(neo-)adjuvant therapy for her-2+ ebc · 1694 1 1 72 885 532 268 127 220 1 year trastuzumab...
TRANSCRIPT
-
(NEO-)ADJUVANT THERAPY FOR HER-2+ EBC
F. Cardoso, MDDirector, Breast Unit, Champalimaud Clinical Center, Lisbon, Portugal
ESO Breast Cancer Program CoordinatorESMO Board of Directors & NR Committee Chair
EORTC Breast Group Past-Chair
www.abc-lisbon.org
-
DISCLOSURES
Consultant/Ad Board:
Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo,
Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics,
Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer,
Pierre-Fabre, Roche, Sanofi, Seattle Genetics, Teva
-
MANAGEMENT OF HER-2 + BC: Lessons learned & Questions unanswered
• HER-2 + BC is a well identified subtype
• Quality of HER-2 testing essential
• Crucial role of patient selection
• Several efficacious anti-HER-2 agents available (challenge: the best sequence and/or combinations)
• Lack of predictive markers beyond HER-2 (particularly to select among different anti-HER-2 agents)
• Even with target/targeted drug resistance occurs
-
SABCS 2005
100
80
60
40
20
0
Patients
(%)
Months from randomisation
6 12 18 24
1740 1567 1353 1083 779
1646 1466 1256 1005 703
138
170
1 year trastuzumab
Observation
0
No.
at risk
Events HR 95% CI p value
0.88 0.71, 1.11 0.29
2-year
DFS
93.4
92.5
Disease-free survival
HER-2 Pos & Her-2 Neg Patients
Median follow-up: 1.8 yearsHR, hazard ratio; CI, confidence interval
Simulation by Aparna Keshaviah, Sc.M.
SABCS 2005
100
80
60
40
20
0
Patients
(%)
Months from randomisation
6 12 18 24
1693 1108 767 445 224
1694 1172 885 532 268
127127
220220
1 year trastuzumab
Observation
0
No.
at risk
Events HR 95% CI p value
0.54 0.43, 0.67
-
MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era &
Questions unanswered
• Consistent & significant benefit of adjuvant trastuzumab
• Optimal duration
•Neoadjuvant or adjuvant setting
•Concomitant vs. sequential with CT
• Optimal CT regimen (anthracyclines: to give or not give!)
• The principle of dual blockade (neo and adjuvant)
• Without CT or less CT in certain cases?
• Extended anti-HER2 therapy
-
MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era &
Questions unanswered
• Consistent & significant benefit of adjuvant trastuzumab
• Optimal duration
•Neoadjuvant or adjuvant setting
•Concomitant vs. sequential with CT
• Optimal CT regimen (anthracyclines: to give or not give!)
• The principle of dual blockade (neo and adjuvant)
• Without CT or less CT in certain cases?
• Extended anti-HER2 therapy
-
Adjuvant chemotherapy + trastuzumab: 6 large adjuvant
BC trials, all N+ or high risk N (>13,000 patients)
AC/FEC Paclitaxel
Docetaxel (D)
Carbo+DTrastuzumab (T)
D or Vinorelbine Standard chemotherapy (CTX)FEC or ED
NSABP-B31
(n=1960)
AC for 4 cycles, followed by
paclitaxel for 4 cycles
+ Weekly T for 1 y
Reference
Romond
2005
NCCTG N9831
(n=3046)
AC q 3w for 4 cycles, followed by
12 weekly doses of paclitaxel
+Weekly T for 1 y
+Weekly T for 1 y
Romond
2005
HERA
(global ex-US)
(n=5090)
Standard CTX + observation only
Standard CTX + T 3-wkly for 1 y
Standard CTX + T 3-wkly for 2 y
Piccart-
Gebhart
2005
BCIRG 006
(global)
(n=3222)
AC for 4 cycles, followed by
docetaxel for 4 cycles
+ T 3-wkly for 1 y
Carbo + docetaxel for 6 cycles,
+ T 3-wkly for 1 y
Slamon
2006
FinHer
(n=232)
Docetaxel or vinorelbine for 3
cycles, followed by FEC for 3
cycles
+ Weekly T for 9 weeks
Joensuu
2006
PACS 04
(n=528)
FEC or ED for 6 cycles
+ Weekly T for 1 year
Spielmann
2007
See Glossary on last slide for explanations of all abbreviations here, unless previously defined.
-
210
Combined US (n=3968)b
HERA (n=3401)
BCIRG AC-DT (n=1074)
BCIRG DCarboT (n=1075)
FinHER (n=232)
PACS-04 (n=528)
aAbsolute difference in percentage of patients with DFS at 4 or 3 yearsbCombined US: Joint analysis of NSABP B-31 and NCCTG N9831
A, doxorubicin; C, cyclophosphamide; Carbo, carboplatin; D, docetaxel; T, trastuzumab;
DFS, disease-free survival; FU, follow-up; HR, hazard ratio
Absolute
benefit at
4y/3ya
Median
FU yrsHR
30.49 12.8%
20.64 6.3%*
30.61 6%
30.67 5%
0.42 11% 3
40.86 –0.5%
p
-
HR
210
0.63
0.66
0.59
0.66
0.41
1.27
3.2%
2.7%*
6%
5%
6.6%*
Difference at
4y/3ya
–1.5%
3
Median
FU yrs
3
3
2
3
p
0.004
0.017
0.0115
0.07
n.s.
* Benefit at
3 y
4
Favours trastuzumab Favours chemotherapy only
Combined US (n=3969)b
HERA (n=3401)
BCIRG AC-DT (n=1074)
BCIRG DCarboT (n=1075)
FinHER (n=232)
PACS-04 (n=528)
Reference
Smith 2007
Slamon 2006
Joensuu 2006
Spielmann 2007
0.0004
aAbsolute difference in percentage of patients with OS at 4 or 3 yearsbCombined US: Joint analysis of NSABP B-31 and NCCTG N9831
Perez 2007
*Benefit at 3y
Adjuvant chemotherapy ± trastuzumab trials: overall survival
Slamon 2006
REDUCTION IN MORTALITY RISK: 34%-59% IN EBC
COST TRASTUZUMAB: 2.300 €/cycle (s.c T)
MCBS: A
-
Copyrights for this presentation are held by the author/presenter. Contact for permission to reprint and/or distribute.
