Transcript template

®
Herceptin :
leading the way in metastatic breast
cancer care
Steffen Kahlert
Herceptin® in metastatic breast cancer
 HER2-positive breast cancer is an aggressive cancer
and is associated with a poor prognosis
 Herceptin® is currently licensed for the treatment of
HER2-positive metastatic breast cancer (MBC)
– first-line in combination with docetaxel in patients
with no prior chemotherapy for MBC
– first-line in combination with paclitaxel in patients
who have received prior anthracyclines or for
whom an anthracyline is not suitable
– as monotherapy in patients who have received prior
treatment for MBC
Herceptin® plus docetaxel (M77001)
Herceptin® plus docetaxel (M77001):
trial design
HER2-positive MBC
(IHC 3+ and/or FISH+) n=188
n=94
Two patients did not
receive study medication
n=92
Docetaxel*
100mg/m q3w x 6
Docetaxel
100mg/m q3w x 6
*Patients progressing on docetaxel
alone could crossover to receive
Herceptin®
+
2
2
Herceptin
4mg/kg loading,
 2mg/kg weekly
until PD
®
Marty M, et al. J Clin Oncol 2005;23:4265–74
Herceptin® plus docetaxel (M77001):
inclusion criteria
 MBC
– measurable disease
 HER2-positive
– IHC 3+ and/or FISH+
– IHC 2+ initially allowed (July 1999–August 2000)
 ECOG 2
 Life expectancy 12 weeks
 LVEF >50%
 Adequate bone marrow, hepatic and renal function
 Prior chemotherapy
– none for MBC
– no prior taxanes or anti-HER therapy
Marty M, et al. J Clin Oncol 2005;23:4265–74
Herceptin® plus docetaxel (M77001):
patient demographics
Herceptin
+ docetaxel
(n=92)
Docetaxel
alone
(n=94)
53
(32–80)
55
(24–79)
97
3
41
94
6
56
0
(0–4)
0
(0–2)
®
Age median
(range)
HER2 status (%)
IHC 3+ and/or FISH+
Other*
ER+ and/or PgR+ (%)
ECOG median
(range)
*Eight patients IHC 2+/FISH–; one patient IHC 0/1+/FISH unknown (docetaxel alone)
Marty M, et al. J Clin Oncol 2005;23:4265–74
Herceptin® plus docetaxel (M77001):
patient demographics
®
Herceptin + docetaxel
(n=92)
Docetaxel alone
(n=94)
4 (1–12)
2 (1–5)
4 (1–12)
2 (1–5)
Site (%)
Lung
Liver
Bone
Soft tissue
Other
40
49
34
48
60
43
54
38
50
59
Previous therapy (%)
Chemotherapy
Anthracyclines
Hormonal therapy
Radiotherapy
71
64
44
64
68
55
47
66
Metastases median (range)
No. lesions/patient
No. sites/patient
Marty M, et al. J Clin Oncol 2005;23:4265–74
Herceptin® plus docetaxel (M77001):
OS at 24 months
Herceptin® + docetaxel
Docetaxel alone
Estimated probability
1.0
0.8
0.6
0.4
0.2
31.2
22.7
0
0
5
10
15
20
25
30
35
40
45
50
8.5 months
Months
Intent-to-treat population, 24-month cut-off
Documented crossover = 57%
Marty M, et al. J Clin Oncol 2005;23:4265–74
Herceptin® plus docetaxel (M77001):
OS at 24 months
Herceptin® + docetaxel (n=92)
Docetaxel alone/crossover (n=45)
Docetaxel alone (n=49)
