract 763)
6Glogowska I, et al. J Clin Oncol 2004;22(Suppl. 23):235s (Abstract 3165)
7De Wit M, et al. J Clin Oncol 2004;22(Suppl. 23):84s (Abstract 831)
8Burstein HJ, et al. J Clin Oncol 2001;19:2722–30; 9Papaldo P, et al. Ann Oncol 2006;17:630–6
Trastuzumab plus gemcitabine in MBC
Phase II study
O’Shaughnessy et al. Christodoulou et al.
Patients (n)
64
28
Gemcitabine
regimen
1,200mg/m2
days 1, 8 q3w
1,000mg/m2
days 1, 8, 15 q4w
Anthracycline-/taxanepretreated (%)
95
100
ORR (%)
38
36
CR (%)
0
4
PR (%)
38
32
Median TTP (months)
5.8
7.8
Median OS (months)
14.7
18.7
q4w = every 4 weeks
O’Shaughnessy JA, et al. Clin Breast Cancer 2004;5:142–7
Christodoulou C, et al. Proc Am Soc Clin Oncol
2003;22:42 (Abstract 166)
Trastuzumab plus anthracycline:
clinical trials in MBC
n
ORR
(%)
CHF
(%)
EC (60/600mg/m2)
EC (90/600mg/m2)
26
25
62
64
0
8
Liposomal doxarubicin
(50mg/m2 q3w)
P (80mg/m2 qw)
24
91
0
Theodoulou et al. 2002 Liposomal doxarubicin
(60mg/m2 q3w)
37
58
3
Author
Untch et al. 2004
Baselga et al. 2004
EC = epirubicin/
cyclophosphamide
CHF = congestive
heart failure
Regimen
(+ trastuzumab)
Untch M, et al. Eur J Cancer 2004;40:988–97
Baselga J, et al. Eur J Cancer 2004;2:132 (Abstract 262)
Theodoulou M, et al. Proc Am Soc Clin Oncol 2002;21:55a (Abstract 216)
Trastuzumab plus non-taxane
combinations
 Promising phase II data for trastuzumab plus vinorelbine in
HER2-positive MBC; high activity, favourable safety
and tolerability
– RR 6080% in first line; activity comparable to weekly taxane
– active and well tolerated when used beyond disease
progression
 Trastuzumab plus gemcitabine has shown activity in several
phase II trials
 High RR shown with trastuzumab plus anthracycline
 Further clinical trials will better define the role for
non-taxane combinations
Potential for new treatment options
based on trastuzumab
2. Trastuzumab-based triplet regimens
Trastuzumab-based triplet regimens
 Combining more than two agents has the potential to
further improve ORR and increase survival
 Several trastuzumab combinations of interest
–
–
–
–
trastuzumab/docetaxel/capecitabine (CHAT study)
trastuzumab/paclitaxel/carboplatin
trastuzumab/docetaxel/epirubicin
trastuzumab/paclitaxel/gemcitabine
Phase II study of trastuzumab plus docetaxel ±
capecitabine in first-line MBC (CHAT)
HER2-positive
LABC and
MBC patients
(n=225*)
Trastuzumab 8mg/kg loading dose,
then 6mg/kg
+ docetaxel 100mg/m2, q3w
(n=110)
Trastuzumab 8mg/kg loading dose,
then 6mg/kg
+ docetaxel 75mg/m2, q3w
+ capecitabine 950mg/m2 b.i.d.,
days 1–14
(n=112)
*Three patients did not receive treatment
b.i.d. = twice daily
Death or
disease
progression
Wardley A, et al. Breast Cancer Res Treat
2006;100(Suppl. 1):S101 (Abstract 2063)
CHAT: TTP significantly increased with
the triplet than the doublet
Estimated probability
1.0
Events
HR
95% CI
p value
70
82
0.704
0.51–0.971
0.029
TDC
TD
0.8
0.6
0.4
0.2
13.6
0
0
5
10
18.6
15
20
25
30
35
40
45
50
Months
HR = hazard ratio
C = capecitabine
Wardley A, et al. Breast Cancer Res Treat
2007;106(Suppl. 1):S31 (Abstract 309)
CHAT: longer median PFS with the triplet
than the doublet
Estimated probability
1.0
Events
HR
95% CI
p value
75
85
0.725
0.529–0.99
0.0402
TDC
TD
0.8
0.6
0.4
0.2
12.8
0
0
5
10
17.9
15
20
25
30
35
40
45
50
Months
PFS = progression-free survival
Wardley A, et al. Breast Cancer Res Treat
2007;106(Suppl. 1):S31 (Abstract 309)
Manageable safety profile
Adverse event (AE)
Alopecia
Diarrhoea
Nausea
Hand-foot syndrome
Vomiting
Asthenia
Fatigue
Mucosal inflammation