8th European Breast Cancer Conference
21̶-24 March 2012, Vienna, Austria
Abstract 1BA
11
HannaH Phase III Study
Objective:
Show non-inferiority of SC vs. IV based on co-primary endpoints• PK: observed trastuzumab Ctrough pre-dose Cycle 8 (pre-surgery)
• Efficacy: pathological complete response (pCR) in the breast
HER2-
positive
EBC
(N=596)*
SC trastuzumab
IV trastuzumab
Su
rgery
Fo
llo
w-u
p:
24
mo
pCR
18 c
ycle
s/
1 y
ear
Trastuzumab SC 600 mg/5 mL q3w
(fixed dose)
Trastuzumab IV
6 mg/kg q3w
(8 mg/kg loading dose)
Docetaxel75 mg/m2
FEC500/75/500
Neoadjuvant Adjuvant
R
1:1
Clinical stage Ic to IIIc
including IBC
IBC, inflammatory breast cancer. FEC, 5-fluorouracil, epirubicin and cyclophosphamide
* Central HER2 testing was carried out by TARGOS Molecular Pathology GmbH
C Jackisch et al, EBCC 2012
-
Copyrights for this presentation are held by the author/presenter. Contact for permission to reprint and/or distribute.
8th European Breast Cancer Conference
21̶-24 March 2012, Vienna, Austria
Abstract 1BA
18
Summary and Conclusions
• HannaH provides the first demonstration that comparable
trastuzumab drug exposure and efficacy can be achieved for
trastuzumab SC and IV
• Efficacy is robust and consistent across subgroups and analysis
populations
• pCR rate is independent of body weight or trastuzumab trough level
• Trastuzumab trough levels are higher in SC, but exposure (AUC) is
comparable between IV and SC
• Overall, the safety profiles of the trastuzumab SC and IV
formulations are comparable and consistent with the known
safety profile of trastuzumab
• SC trastuzumab 600 mg fixed dose administered q3w in
approximately 5 minutes provides a valid treatment alternative to
the q3w IV regimen
C Jackisch et al, EBCC 2012
-
MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era &
Questions unanswered
• Consistent & significant benefit of adjuvant trastuzumab
• Optimal duration
Neoadjuvant or adjuvant setting•
Concomitant vs. sequential with CT•
• Optimal CT regimen (anthracyclines: to give or not give!)
• The principle of dual blockade (neo and adjuvant)
• Without CT or less CT in certain cases?
• Extended anti-HER2 therapy
-
TRIALS EVALUATING ADJUVANT TRASTUZUMAB DURATION
1 vs. 2 years: HERA
9 weeks: FinHER (Finland)
1 year vs. 3 ms: E 2198 (US)
1 year vs. 9 weeks: ShortHER
1 year vs. 9 weeks: SOLD
1 year vs. 6 ms: PHARE (France)
1 year vs. 6 ms: HeCOG (Greece)
1 year vs. 6 ms: Persephone (UK)
-
OBSERVATIONn=1698
Women with locally determined HER2-positive invasive early breast cancer
Surgery + (neo)adjuvant CT ± RT
Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55%
Randomization
1 year Trastuzumab8 mg/kg – 6 mg/kg3 weekly schedule
n=1703
2 years Trastuzumab8 mg/kg – 6 mg/kg3 weekly schedule
n=1701
After ASCO 2005, option of switchto Trastuzumab
HERA TRIAL DESIGNACCRUAL 2001 – 2005 (N=5102)
CT, chemotherapy; RT, radiotherapy Goldhirsch & Gelber et al, ESMO 2012, LBA 6
-
Dis
ease-f
ree s
urv
ival
(%)
Years from randomization
89.1%
86.7%81.0%
81.6%
75.8%
76.0%
DFS FOR 2 YEARS VS. 1 YEAR TRASTUZUMAB AT 8 YRS MEDIAN FU & 734 DFS EVENTS
100
80
60
40
20
0
0 1 2 3 4 5 6 7 8 9
No. at risk
Trastuzumab 2 years 1553 1553 1442 1361 1292 1223 1153 1051 633 194
Trastuzumab 1 year 1552 1552 1413 1319 1265 1214 1180 1071 649 205
Trastuzumab 1 year
Trastuzumab 2 years
Pts Events HR (2 vs 1) 95% CI p-value
2 years 1553 367 0.99 (0.85-1.14) 0.86
1 year 1552 367
Goldhirsch & Gelber et al, ESMO 2012, LBA 6
Ov
era
ll S
urv
ival
(%)
Years from randomizationNo. at risk
Trastuzumab 2 years 1553 1553 1525 1485 1438 1382 1317 1193 708 208
Trastuzumab 1 year 1552 1552 1513 1461 1413 1364 1329 1218 732 225
100
80
60
40
20
0
0 1 2 3 4 5 6 7 8 9
97.4%
96.5%91.4%
92.6%86.4%
87.6%
Trastuzumab 1 year
Trastuzumab 2 years
Pts Events HR (2 vs 1) 95% CI p-value
2 years 1553 196 1.05 (0.86-1.28) 0.63
1 year 1552 186
OS FOR 2 YEARS VS. 1 YEAR TRASTUZUMAB AT 8 YRS MEDIAN FU & 734 DFS EVENTS
Goldhirsch & Gelber et al, ESMO 2012, LBA 6
•No added benefit for 2 years•Independent of ER status•Higher cardiac toxicity for 2 years
-
www.esmo2012.org
PHARE Study design
trastuzumab 6 months
trastuzumab up to 12 months1690 patients
stop trastuzumab (i.e. 6 months)1690 patients
Clinical examLVEF
3
Mammography
6 9 12 15 18 21 24 30 mos
…
0
R
R: Randomization after informed consent
Up to 60 mos…