Estimated probability
1.0
0.8
0.6
0.4
0.2
16.6
0
0
5
10
15
30.3
20
25
30
31.2
35
40
45
50
Months
Intent-to-treat population, 24-month cut-off
Marty M, et al. J Clin Oncol 2005;23:4265–74
Herceptin® plus docetaxel (M77001):
efficacy 24 month follow up
®
Outcome
Herceptin
+ docetaxel
(n=92)
Docetaxel
alone
(n=94)
p-value
ORR (%)
61.0
34.0
0.0002
DR (median, months)
11.7
5.7
0.009
TTP (median, months)
11.7
6.1
0.0001
OS (median, months)
31.2
22.7
0.0325
Marty M, et al. J Clin Oncol 2005;23:4265–74
Herceptin® plus docetaxel (M77001):
non-haematological toxicity (grade 3/4)
Herceptin
+ docetaxel
(n=92)
Docetaxel
alone
(n=94)
Alopecia
10
6
Asthenia
10
6
Diarrhoea
5
2
Headache
5
1
CHF
1
0
®
Adverse event (%)
Adverse events occurring in ≥5% and congestive heart failure (CHF)
Marty M, et al. J Clin Oncol 2005;23:4265–74
Herceptin® plus docetaxel (M77001):
haematological toxicity (grade 3/4)
Herceptin
+ docetaxel
(n=92)
Docetaxel
alone
(n=94)
Anaemia
1
1
Thrombocytopenia
0
0
Leucopenia
21
17
Neutropenia
32
22
Febrile neutropenia/
neutropenic sepsis
23
17
®
Adverse event (%)
Marty M, et al. J Clin Oncol 2005;23:4265–74
Herceptin® plus docetaxel (M77001):
conclusions
®
 Adding Herceptin to docetaxel improves all clinical
outcomes parameters
– ORR (from 34 to 61%)
– TTP (from 6.1 to 11.7 months)
– OS (from 22.7 to 31.2 months)
®
 Herceptin adds little to the toxicity profile
of docetaxel
®
 Herceptin plus docetaxel should be used upfront for
greatest clinical benefit in patients with HER2-positive
MBC
 These 24-month data provide evidence of a long-term
®
survival benefit following the addition of Herceptin to
docetaxel
Herceptin® plus paclitaxel (H0648g)
Herceptin® plus paclitaxel (H0648g):
design and enrolment
Patients (n=469)
No prior anthracyclines
Herceptin + AC
(n=143)
®
AC
(n=138)





MBC
HER2 IHC 2+/3+ (CTA)
No prior CT for MBC
Measurable disease
KPS 60%
Prior anthracyclines
Herceptin + paclitaxel
(n=92)
®
Paclitaxel
(n=96)
Slamon DJ, et al. N Engl J Med 2001;334:783–92
Herceptin® plus paclitaxel (H0648g):
treatment plan
 Chemotherapy q3w x 6
– AC =
doxorubicin (60mg/m ) or epirubicin (75mg/m )
+ cyclophosphamide (600mg/m )
2
2
2
– Paclitaxel (175mg/m )
2
 Herceptin
®
– 4mg/kg loading, 2mg/kg qw until PD
Slamon DJ, et al. N Engl J Med 2001;334:783–92
Herceptin® plus paclitaxel (H0648g):
demographics
Herceptin
+ AC
(n=143)
®
®
AC
(n=138)
Herceptin
+ paclitaxel
(n=92)
Paclitaxel
(n=96)
54 (27–76)
54 (25–75)
51 (25–77)
51 (26–73)
KPS 80 (%)
34
34
24
35
Metastatic sites 3 (%)
40
29
31
35
76
71
65
71
HER2 3+ (%)
76
70
74
80
ER negative (%)
46
49
55
63
>4+ nodes (%)
30
27
59
64
Median DFI (months)
25
23
22
19
Mean age / range (years)
liver or lung (%)
Slamon DJ, et al. N Engl J Med 2001;334:783–92