Peripheral oedema
Myalgia
Patients with grade 3/4
treatment-related AEs (%)
TDC
TD
(n=112)
(n=110)
6
8
11
4
1
0
17
1
4
0
4
3
1
2
1
2
1
4
0
1
Wardley A, et al. Breast Cancer Res Treat 2007;106(Suppl. 1):S31 (Abstract 309)
CHAT: summary
 Effective first-line strategy for HER2-positive MBC
 TDC significantly prolonged both TTP (0.029) and PFS
(0.0402) by approximately 5 months compared
with TD
 High tumour RRs and good tolerability
 The potential of these agents as sequential therapy
was not addressed in this trial
Wardley A, et al. Breast Cancer Res Treat 2007;106(Suppl. 1):S31 (Abstract 309)
Paclitaxel plus trastuzumab plus
carboplatin
(%)
Paclitaxel
Paclitaxel + Weekly paclitaxel
Paclitaxel + trastuzumab
+ trastuzumab
trastuzumab + carboplatin
+ carboplatin
RR1
65
RR2
RR3
36*
57*
41
17
1Perez
*HER2 IHC3+
71
E, et al. Breast Cancer Res Treat 2003;82(Suppl. 1) (Abstract 216)
2Robert N, et al. J Clin Oncol 2006;24:2786–92
3Slamon DJ, et al. N Engl J Med 2001;344:783–92
Potential for new treatment options
based on trastuzumab
3. Trastuzumab plus endocrine therapy
Trastuzumab plus hormonal
therapy: rationale
 Up to 50% of HER2-positive breast cancers are also
ER-positive
 Evidence of crosstalk between HER2 and ER
signalling pathways
 Simultaneous targeting of both pathways may
improve outcomes over monotherapy
 Not all patients require chemotherapy (i.e. ER-positive
patients at low risk)
Ellis M. Oncologist 2004;9(Suppl. 3):20–26
Piccart-Gebhart MJ, et al. N Engl J Med 2005;353:1659–72
Crosstalk between signal transduction
and endocrine pathways
Growth factor
Oestrogen
Trastuzumab
IGFR
EGFR/HER2
Plasma
membrane
P
P
P
P
P
Anastrozole
PI3-K
Cell
survival
Akt
P
SOS
RAS
RAF
P
MEK
P
ER
p90RSK
P
MAPK
Cell
growth
Cytoplasm
P
Nucleus
EGFR = epidermal growth factor receptor
ERE = oestrogen response element
IGFR = insulin-like growth factor receptor
P P
P
P
Basal
transcription
machinery
ER p160
ER
CBP
ERE
ER target gene transcription
Adapted from Johnston S.
Clin Cancer Res 2005;11:889s–99s
Phase III study of first-line trastuzumab
plus anastrozole in MBC (TAnDEM)
Postmenopausal
women with HER2positive (IHC3positive and/or FISHpositive) and ERand/or PR-positive
MBC
(n=207)
Anastrozole 1mg/day p.o.*
(n=104)
Anastrozole 1mg/day p.o. +
trastuzumab 4mg/kg i.v. loading
dose then 2mg/kg weekly
(n=103)
*Trastuzumab offered to patients
who progressed on anastrozole alone
Disease
progression
Mackey JR, et al. Breast Cancer Res
Treat 2006;100(Suppl. 1):S5–6 (Abstract 3)
Doubled PFS in HER2-positive MBC:
TAnDEM trial
1.0
Events
Probability
0.8
An + T
An only
Median PFS
(months)
95% CI
4.8
2.4
87
99
3.7–7.0
2.0–4.6
p value
HR
0.0016
0.63
0.6
0.4
0.2
0
No. at risk
An + T
An only
An = anastrozole
0
5
10
15
20
25
103
104
48
36
31
22
17
9
14
5
13
4
30 35
Months
11
2
9
1
40
45
50
55
60
4
0
1
0
1
0
0
0
0
0
Mackey JR, et al. Breast Cancer Res Treat
2006;100(Suppl. 1):S5–6 (Abstract 3)
TAnDEM: summary
 Addition of trastuzumab to anastrozole significantly
extended PFS in women with HER2-positive, hormone
receptor-positive MBC
 >15% of patients receiving anastrozole plus
trastuzumab experienced 2 years PFS
– could allow delay in use of chemotherapy
 Addition of trastuzumab improved median OS
– although increase was non-significant (p=0.325)
 AEs were as expected and manageable
Mackey JR, et al. Breast Cancer Res Treat 2006;100(Suppl. 1):S5–6 (Abstract 3)
Trastuzumab therapy in
multiple lines
No resistance to trastuzumab
 Issue of anti-HER2 therapy resistance
remains unproven
– is this true resistance?