Stratification1. ER pos / neg2. Chemo: conco/ seq
3384 ptsrandomised
Pivot et al, ESMO 2012, LBA 5
Protocol of Herceptin®
Adjuvant withReduced Exposure
-
www.esmo2012.org
0.00
0.25
0.50
0.75
1.00
Pro
babili
ty
1690 1586 1353 939 526 23H 6m1690 1613 1390 980 544 18H-12m
At risk
0 12 24 36 48 60Months
H-12m H-6m
Disease Free Survival
* Cox model stratified by ER status and concomitant chemotherapy
95.5 91.2 87.8 84.9
97.0 93.8 90.7 87.8
Events HR 95%CI p-valueH 12m 176H 6m 219 1.28 (1.05 – 1.56) 0.29
Pivot et al, ESMO 2012, LBA 5
www.esmo2012.org
0.00
0.25
0.50
0.75
1.00
Pro
bab
ility
1690 1645 1438 1016 566 25H 6m1690 1662 1463 1042 583 19H-12m
At risk
0 12 24 36 48 60Months
H-12m H-6m
Overall Survival
* Cox model stratified by ER status and concomitant chemotherapy
42.5mos. median FU
99.3 97.2 95.2 93.1
99.9 98.7 96.9 95.0
Events HR 95%CI p-valueH 12m 66H 6m 93 1.47 (1.07 – 2.02)
Pivot et al, ESMO 2012, LBA 5
www.esmo2012.org
Equivalent
Superior
Non Inferior
Inferior
A
B
C
D
E
.85 1 1.15 1.3 1.45 1.6HR
Primary endpoint scenarii
PHARE trial
Pivot et al, ESMO 2012, LBA 5
-
Presented by: Carey K. Anders, MD
Short-HER: Study Design
Stratification factors: HR status, Nodal statusRadiotherapy and hormonal therapy started at the completion of ChemoRx, when indicated
EUDRACT number: 2007-004326-25
NCI ClinicalTrials.gov number: NCT00629278
Non-inferiority study:
HR = 1.29,
Alpha: 0.05 (one tail)
Power: 80%
n = 1250 pts
-
SHORTHer Primary Objective of DFS
Presented by: Carey K. Anders, MD
5.2 yrs Follow-up
N = 1253
0.0
00
.25
0.5
00
.75
1.0
0
626 601 576 554 476 351 233 120 46B short627 608 592 566 482 374 239 132 43A long
Number at risk
0 12 24 36 48 60 72 84 96Months from randomization
A long B short
HR = 1.15 (0.91 – 1.46); 0.78 probability
5yr DFS (87.5% LONG vs. 85.4% SHORT)
Subset Analyses:
HR>1.0 favors LONG
Ratio of HRs
(90%CI)
p-value
Stage
III vs I+II
2.30
(1.35, 3.94) < 0.001
Nodal status
N2+N3 vs N0+N1
2.25
(1.33, 3.83) < 0.001
No difference in 5 yr OS (95.1 vs 95%)
-
Presented by: Carey K. Anders, MD
ShortHER: Cardiac Adverse Events
Long
N=627
Short
N=626
Grade N(%) N(%)
2 69 (11.0) 22 (3.5)
3 12 (1.9) 5 (0.8)
4 1 (0.2) 0
Total 82 (13.1) 27 (4.3)P
-
TAKE HOME MESSAGES
Duration of adjuvant trastuzumab: DON’T CHANGE YOUR PRACTICE
In total about 15.000 pts enrolled to answer duration question!Really needed?
Can we be smarter in trial design?Can sponsors be more flexible?
Duration of adjuvant trastuzumab: STORY NOT FINISHEDRole of concurrent administrationAny subgroup of pts needing shorter or longer duration?Wait for other trial results & longer FU of PHARE and ShortHER
-
MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era &
Questions unanswered
• Consistent & significant benefit of adjuvant trastuzumab
• Optimal duration
Neoadjuvant or adjuvant setting•
Concomitant vs. sequential with CT•
• Optimal CT regimen (anthracyclines: to give or not give!)
• The principle of dual blockade (neo and adjuvant)
• Without CT or less CT in certain cases?
• Extended anti-HER2 therapy
-
Meta-analysis: Neoadjuvant
anthracyclines/taxanes with or without
trastuzumab
Von Minckwitz et al, SABCS 2008, Abstract 79
All cooperative neoadjuvant trials in Germany between 1998 and 2006
using anthra/taxanes (N=4913) plus GeparQuattro and TECHNO trials
(N=1721) using trastuzumab for HER2+ tumors
Goals:
• Overall pCR rate
• Effects according to treatment:
- Trastuzumab
- Dose-Density
- Duration
- Concurrent versus sequential
Total 6634 pts
-
Von Minckwitz, SABCS 2008, Abstract 79
Meta-analysis: pCR rate based on treatment
Trastuzumab
(N=671)
No Trastuzumab
(N=736)
P-value
pCR rate 41% 23%
-
a CT: AP x 3 followed by P x 4, followed by CMF x 3
HER2-positive LABC
(IHC 3+ or FISH+)
HER2-negative LABC
(IHC 0/1+)
ChemotherapyaChemotherapyaTrastuzumab +
chemotherapya
Surgery followed by radiotherapyb
Trastuzumab
continued to week 52
n = 115 n = 113 n = 99
19 patients crossed
over to trastuzumab
NOAH: Phase III, Open-Label Trial of Neoadjuvant Trastuzumab
Gianni L, et al. Lancet. 2010;375(9712):377-384.
bHR+ pts received adjuvant tamoxifen
-
NOAH: Event-Free Survival (EFS) and OS in HER2-Positive Population (ITT)
EFS OS
Gianni L, et al. Lancet. 2010;375(9712):377-384.
-
Neoadjuvant therapy for HER-2+ breast cancer
Anti• -HER-2 agent in neoadjuvant or adjuvant setting?
