Transcript Diapositiva 1

Adjuvant therapy of HER2
positive early breast cancer
The Evidences
Antonio Frassoldati
Oncologia Clinica - Ferrara
Evidences on adjuvant trastuzumab are
based on randomized trials in over 14,000
women
Trial
Pt. N.
Trastuz.
Duration
Median FU
Published
results
B31/N9831
3351
C+S
1y
48 mos
Y
N9831
3046
S or C+S
1y
72 mos
Y*
HERA
5090
S
1 or 2 y
48 mos
Y
BCIRG006
3222
C+S
1y
65 mos
Y
FinHER
232
C
3m
62 mos
Y
PACS-04
528
S
1y
47 mos
Y
S= sequential; C= concomitant
* Early release after second interim analysis (arm A, B) and first interim analysis (arm B,C)
Main trial designs of
adjuvant Trastuzumab
Paclitaxel q3w x 4
NSABP B-31 AC q3w x 4
Paclitaxel x 4, H qw x 52
Node positive
Paclitaxel qw x 12
N9831
AC q3w x 4
Node pos/neg HR
BCIRG 006
Node pos/neg HR
Paclitaxel qw x 12
Paclitaxel qw x 12, H qw x 52
AC q3w x 4
Docetaxel q3w x 4
Docetaxel q3w x 4
AC q3w x 4
H qw x 12,
q3w † x 14
Carboplatin + Docetaxel q3w† x 6
H qw x 18, q3w x 12
HERA
H qw x 52
Chemotherapy (any)
Node pos/neg HR Chemotherapy (any)  H qw x 52
Chemotherapy (any)  H qw x 104
Main research questions in trials of
adjuvant trastuzumab
• Does trastuzumab reduce the rate of recurrence (and death)?
(All)
• Does the schedule of trastuzumab administration matter?
(N9831, BCIRG006)
• Does the duration of trastuzumab matter? (HERA)
• Does the chemotherapy regimen influence the activity and
safety of trastuzumab? (BCIRG006)
Cross-comparison among the trials of
adjuvant trastuzuamb
Trial
Pt. N.
Primary
endpoint
Crossover
B31/N9831
3351
DFS
15%
N9831
3046
DFS
Y
HERA°
5090
DFS
52%
BCIRG006
3222
DFS
2.1%
FinHER
232
DFS
N
PACS04
528
DFS
N
° Pts in HERA trial were randomized after the end of adjuvant therapy
Relapse
B31/N9831
Efficacy results
HR 0.52 (0.45-0.60)
Perez, JCO 2011
Death
B31/N9831
Efficacy results
HR 0.61 (0.50-0.75)
Perez, JCO 2011
HERA: DFS and overall survival
over time
Median follow-up
(% follow-up time
after selective
crossover)
No. of DFS events
H 1 year vs.
observation
DFS benefit
Median follow-up
(% follow-up time
after selective
crossover)
OS benefit
No. of deaths
H 1 year vs.
observation
20051
1 year
(0%)
127 vs. 220
p<0.0001
20051
1 year
(0%)
29 vs. 37
p=0.26
20062
2 years
(4.3%)
218 vs. 321
p<0.0001
20062
2 years
(4.1%)
59 vs. 90
p=0.0115
20083
4 years
(33.8%)
369 vs. 458
p<0.0001
20083
4 years
(30.9%)
182 vs. 213
p=0.1087
0
1
Favours
trastuzumab
HR
Favours no 2
trastuzumab
0
1 Favours no 2
Favours
trastuzumab
trastuzumab
HR
1. Piccart-Gebhart et al 2005; 2. Smith et al 2007; 3. Gianni et al 2011
HERA - Observation patients
by status on 16 May 2005
1698 patients
originally randomised to observation
16 May
1354 patients
alive and disease free
885 patients
crossed over to
trastuzumab
344 patients
DFS event or lost to follow-up
198 alive post DFS event
469 patients
remained on
observation
2005
344 patients
ineligible for
crossover
Gianni, Lancet Oncol 2011
HERA - DFS (landmark analysis):
selective
crossover and no crossover
100
80
60
Patients
alive and
disease free
(%)
40
HR 0.68 (0.51-0.90)
20
p=0.0077
Selective crossover*
No crossover
0
No.