 Various options can be considered
– continue with trastuzumab, but change
chemotherapy i.e. TBP
– use of other HER2 agent, i.e. lapatinib plus
capecitabine after progression on trastuzumab
therapy for MBC (EGF100151 study)
– retreatment with trastuzumab after second-/
third-line therapy
TBP = treatment beyond progression
Geyer CE, et al. J Clin Oncol
2007;25(Suppl. 18):40s (Abstract 1035)
Patients still benefit from trastuzumab
after progression in the metastatic setting
Treatment in multiple lines
Fountzilas et al. 2003
Gelmon et al. 2004
Tripathy et al. 2004
Garcìa-Sáenz et al. 2005
Stemmler et al. 2005
Bartsch et al. 2006
Montemurro et al. 2006
Morabito et al. 2006
Orlando et al. 2006
Tokajuk et al. 2006
Bachelot et al. 2007
Baselga et al. 2007
Metro et al. 2007
Antoine et al. 2007
Von Minckwitz et al. 2007
NR = not reported
No. of
patients
ORR for second
trastuzumab-based regimen (%)
80
65
93
31
23
54
40
7
11
27
17
33
37
107
78
24
32
11
26
39
26
18
29
18
50
29
18
29
NR
49
GBG-26: trastuzumab beyond
progression study
Capecitabine 1,250mg/m² b.i.d. days 1–14 q3w
Randomisation
n=78 each arm
Capecitabine 1,250mg/m² b.i.d. days 1–14 q3w
+
trastuzumab continuation 6mg/kg q3w
Capecitabine
Capecitabine
+ trastuzumab
24.6
48.9
Median PFS
(months)
5.6
53 events
8.5
48 events
0.71
Median OS
(months)
19.9
31 events
20.3
26 events
0.79
ORR (%)
HR
Von Minckwitz G, et al. Breast Cancer Res Treat 2007;106(Suppl. 1):S185 (Abstract 4056)
Hermine cohort study
Patients with HER2-positive MBC
(n=623)
Trastuzumab as first-line
therapy
(n=221)
Trastuzumab as second-line
therapy
(n=138)
Patients who progressed or died
during 2-year follow-up
(n=185*)
Patients who progressed or died
during 2-year follow-up
(n=121†)
Trastuzumab
continued after
disease progression
(n=107)
Trastuzumab
stopped at disease
progression
(n=70)
*Data unavailable for eight patients
†Data unavailable for four patients
Trastuzumab
continued after
disease progression
(n=87)
Trastuzumab
stopped at disease
progression
(n=30)
Antoine EC, et al. Eur J Cancer 2007;5 (Suppl. 4):213
(Abstract 2099)
HERMINE study: longer OS for patients
receiving trastuzumab as first-line therapy
T continued after disease progression
T stopped at disease progression
Median OS (months)
95% CI
p value
NR
16.8
30.4–NR
12.5–19.4
<0.0001
1.0
Median follow-up: 24.1 months
Probability
0.8
0.6
0.4
0.2
16.8
0
0
5
10
15
20
25
30
35
Months
Median OS from date of progression: 4.6 vs 21.3 months
40
Antoine EC, et al. Eur J Cancer 2007;5(Suppl. 4):213 (Abstract 2099)
HERMINE study: cardiac safety in patients
receiving trastuzumab as first-line therapy
Patients, n (%)
Trastuzumab stopped
at PD (n=70)
Trastuzumab continued
after PD (n=107)
LVEF assessed during study
57 (81)
97 (91)
LVEF worst value
Absolute decrease 15%
Value of <40%
Value of <50%
5 (21.7)
3 (7.3)
10 (24.4)
9 (20.5)
2 (2.6)
10 (12.7)
1 (1.4)
1 (0.9)
Congestive heart failure
LVEF = left ventricular ejection fraction
Antoine EC, et al. Eur J Cancer 2007;5(Suppl. 4):213 (Abstract 2099)
HERMINE study: longer OS for patients
receiving trastuzumab as second-line therapy
T continued after disease progression
T stopped at disease progression
Median OS (months)
95% CI
p value
27.1
15.6
22.7–32.9
6.0–NR
0.08
1.0
Median follow-up: 23.1 months