NO DIRECT COMPARISON ADJUVANT VS. NEOADJUVANT
INDIRECT EVIDENCE (Higher pCR rates!!)
-
MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era &
Questions unanswered
• Consistent & significant benefit of adjuvant trastuzumab
• Optimal duration
•Neoadjuvant or adjuvant setting
•Concomitant vs. sequential with CT
• Optimal CT regimen (anthracyclines: to give or not give!)
• The principle of dual blockade (neo and adjuvant)
• Without CT or less CT in certain cases?
• Extended anti-HER2 therapy
-
Perez, SABCS 2009
-
Perez, SABCS 2009
There is a strong trend for a 25% reduction in the risk
of an event with starting trastuzumab concurrently with
taxane relative to sequentially:
5 yr DFS: 80% vs. 84% (final results would need too long FU)
-
MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era &
Questions unanswered
• Consistent & significant benefit of adjuvant trastuzumab
• Optimal duration
•Neoadjuvant or adjuvant setting
•Concomitant vs. sequential with CT
• Optimal CT regimen (anthracyclines: to give or not give!)
• The principle of dual blockade (neo and adjuvant)
• Without CT or less CT in certain cases?
• Extended anti-HER2 therapy
-
BCIRG 006 Trial Design
HER2+(Central FISH)
N+
or high
risk N−
N=3222
Stratified by nodes and hormonal receptor status
AC→T
AC → TH
TCH
4 x AC60/600 mg/m2
4 x Docetaxel100 mg/m2
4 x AC60/600 mg/m2
4 x Docetaxel100 mg/m2
1 year Trastuzumab
6 x Docetaxel and Carboplatin75 mg/m2 AUC 6
1 year TrastuzumabSlamon D, et al. Cancer Res. 2009;69(24 Suppl): Abstract 62.
-
DFS in all patients
Slamon D et al. N Engl J Med 2011;365:1273-1283
DFS in patients without TOP2A co-amplification
DFS in patients with TOP2A co-amplification
-
Therapeutic Index for Critical Clinical Events
Slamon D et al. N Engl J Med 2011;365:1273-1283
-
CLINICAL IMPLICATIONS OF BCIRG 006
• We don’t know how safe it is to withhold anthracyclines and in which pts (trial not powered to show equivalence; trial hypothesis (TCH better) not proven!)
• TCH associated with less cardiotoxicity and less leukemia (associated with A or C??!!)
• ONLY POSSIBLE CLINICAL RECOMMENDATION:
TCH is a very good option and should be chosen when cardiac risk factors or c.i. for anthracyclines are present
-
MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era &
Questions unanswered
• Consistent & significant benefit of adjuvant trastuzumab
• Optimal duration
•Neoadjuvant or adjuvant setting
•Concomitant vs. sequential with CT
• Optimal CT regimen (anthracyclines: to give or not give!)
• The principle of dual blockade (neo and adjuvant)
• Without CT or less CT in certain cases?
• Extended anti-HER2 therapy
-
NeoALTTO: Trastuzumab + Lapatinib
NSABP B-41: Trastuzumab + Lapatinib
CherLob: Trastuzumab + Lapatinib
NeoSphere: Trastuzumab + Pertuzumab
TRYPHAENA : Trastuzumab + Pertuzumab
TRIALS EVALUATING DUAL BLOCKADE
IN THE NEOADJUVANT SETTING
-
TRIALS EVALUATING DUAL HER2 BLOCKADE
Advanced DiseaseEGF104900Cleopatra PERUSE
PHEREXA
NeoSPHERE TRYPHAENAWSG-ADAPT
KRISTINE
NeoALTTOCherlob
LPT 109096 NSABP B-41
CALGB 40601
Neoadjuvant setting
ALTTO APHINITY Adjuvant setting
STRATEGY A STRATEGY B
Alvaro Moreno-Aspitia et al, ASCO 2017
-
Trastuzumab
Lapatinib
NeoALTTO Study Design
Baselga J, et al. Cancer Res. 2010;70(24 Suppl): Abstract S3-3.
• Invasive
operable
HER2+ BC
• T >2 cm
(inflammatory
BC excluded)
• LVEF ≥50%
N = 450
R
A
N
D
O
M
I
Z
E
S
U
R
G
E
R
Y
Lapatinib
Trastuzumab
Lapatinib
Paclitaxel
Paclitaxel
Trastuzumab
Paclitaxel
6 wks +12 wks
F
E
C
X
3
Lapatinib
Trastuzumab
52 weeks of anti-HER2 therapy
34 wks
Stratification
•T≤5 cm vs T>5 cm
•ER or PgR+ vs
ER & PgR-
•N0-1 vs N≥2
•Conservative
surgery or not
IBC exclusion criteria
-
NeoALTTO: Overall Clinical Responseat 6 weeks (w/o chemo) and at surgery
L = lapatinib; T = trastuzumab
At Week 6 (w/o chemo) At surgery
L
N = 154
T
N = 149
L+T
N = 152
L
N = 154
T
N = 149
L+T
N = 152
P
-
Landmark Analysis: OS by PCR
Tests for interaction: pCR x HR p=0.33
Results of first analysis of EFS/OS are shown in square bracketsto provide comparison with this updateDe Azambuja et al. Lancet Oncol 2014