Herceptin® plus paclitaxel (H0648g):
prior therapy
®
®
AC
(n=138)
Herceptin +
paclitaxel
(n=92)
Paclitaxel
(n=96)
1
1
91
97
57
37
97
100
Prior transplant (%)
0
0
13
22
Prior hormonal (%)
62
57
55
56
Prior radiotherapy (%)
48
56
67
76
Prior anthracyclines (%)
Prior adjuvant CT (%)
Herceptin +
AC
(n=143)
Slamon DJ, et al. N Engl J Med 2001;334:783–92
Herceptin® plus paclitaxel (H0648g):
efficacy (all patients)
H + AC
(n=143)
ORR (%)
56
AC
H+P
(n=138) (n=92)
42
41*
P
(n=96)
17
H + CT
(n=235)
50*
CT
(n=234)
32
Median TTP (months)
7.8*
6.1
6.9*
2.7
7.4*
4.6
Median DR (months)
9.1*
6.7
10.5*
4.5
9.1*
6.1
21.4
22.1
18.4
25.1*
20.3
Survival (months)
26.8
*p<0.05
Slamon DJ, et al. N Engl J Med 2001;334:783–92
Herceptin® plus paclitaxel (H0648g):
TTP
1.0
Herceptin® + chemotherapy
Chemotherapy
Probability
0.8
0.6
p=0.0001
0.4
0.2
0
0
2
4
6
8 10 12 14 16 18 20 22 24
Time (months)
Slamon DJ, et al. N Engl J Med 2001;334:783–92
Herceptin® plus paclitaxel (H0648g):
OS (all patients)
1.0
0.9
Herceptin + CT
CT alone
®
Probability
0.8
0.7
0.6
p<0.05
0.5
0.4
0.3
0.2
0.1
20.3
0.0
0
Crossover 72%
5
10
15
25.1
20
25
30
Time (months)
35
40
45
50
Slamon DJ, et al. N Engl J Med 2001;334:783–92
Herceptin® plus paclitaxel (H0648g):
summary of SAEs
H+
H + AC
AC
paclitaxel Paclitaxel
SAE (%) (n=143) (n=138) (n=92)
(n=96)
Alopecia
25
42
26
26
Anaemia
3
2
1
1
Asthenia
7
7
8
8
Diarrhoea
1
3
1
3
Headache
3
5
7
2
Leucopenia
15
11
6
5
Nausea
6
10
3
3
Slamon DJ, et al. N Engl J Med 2001;344:783–92
Herceptin® plus paclitaxel (H0648g):
summary of cardiac safety
H+AC
(n=143)
AC
(n=135)
H+P
(n=91)
P
(n=95)
NYHA III-IV (%)
28.0
9.6
8.8
4.2
Symptomatic
cardiac event (%)
19.0
3.0
4.0
1.0
Suter T, et al. Breast 2004;13:173–83
Herceptin® plus paclitaxel (H0648g):
efficacy (IHC 3+ versus all)
H + AC
ORR (%)
3+
All
60
56*
AC
42
42
H+P
49
41*
P
17
17
H + CT
56*
50
CT
31
32
Median TTP (months)
8.1*
7.8*
6.0
6.1
7.1*
6.9*
3.0
3.0
7.8*
7.4*
4.6
4.6
Median DR (months)
9.3
9.1*
5.9
6.7
10.9
10.5*
4.6
4.5
10.0
9.1*
5.6
6.1
25
22.1
18
18.4
29*
25.1*
20
20.3
Survival (months)
31*
26.8
21
21.4
*p<0.05
3+: n=349
All: n=469
Slamon DJ, et al. N Engl J Med 2001;344:783–92
Baselga J. Oncology 2001;61 (Suppl 2):15–21
Herceptin® plus paclitaxel (H0648g):
conclusions
 Adding Herceptin to paclitaxel improves all clinical
®
outcome parameters
– ORR (from 17 to 49%*)
– TTP (from 3 to 7 months*)
– OS (from 18 to 25 months*)
 Herceptin adds little to the toxicity profile
®
of paclitaxel
 Herceptin plus paclitaxel should be considered as
first-line therapy in HER2-positive MBC
*IHC 3+ patients
Other Herceptin® trials in MBC
Phase II Herceptin® plus vinorelbine:
efficacy
Vinorelbine
(n=33)
Vinorelbine +