Probability
0.8
0.6
0.4
0.2
15.6
0
0
5
10
15
27.1
20
25
30
35
Months
Median OS from date of progression: 11.0 vs 15.3 months
40
Antoine EC, et al. Eur J Cancer 2007;5(Suppl. 4):213 (Abstract 2099)
Importance of side effects in the
treatment of breast cancer
 Patients with breast cancer can expect to receive multiple lines
of therapy during the course of their disease
First diagnosis
Surgery
Neoadjuvant
Adjuvant
MBC
First line
Second line
 Safety is important for all women with breast cancer, but for
women receiving multiple lines of treatment, safety is of
particular importance
Trastuzumab: safety and tolerability
 Trastuzumab is generally well tolerated and not associated
with the typical side effects of chemotherapy
 The most relevant AEs associated with trastuzumab are
– serious infusion-related reactions (0.3%)
– congestive heart failure (2% in MBC trials)1
 Patients at risk can be identified prior to therapy and the
majority of events are manageable
 Cardiac safety and clinical symptoms should be
continuously monitored (i.e. every 3 months) during
trastuzumab therapy
1Ewer
MS, O’Shaughnessy JA. Clin Breast Cancer 2007;7:600–7
Pertuzumab: a new class of
anti-HER2 therapy
Pertuzumab
 Monoclonal antibody against HER2
 Binds different HER2 epitope to trastuzumab1
– prevents receptor dimerisation1
– inhibits HER2-mediated signalling1
 First in a new class of HER2-targeted therapies
 Complementary mechanism of action to trastuzumab
suggested by preclinical evidence2,3
1Agus
DB, et al. J Clin Oncol 2005;23:2534–43
T, et al. Ann Oncol 2006;17(Suppl. 9):ix58
3Arpino G, et al. J Natl Cancer Inst 2007;99:694–705
2Friess
Phase II trial: pertuzumab plus trastuzumab in
MBC progressing during treatment with
trastuzumab
Stage I (n=24)
Trastuzumab +
pertuzumab*




2 PR or 1 PR + 12 SD
or 13 SD
Safety evaluation
for IDSMB
YES
Stage II (n=66)
NO
Stop trial
n=58 fully evaluable patients
ORR = 18.2%
Clinical benefit rate = 39.4%
Updated efficacy data will be reported in 2008
 The study is being monitored by an IDSMB
 No safety objections raised, study continuing to stage II
– only two patients had a falling LVEF (≤50% and ≥10%)
*Trastuzumab: 4mg/kg loading dose  2mg/kg qw or
8mg/kg loading dose  6mg/kg q3w;
Pertuzumab: 840mg loading dose  420mg q3w
IDSMB = International Data Safety Monitoring Board
Baselga J, et al. J Clin Oncol
2007;25(Suppl. 18S):33s (Abstract 1004)
Phase III trastuzumab plus pertuzumab
trial in first-line MBC
A
400
patients
Placebo + trastuzumab
+ docetaxel
Tumour assessments
R
B
400
patients
Endpoints
 PFS
 OS
 Quality of life
Pertuzumab + trastuzumab
+ docetaxel
Survival follow-up
A decade of success: the first agent to
improve survival in HER2-positive MBC
 Introduction of first-line trastuzumab has shown OS can be
significantly improved in HER2-positive MBC
 Trastuzumab is effective and well tolerated
– adding little to the toxicity of systemic chemotherapy
regimens and without impacting quality of life
– limited long-lasting/acute side effects
 Trastuzumab should be used as soon as HER2-positive
status is identified for best results
 Several trastuzumab-based regimens are now available,
providing clinicians with treatment options in different
lines of therapy and for a broad range of patients