Ove
rall
surv
ival
Ove
rall
surv
ival
NeoALTTO trial
MEDIAN FU: 6.7 yearsJens Huober et al, ESMO 2017
-
Overall Survival Analysis by treatment arm
Tests for interaction: L + T vs T x HR p= 0.45L vs T x HR p=0.72
Results of first analysis of EFS/OS are shown in square bracketsto provide comparison with this updateDe Azambuja et al. Lancet Oncol 2014
Ove
rall
surv
ival
NeoALTTO trial
MEDIAN FU: 6.7 yearsJens Huober et al, ESMO 2017
-
NSABP B-41 Schema
Operable
Breast
Cancer
HER-2 neu
Positive
R
AC → WP+T
AC → WP+L
AC →
WP+T+L
S
U
R
G
E
R
Y
Tissue for Biomarkers
Trastuzumab
for a total of
1 year
WP=Weekly Paclitaxel
Tissue for Biomarkers
Accrued 529 patients from July 16, 2007 to June 30, 2011
-
NSABP B-41Summary Treatment Regimens
• Neither the addition of lapatinib to trastuzumab (AC→WP+T+L) nor the substitution of lapatinib for trastuzumab (AC→WP+L) demonstrated statistical superiority to trastuzumab (AC→WP+T) for RFI or OS in protocol specified pair-wise comparisons
• Exploratory analyses suggest the three treatment arms are different in long-term outcomes (p=0.049 for RFI and p=0.07 for OS)
• Exploratory analyses of RFI by HR status showed similar trends in patients with HR-negative and those with HR-positive tumors
-
ALTTO trial
-
Presented by:
DISEASE-FREE SURVIVAL (DFS) ANALYSIS
*Bracketed data in all KM curves represent results of the Primary Analysis – ASCO 2014
*
Alvaro Moreno-Aspitia et al, ASCO 2017
Absolute difference: 2 to 3%
-
Presented by:
DFS BY CHEMOTHERAPY TIMING
Median Clinical Follow-upSequential: 7.0 yearsConcurrent: 6.0 years
Alvaro Moreno-Aspitia et al, ASCO 2017
Absolute difference: 1 %Absolute difference: 3-4 %
-
Presented by:
DFS BY HORMONE RECEPTOR STATUS
Median Clinical Follow-upHR positive: 6.9 yearsHR negative: 6.9 years
Alvaro Moreno-Aspitia et al, ASCO 2017
Absolute difference: 2-4 %Absolute difference: 2 %
-
Presented by:
OVERALL SURVIVAL (OS) ANALYSIS
Alvaro Moreno-Aspitia et al, ASCO 2017
-
ALTTO trial
SAFETY
Alvaro Moreno-Aspitia et al, ASCO 2017
Presented by:
Safety Analysis - Overall AE summary by Arm
Lap+Tras
(N=2061)
Tras->Lap
(N=2076)
Lap
(N=2057)
Tras
(N=2076)
Any AE 1979 (96%) 1956 (94%) 1964 (95%) 1834 (88%)
AEs related to study t reatment 1922 (93%) 1801 (87%) 1857 (90%) 1329 (64%)
AEs leading to permanent
discont inuat ion 481(23%) 261(13%) 317 (15%) 171 (8%)
AEs leading to dose reduct ions 413 (20%) 275 (13%) 448 (22%) 81(4%)
AEs leading to dose interrupt ions/ delays 945(46%) 668 (32%) 821 (40%) 419 (20%)
Any SAE 459 (22%) 391 (19%) 461 (22%) 326 (16%)
SAEs related to study t reatment 276 (13%) 191 (9%) 275 (13%) 116 (6%)
Fatal SAEs 19 (
-
ALTTO trial
Presented by:
DISEASE-FREE SURVIVAL (DFS) ANALYSIS
ALTTO investigators
*Bracketed data in all KM
curves represent results of
the Primary Analysis –
ASCO 2014
*
A. Moreno-Aspitia et al, ASCO 2017
DUAL BLOCKADE COST: 5.800 €/cycle
MCBS: No Evaluable Benefit
COST LAPATINIB: 3.500 €/cycle
-
NeoSphere Study Design
TH (n = 107)
docetaxel +
trastuzumab
Gianni L, et al. Cancer Res. 2010;70(24 Suppl): Abstract S3-2.
BC, breast cancer; FEC, 5-fluorouracil, epirubicin, and cyclophosphamide; H, trastuzumab; P, pertuzumab; T, docetaxel
*Locally advanced = T2-3, N2-3, M0 or T4a-c, any N, M0; operable = T2-3, N0-1, M0; inflammatory = T4d, any N, M0
THP (n = 107)
docetaxel +
trastuzumab +
pertuzumab
HP (n = 107)
trastuzumab +
pertuzumab
TP (n = 96)
docetaxel +
pertuzumab
S
U
R
G
E
R
Y
Patients with
operable or
locally advanced/
inflammatory*
HER2-positive
breast cancer
Chemo-naïve
and primary
tumors >2 cm
(N = 417)
FEC q3w x 3
Trastuzumab q3w cycles 5-17
FEC q3 x 3
Trastuzumab q3w cycles 5-17
Docetaxel q3w x 4FEC q3w x 3
Trastuzumab q3w cycles 5-17
FEC q3w x 3
Trastuzumab q3w cycles 5-21
Study dosing: q3w x 4
-
NeoSphere: pCR Rates (ITT Population)
CI, confidence interval; H, trastuzumab; P, pertuzumab; pCR, pathologic complete response; T, docetaxel
Gianni L, et al. Cancer Res. 2010;70(24 Suppl): Abstract S3-2.
