Adjuvant therapy of HER2 positive early breast cancer The Evidences Antonio Frassoldati Oncologia Clinica - Ferrara
Feb 24, 2016
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 1 y 48 mos Y
N9831 3046 S or C+S 1 y 72 mos Y*
HERA 5090 S 1 or 2 y 48 mos Y
BCIRG006 3222 C+S 1 y 65 mos Y
FinHER 232 C 3 m 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
NSABP B-31Node positive
N9831 Node pos/neg HR
Paclitaxel q3w x 4
Paclitaxel x 4, H qw x 52 AC q3w x 4
H qw x 52
Paclitaxel qw x 12
Paclitaxel qw x 12
Paclitaxel qw x 12, H qw x 52
AC q3w x 4
BCIRG 006 Node pos/neg HR
Docetaxel q3w x 4AC q3w x 4
AC q3w x 4H qw x 12, q3w† x 14
Docetaxel q3w x 4
Carboplatin + Docetaxel q3w† x 6H qw x 18, q3w x 12
HERA 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
B31/N9831Efficacy results
Perez, JCO 2011
Rel
apse
HR 0.52 (0.45-0.60)
B31/N9831Efficacy results
Perez, JCO 2011
Dea
th
HR 0.61 (0.50-0.75)
No. of deathsH 1 year vs. observation
0 1 2Favourstrastuzumab
Favours notrastuzumab
HR
OS benefit
29 vs. 37p=0.26
20051
1 year(0%)
59 vs. 90p=0.0115
182 vs. 213p=0.1087
Median follow-up (% follow-up time
after selective crossover)
20062
2 years(4.1%)
20083
4 years(30.9%)
20051
1 year (0%)
Median follow-up (% follow-up time
after selective crossover)
20062
2 years (4.3%)
20083
4 years (33.8%)
No. of DFS eventsH 1 year vs. observation
127 vs. 220p<0.0001
218 vs. 321p<0.0001
369 vs. 458p<0.0001
0 1 2Favourstrastuzumab
Favours notrastuzumab
HR
DFS benefit
1. Piccart-Gebhart et al 2005; 2. Smith et al 2007; 3. Gianni et al 2011
HERA: DFS and overall survival over time
HERA - Observation patients by status on 16 May 2005
1698 patients originally randomised to observation
1354 patients alive and disease free 16 May 2005
344 patients DFS event or lost to follow-up
198 alive post DFS event
469 patients remained on observation
344 patients ineligible for
crossover
Gianni, Lancet Oncol 2011
885 patients crossed over to
trastuzumab
HERA - DFS (landmark analysis): selective crossover and no crossover
100
80
60
40
20
00
Months from randomisation
No. at risk
Patients alive and disease free (%)
Selective crossover*No crossover
6 12 18 24 30 36 42 48
885 885 884 878 870 851 822 690 480469 468 455 438 408 388 358 302 232
HR 0.68 (0.51-0.90)
p=0.0077
Gianni, Lancet Oncol 2011* Median time to start trastuzumab: 22.8 mos (4.5-52.7)
N9831Efficacy results
Sequ
entia
l vs
Con
com
itant
+ s
eque
ntia
l
Perez, JCO 2011
BCIRG006Efficacy results
Slamon, NEJM 2011
DFS HR
AC-TH vs AC-T 0.64
TCH vs AC-T 0.75
FinHEREfficacy results
Joensuu, JCO 2009
Efficacy of adjuvant trastuzuambon Survival
Trial HR Median FU
B31/N9831 0.61 48 mos
N9831AC-T vs AC-T-H
AC-T-H vs AC-TH-H0.880.78
72 mos
HERA° 0.85 48 mos
BCIRG006AC-T vs AC-TH-H
AC-T vs TCH0.630.77
65 mos
FinHER 0.55 62 mos
° ITT, not adjusted for selective crossover
Efficacy in subgroupsER and Nodal status
Slamon, NEJM 2011
AC-TH-H
TCH
Time-dependent Hazard Rate for recurrence by hormone receptor status
ER positive
ER negative
Untch, Ann Oncol 2008HERA trial
Efficacy in subgroupsSmall tumors
Gonzalez-Angulo, JCO 2009
MD
AC
C
965 pT1a-b N0
Hazard Ratio for recurrence 5.3
97.2%
86.4%
Efficacy in subgroupsSmall tumors
Slamon, NEJM 2011
BC
IRG
006
Efficacy in subgroupsTopo2A status
Slamon, NEJM 2011
With Topo2A coamplification
Without Topo2A coamplification
Cardiac safety
Trial Not starting trastuzuamb
Trastuz. Discontin.
Cardiac dysfunction°
CHF
B31/N9831 4.3% 17.3% 17.3%320/1845
3.8%
N9831 (C+S) 2.8% 19% 9.1% 87/949
2.2%
HERA -- 5.2% 3.7% 0.8%
BCIRG006 AC-TH 2.1% n.r. AC-TH 18.6% TCH 9.4%
AC-TH 2.0% TCH 0.4%
FinHER -- 4-7% of doses
3.9%* 0.9% *
° >10 points relative reduction in LVEF *after CT
0.00
Suter et al 2007aMedian follow-up 12 months; DFS, disease-free survival
Obs; any cardiac end point
H; any cardiac end point
Obs; DFS eventsH; DFS events
6 12 18 24Monthsa
0.05
0.10
0.15
0.20
0.25Pr
obab
ility
No. at riskObservationTrastuzumab
1693 1106 784 455 2261693 1139 861 520 260
0
HERA: risk-benefit ratio with adjuvant trastuzumaba
Cardiac outcomes after any type of cardiac endpoint
No acute recoveryAcute recovery
Trastuzumab patients who have any type of CE (n=73)
Trastuzumab patients who reached acuterecovery after any type of CE (n=59)
Trastuzumab patients who had a furtherLVEF drop to <50% (n=59)
19.2%
80.8%
Further LVEF drop to <50%No further LVEF drop to <50%
71.2%
28.8%
Progressive diseaseFavorable outcome
35.3%
64.7%
Duration of Trastuzumab
Trial Duration in months
CT regimen No. of pts
HERA (BIG) 12 vs. 24 Center’s choice
3,387
PHARE (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
SOLD (Finland & BCG)
3 vs 12 T+FEC 3,000
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