at risk
0
6
12
18
24
30
36
Months from randomisation
885
469
885
468
884
455
878
438
870
408
* Median time to start trastuzumab: 22.8 mos (4.5-52.7)
851
388
822
358
42
48
690
302
480
232
Gianni, Lancet Oncol 2011
Sequential vs
Concomitant + sequential
N9831
Efficacy results
Perez, JCO 2011
BCIRG006
Efficacy results
DFS HR
AC-TH vs
AC-T 0.64
TCH vs ACT 0.75
Slamon, NEJM 2011
FinHER
Efficacy results
Joensuu, JCO 2009
Efficacy of adjuvant trastuzuamb
on Survival
Trial
B31/N9831
HR
Median FU
0.61
48 mos
N9831
72 mos
AC-T vs AC-T-H
AC-T-H vs AC-TH-H
HERA°
0.88
0.78
0.85
BCIRG006
48 mos
65 mos
AC-T vs AC-TH-H
AC-T vs TCH
FinHER
° ITT, not adjusted for selective crossover
0.63
0.77
0.55
62 mos
Efficacy in subgroups
ER and Nodal status
AC-TH-H
TCH
Slamon, NEJM 2011
Time-dependent Hazard Rate for
recurrence by hormone receptor status
ER positive
ER negative
HERA trial
Untch, Ann Oncol 2008
Efficacy in subgroups
Small tumors
97.2%
MDACC
86.4%
Hazard Ratio for recurrence 5.3
965 pT1a-b N0
Gonzalez-Angulo, JCO 2009
BCIRG006
Efficacy in subgroups
Small tumors
Slamon, NEJM 2011
Efficacy in subgroups
Topo2A status
Without Topo2A
coamplification
With Topo2A
coamplification
Slamon, NEJM 2011
Cardiac safety
Trial
B31/N9831
Not starting
trastuzuamb
Trastuz.
Discontin.
Cardiac
dysfunction°
CHF
4.3%
17.3%
17.3%
3.8%
320/1845
N9831 (C+S)
2.8%
19%
9.1%
2.2%
87/949
HERA
BCIRG006
FinHER
--
5.2%
3.7%
0.8%
AC-TH 2.1%
n.r.
AC-TH 18.6%
TCH 9.4%
AC-TH 2.0%
TCH 0.4%
--
4-7% of
doses
3.9%*
0.9% *
° >10 points relative reduction in LVEF
*after CT
HERA: risk-benefit ratio with
adjuvant trastuzumaba
0.25
Obs; DFS events
Probability
H; DFS events
0.20
H; any cardiac
end point
0.15
Obs; any cardiac
end point
0.10
0.05
0.00
No. at risk
Observation
Trastuzumab
aMedian
0
6
12
Monthsa
18
24
1693
1693
1106
1139
784
861
455
520
226
260
follow-up 12 months; DFS, disease-free survival
Suter et al 2007
Cardiac outcomes after any
type of cardiac endpoint
Trastuzumab patients who have any type of CE (n=73)
No acute recovery
19.2%
Acute recovery
80.8%
Trastuzumab patients who reached acute
recovery after any type of CE (n=59)
Trastuzumab patients who had a further
LVEF drop to <50% (n=59)
Further LVEF drop to <50%
Progressive disease
No further LVEF drop to <50%
Favorable outcome
28.8%
35.3%
71.2%
64.7%
Duration of Trastuzumab
Trial
Duration in
months
CT regimen No. of pts
(BIG)
12 vs. 24
Center’s
choice
3,387
(France)
6 vs. 12
Center’s
choice
3,400
PERSEPHONE (UK)
6 vs. 12
Center’s
choice
4,000
SHORTER
(Italy)
3 vs.12
A+T vs.
T+FEC
1,500
(Finland
& BCG)
3 vs 12
T+FEC
3,000
HERA
PHARE
SOLD
Adjuvant HER2- directed Therapy
Questions to be solved:
– Indication for the better regimen for combination with
trastuzumab (Anthracycline/taxane or docetaxel/carboplatin)
– Role of shorter trastuzumab regimens
– Treatment of triple-positive tumor migth avoid
chemotherapy, particularly on small tumors (T1a,b N0)
– Prediction of response to individual HER2-directed agents
– Role of dual HER2 inhibition
Double inhibition of HER2
Trastuzumab
clearly changed the
prognosis of HER2
breast cancer
patients.
Several new ways
for further
improvements can
now to be explored
HER2 street