P = .0198
P = .0141 P = .003
pC
R,
% ±
95%
CI
-
74The slides are the property of BIG. Permission required for reuse
APHINITY: Trial Design
Chemotherapy* + trastuzumab+ placebo
Chemotherapy* + trastuzumab+ pertuzumab
Randomisation and treatmentwithin 8 weeks of surgery
Anti-HER2 therapy for a total of 1 year (52 weeks)(concurrent with start of taxane)
Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy
Central confirmation
of HER2 status(N = 4805)
FOLLOW-UP
10
YEARS
R
S
U
R
G
E
R
Y
*A number of standard anthracycline-taxane-sequences or a non-anthracycline (TCH) regimen were allowed
G. von Minckwitz et al, ASCO 2017, NEJM 2017
-
75The slides are the property of BIG. Permission required for reuse
APHINITY: Intent-to-Treat Primary Endpoint Analysis Invasive Disease-free Survival
Number needed to treat: 112
expected: 89.2%
G. von Minckwitz et al, ASCO 2017, NEJM 2017
Absolute difference: 2 %
-
53The slides are the property of BIG. Permission required for reuse
APHINITY: Node-positive Subgroup
Number needed to treat: 56
G. von Minckwitz et al, ASCO 2017
55The slides are the property of BIG. Permission required for reuse
APHINITY: Node-negative Subgroup
G. von Minckwitz et al, ASCO 2017
EFFICACY BY NODAL STATUS
G. von Minckwitz et al, ASCO 2017, NEJM 2017
Absolute difference: 3 %
Absolute difference: 0 %
-
EFFICACY BY HR STATUS
56The slides are the property of BIG. Permission required for reuse
APHINITY: Hormone Receptor-negative Subgroup
Number needed to treat: 63
G. von Minckwitz et al, ASCO 2017
57The slides are the property of BIG. Permission required for reuse
APHINITY: Hormone Receptor-positive Subgroup
G. von Minckwitz et al, ASCO 2017
G. von Minckwitz et al, ASCO 2017, NEJM 2017
Absolute difference: 3 %
Absolute difference: 1.5 %
-
What were the cardiac and other “costs” of pertuzumab?
Presented by: Carey K. Anders, MD
Δ 9 pts
Δ 3 pts
Grade 3 diarrhea seen in 9.8% (H/P) and 3.7% (H/placebo); more in TCHP arm
12 pts = 0.05%
N (%) Pertuzumab(ptz)
n=2364
Treatmentptz vs. pla (95%
CI)
Placebo(pla)
n=2405
Primary cardiac endpoint 17 (0.7) 0.4 (0.0, 0.8) 8 (0.3)
• Heart failure NYHA III/IV + LVEF drop*
• Cardiac death**
15 (0.6)2 (0.08)
6 (0.2)2 (0.08)
• Recovered according to LVEF 7 4
Secondary cardiac endpointAsymptomatic or mildly symptomaticLVEF drop*
64 (2.7) -0.1 (-1.0, 0.9) 67 (2.8)
-
82The slides are the property of BIG. Permission required for reuse
63The slides are the property of BIG. Permission required for reuse
APHINITY: Trial Design
Chemotherapy* + trastuzumab+ placebo
Chemotherapy* + trastuzumab+ pertuzumab
Randomisation and treatmentwithin 8 weeks of surgery
Anti-HER2 therapy for a total of 1 year (52 weeks)(concurrent with start of taxane)
Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy
Central confirmation
of HER2 status(N = 4805)
FOLLOW-UP
10
YEARS
R
S
U
R
G
E
R
Y
*A number of standard anthracycline-taxane-sequences or a non-anthracycline (TCH) regimen were allowed
G. von Minckwitz et al, ASCO 2017, NEJM 2017
65The slides are the property of BIG. Permission required for reuse
APHINITY: Intent-to-Treat Primary Endpoint Analysis Invasive Disease-free Survival
Number needed to treat: 112
expected: 89.2%
G. von Minckwitz et al, ASCO 2017, NEJM 2017
APHINITY trial
DUAL BLOCKADE COST: 6.400 €/cycle
Provisional MCBS: B
COST PERTUZUMAB: 4.100 €/cycle
-
TRIALS EVALUATING DUAL BLOCKADE
IN THE NEOADJUVANT SETTING
Main conclusions
• In general trastuzumab + CT better than the other anti-HER-2 agent + CT
• Dual blockage beneficial particularly in ER negative disease, in terms of pCR rates
• Interesting RR of 2 anti-HER-2 agents alone (with no CT)
• NOT FULLY CONFIRMED IN THE LARGE ADJUVANT TRIALS
-
MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era &
Questions unanswered
• Consistent & significant benefit of adjuvant trastuzumab
• Optimal duration
Neoadjuvant or adjuvant setting•
Concomitant vs. sequential with CT•
• Optimal CT regimen (anthracyclines: to give or not give!)
• The principle of dual blockade (neo and adjuvant)
• Without CT or less CT in certain cases?
• Extended anti-HER2 therapy
-
De-Escalation
Tolaney S, NEJM 2015
-
pT1-pT3 pN0 HER2+
Tolaney S, NEJM 2015
-
MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era &
Questions unanswered
• Consistent & significant benefit of adjuvant trastuzumab
• Optimal duration
•Neoadjuvant or adjuvant setting
•Concomitant vs. sequential with CT
• Optimal CT regimen (anthracyclines: to give or not give!)
• The principle of dual blockade (neo and adjuvant)
• Without CT or less CT in certain cases?