Herceptin (n=35)
27.3
(95% CI 12.1, 42.5)
51.4
(95% CI 32.9, 68)
Complete response (%)
3.0
2.9
Partial response (%)
24.2
48.5
Stable disease (%)
36.4
28.6
Progressive disease
36.4
20.0
Median TTP (months)
6.0 (95% CI: 4, 8)
9.0 (95% CI: 7, 11)
Overall response (%)
Median OS (months)
22 (95% CI: 12, 32) 27 (95% CI: 19, 35)
Papaldo P, et al. Ann Oncol 2006
Phase II Herceptin® plus vinorelbine:
safety
Toxicity (Grade 3/4) (%)
Vinorelbine (n=33)
Vinorelbine + Herceptin (n=35)
Leucopenia
3
-
Neutropenia
51
49
Febrile neutropenia
6
-
Anaemia
6
3
Thrombocytopenia
3
-
Nausea/vomiting
-
-
Mucositis
3
-
Peripheral neuropathy
-
-
Liver
-
-
Diarrhoea
3
-
Stipsis
-
-
Cardiac toxicity
-
3
Papaldo P, et al. Ann Oncol 2006
Serum concentration (µg/mL)
Herceptin® q3w: rationale
1,000
3-weekly regimen
100
10
Weekly regimen
1
0
3
6
9 12 15 18 21 24 27 30 33 36 39 42 45 48
Time (weeks)
Ghahramani P, et al. The Breast 2003;12(Suppl. 1):S40 (Abstract P89)
Herceptin q3w plus paclitaxel(BO15935)
Outcome
n=32
ORR (%)
59
CR (%)
13
PR (%)
47
SD (%)
22
Median TTP (months)
12.2
Median DR (months)
10.5
Leyland-Jones B, et al. J Clin Oncol 2003;21:3965–71
Herceptin® monotherapy trials in MBC
H0650g
WO16229
H0649g
First
First
Second/third
4mg/kg LD, 2mg/kg
qw or 8mg/kg LD,
4mg/kg qw
8mg/kg LD, 6mg/kg
q3w
4mg/kg LD, 2mg/kg
qw
114
83*
222
Overall
26
23
15
IHC 3+
35
NR
18
IHC 2+
0
NA
6
FISH positive
34
NR
19
FISH negative
7
NR
0
TTP (months)
3.5, 3.8†
3.4
3.1
DR (months)
NR
10.0
9.1
OS (months
24.4
NR
13
Line of therapy
Regimen
No of patients
ORR (%)
LD=loading dose; NR=not recorded; NA=not applicable; qw=weekly; q3w= every 3 weeks
*Results from per protocol subset
†TTP given for standard and higher Herceptin® dose regimens, respectively
Summary:
Herceptin® combinations in MBC
H0648g1
BO159352
H+P
P
alone
H+P
ORR (%)
41
17
TTP
(months)
6.9
OS
(months)
22.1
M770013
H+D
D
alone
H + V4
V
alone4
59
61
34
51.4
27.3
2.7
12.2
11.7
6.1
9.0
6.0
18
NR
31.2
22.7
27
22
NR=not recorded
H=Herceptin®; P=paclitaxel; D=docetaxel; V=vinorelbine
Slamon DJ, et al. N Engl J Med 2001;344:783–92
B, et al. J Clin Oncol 2003;21:3965–71
3
Marty M, et al. J Clin Oncol 2005;23:4265-74
4Papaldo P, et al. Ann Oncol 2006
1
2Leyland-Jones
Herceptin® in MBC:
conclusions
 In metastatic breast cancer patients
– Herceptin® in combination with chemotherapy leads
to an improvement in survival compared to
chemotherapy alone
• adverse events associated with chemotherapy
are not exacerbated by addition of Herceptin®
– Herceptin® monotherapy has also been shown to be
effective
 Cardiac events are reversible and manageable
– the rate of asymptomatic cardiac events in clinical
trials has fallen to 2% based on selection criteria
and cardiac monitoring