• Extended anti-HER2 therapy
-
Timing of Distant Recurrences in relation to Adjuvant Trastuzumab
Romond EH, N Engl J Med 2005; 353:1673-1684. NSABP B-31 and NCCTG N9831
< 2% of patients relapse on adjuvant trastuzumab
and < 5% in the year following
Courtesy G. Curigliano
-
ExteNET: study design
Chan et al. Lancet Oncol 2016Clinicaltrials.gov identifier: NCT00878709
• HER2+ breast cancer
– IHC 3+ or ISH amplified (locally determined)
– Prior adjuvant trastuzumab + chemotherapy
– Lymph node +/–, or residual invasive disease after neoadjuvant therapy
• Stratified by: nodal status, hormone receptor status, concurrent vssequential trastuzumab R
and
om
izat
ion
(1
:1) Neratinib x 1 year
240 mg/day
Placebo x 1 year
2-y
ear
fo
llow
-up
for
iDFS
5-y
ear
fo
llow
-up
for
iDFS
Ove
rall
surv
ival
Part A Part B Part C
N=2840
Primary endpoint: invasive disease-free survival (iDFS)
Secondary endpoints: DFS-DCIS, time to distant recurrence, distant DFS, CNS recurrences, OS, safety
Other analyses: biomarkers, health outcome assessments (FACT-B, EQ-5D)
Endocrine adjuvant therapy given to patients with HR-positive tumors according to local practice
M. Martin et al, ESMO 2017
-
HR (95% CI) = 0.73 (0.57–0.92)Two-sided P = 0.008
Intention-to-treat population. Cut-off date: March 1, 2017
NeratinibPlacebo
50
60
70
80
90
0 6 12 18 24 30 36 42 48 54 60
No. at risk Neratinib Placebo
1420 1420
1316 1354
1272 1298
1225 1248
1106 1142
978 1029
965 1011
949 991
938 978
920 958
885 927
Months after randomization
Inva
sive
dis
ease
-fre
e s
urv
ival
(%
)100
95.5%∆ 2.4%
97.9%
91.7%∆ 2.6%
94.3%
90.2%∆ 2.0%
92.2%
89.1%
∆ 2.1%
91.2%
87.7%∆ 2.5%
90.2%
0
Treatment
ExteNET: 5-year analysis: iDFS
M. Martin et al, ESMO 2017
Absolute difference: 3.5 %
-
ExtNET: iDFS by hormone receptor status
95
Neratinib
Placebo
50
60
70
80
90
0 6 12 18 24 30 36 42 48 54 60
No. at risk
Neratinib
Placebo
816
815
757
779
731
750
705
719
642
647
571
581
565
567
558
556
554
551
544
542
523
525
Months after randomization
HR-positive subgroup
Inva
sive
dis
ease
-fre
e s
urv
ival
(%
)
100
96.1%
98.1%
91.7%
95.4%
89.8%
93.6%
88.5%
92.6%
86.8%
91.2%
0
50
60
70
Two-sided P = 0.762
HR (95% CI) = 0.95 (0.66–1.35)
80
90
0 6 12 18 24 30 36 42 48 54 60
No. at risk
Neratinib
Placebo
604
605
559
575
541
548
520
529
464
495
407
448
400
444
391
435
384
427
376
416
362
402
Months after randomization
HR-negative subgroup100
94.7%
97.5%
91.8%
92.8%
90.4%
90.8%
89.3%
89.9%
88.8%88.9%
0
Inva
sive
dis
ease
-fre
e s
urv
ival
(%
)
Neratinib
Placebo
Two-sided P = 0.002
HR (95% CI) = 0.60 (0.43–0.83)
Intention-to-treat population. Cut-off date: March 1, 2017M. Martin et al, ESMO 2017
Absolute difference: 5.6 % Absolute difference: 0 %
-
ExteNET: Side Effects
Chan i wsp. Abst.508
N % Neratinib (n=14080) Placebo (n=1408)
All grades G3-4 All grades G3-4
Diarrhea 1343 (95.4) 562 (39,9) 499 (35,4) 23 (1,6)
Dose reduction: 26%
Tx termination: 17%
What does G 3 diarrhea mean ?- > 7 stools daily- incontinence;
hospitalization- indicated- limiting self care ADL
Courtesy of Dr Aleksandra Łacko
-
ANTIDIARRHEAL PROPHYLAXIS REDUCES THE INCIDENCE OF SEVERE DIARRHEA
22%
24%23%
31% 25%
28%27%
20%
ExteNET
n=1408Loperamide
n=137Budesonide + Loperamide
n=64
CONTROL Trial
Colesttipol (bile acid sequestrant) cohort to be presented at SABCS 2017
ODAC presentation, 2017 Courtesy of Dr H. Rugo, ESMO 2017
-
OTHER NEOADJUVANT TRIALS IN HER-2+ EBC
-
ADAPT HER2+/HR+ TRIAL
International, prospective, randomized phase II trial•
Primary endpoint: • pCR (no invasive carcinoma in breast/nodes)
Secondary endpoints: dynamic testing evaluation, EFS, OS, safety•
Pts with ER+ and/or PgR+, HER2+, cT1c - cT4a-c, cN,
cM0 BC and adequate organ function, LVEF ≥
50%, normal ECG(N = 375)
T-DM1 3.6 mg/kg Q3W(n = 119)
Trastuzumab 8 mg/kg loading dose, then 6 mg/kg Q3W + ET*
(n = 129)
T-DM1 3.6 mg/kg Q3W + ET*(n = 127)
1. Harbeck N, et al. SABCS 2015. Abstract S5-03. 2. Hofmann D, et al. Trials. 2013;14:261.
Surgery†
Wk 12
*Tamoxifen if premenopausal; aromatase inhibitor (of investigator’s choice) if postmenopausal.†Standard chemotherapy (1-yr trastuzumab) recommended after surgery or 12-wk biopsy (if clinical non-pCR).
-
ADAPT Trial
Harbeck N, et al. SABCS 2015. Abstract S5-03.
• 12-wk T-DM1 increased pCR rate vs trastuzumab + ET in women with HER2+/HR+ EBC
– 41% vs 15%, respectively (P < .001)
– Addition of ET to T-DM1 did not raise pCR rate
– Menopausal status had minimal bearing on results
• Tolerable safety profile with low toxicity
• Early response significantly associated with increased pCR rate
– Detectable after 3 wks
– Authors conclude further investigation of T-DM1 in pts with EBC warranted
-
ADAPT HER2+/HR-: Design
• ER / PR negative ( 50%; LVEF within
normal institutional limits by
echocardiography; normal
ECG
N. Harbeck, ASCO 2016
-
ADAPT HER2+/HR-: Conclusions
WSG ADAPT HER• 2+/HR- is a unique phase II trial in
focusing only on HER2+ HR- early breast cancer (eBC)
90.5• % pCR rate with T+P+Pac is substantial
Adding chemotherapy to dual blockade more than •
doubles pCR rate in HER2+ HR- eBC
34.4• % pCR rate with P + T is clinically meaningful (e.g.
frail patients, small tumors)
Early response at • 3-weeks seems to be positively
correlated with pCR. Yet, missing data does not allow
any definite conclusions
N. Harbeck, ASCO 2016
-
Primary endpoint: pCR by local assessment (ypT0/is, ypN0)
Stratification factors: • local HR status, geographic location, and clinical stage at presentation
KRISTINE Study Design
• Centrally confirmed
HER2-positive,
operable, locally
advanced or
inflammatory
breast cancer
• Tumor >2cm
N=432
Docetaxel
Carboplatin
Trastuzumab
Pertuzumab
Pertuzumab
T-DM1
6 cycles of
neoadjuvant therapy
TCH+P
T-DM1+P
aAdjuvant chemotherapy was recommended for patients in the T-DM1+P arm who had residual disease in lymph node(s) or in the breast (>1cm).
R
A
N
D
O
M
I
Z
A
T
I
O
N
S
U
R
G
E
R
Y
F
O
L
L
O
W
-
U
P
Trastuzumab
Pertuzumab
Pertuzumab
T-DM1
12 cycles of
adjuvant
HER2-therapya
1
1
0
-
Difference: -11.3
95% CI: -20.5, -2.0
Stratified 2-sided P−value: 0.0155b
Primary Endpoint: pCR (ypT0/is, ypN0)
Presented by: Dr Sara
Hurvitz
123/221 99/223
apCR rate and 95% CI are shown. Patients with missing or unevaluable pCR status were considered nonresponders: TCH+P, 7 (3.2%); T-DM1+P, 18 (8.1%).
Treatment discontinuation in the neoadjuvant phase for progressive disease: TCH+P, 0% of patients; T-DM1+P, 7% of patients.bCochran-Mantel-Haenszel Chi-square.
56%44%
7
6
pCR by Central ER/PR Receptor Status
Presented by:
pC
R(%
)a
ER and PR negative ER and/or PR positive
60/82 45/83 56/128 46/131
TCH+P T-DM1+P TCH+P T-DM1+P
aypT0/is, ypN0; patients with missing or unevaluable pCR status were considered nonresponders. Twenty patients had “unknown” ER/PR status by
central analysis.
Difference (95% CI):
−19.0 (−33.3, −4.6)
Difference (95% CI):
−8.6 (−20.5, 3.2)
73%
54%
44%35%
-
Maintenance of HRQoL and Physical Function
Maintenance of HRQoLa
Presented by:
aData are based on the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and QLQ-
modified breast cancer module (BR23). Maintenance of health-related quality of life (HRQoL) and physical function were assessed as the time to
deterioration defined as the time from baseline to first 10-point (or greater) decrease.
Only data from the neoadjuvant treatment phase including pre-surgery visit are used. Patients of the ITT population with a baseline assessment and at
least 1 post-treatment assessment are included in this analysis.
0 1 5
Time (mo.)
2 3 4
T-DM1+P (n=200)
TCH+P (n=191)
100
80
60
40
20
0
De
terio
ratio
n-F
ree
Su
rviv
al (%
)
HR (95% CI): 0.60 (0.46–0.78)
6
Maintenance of physical functiona
T-DM1+P (n=200)
TCH+P (n=191)
HR (95% CI): 0.47 (0.36–0.62)
0 1 5
Time (mo.)
2 3 4
100
80
60
40
20
0
De
terio
ratio
n-F
ree
Su
rviv
al (%
) 6
-
Conclusions
Neoadjuvant • TCH+P achieved a superior pCR rate compared with T-
DM1+P (56% vs 44%)
Neoadjuvant TCH+P was associated with a • higher BCS rate (53% vs
42%)
Neoadjuvant • T-DM1+P had a more favorable safety profile
Lower incidence of grade ≥– 3 adverse events (13% vs 64%), serious
adverse events (5% vs 29%), and adverse events leading to treatment
discontinuation (3% vs 9%)
Neoadjuvant T• -DM1+P was associated with longer maintenance of
patient-reported HRQoL and physical function
1
1
5
Upcoming phase III T-DM1 data in EBC: KATHERINE – T-DM1 vs trastuzumab adjuvant in patients without pCR;
KAITLIN – T-DM1+P vs HP+taxane adjuvant.
-
116
Hormone therapy (ER+)
Hormone therapy (ER+)
Hormone therapy (ER+)
S
u
r
g
e
r
y
TCbHP×6Group A
Group B
Group C Group C1 (T-DM1+P×2)
Group C2 (FEC×4)
CNB MRI
TCbHP×4➡T-DM1+P×4
T-DM1+P×4
cT1c–cT3, cN0–cN1, M0
T ≤7 cm
HER2+ (central assessment)
primary invasive cancer
Allocation adjustment factors
ER+ / -
Menopausal status
T1-2 / T3
N0 / N1
Institution
R1:1:2
ResponderscCR
cPR & Ki67 ≤10%no invasive cancer
Docetaxel/ carboplatin/ trastuzumab
(75 mg/m2/ AUC6/ 8 mg/kg 6 mg/kg)
Pertuzumab (840 mg/kg 420 mg/kg)
T-DM1 (3.6 mg/kg)FEC (500 / 100 / 500 mg/m2)Hormone therapy in ER+ patients
Non-Responders
N=200
JBCRG-20 TRIAL (Randomized Ph 2):
Neoadjuvant therapy with trastuzumab emtansine and pertuzumab in patients with her2-positive primary breast cancer
Norikazu Masuda et al, ESMO 2017
-
117
pC
Rra
te (
%)
p = 0.013p = 0.047
All ER- ER+ All ER- ER+ All ER- ER+ All ER- ER+ All ER- ER+
n 51 21 30 52 23 29 101 42 59 80 36 44 21 6 15
JBCRG-20 TRIAL Primary endpoint; pCR (ypT0/isypN0) rate
All patients
ER-negative
ER-positive
Group A(TCbHP)
Group B (TCbHP T-DM1+P)
Group C2(T-DM1+P FEC)
Group C Group C1(T-DM1+P)
Norikazu Masuda et al, ESMO 2017
-
OTHER ADJUVANT TRIALS IN HER-2+ EBC
-
Katherine (POST-NEOAJUVANT)
Neoadjuvant CT+
trastuzumab
Residual
invasive
cancerR
T-DM1
Trastuzumab
Primary endpoint : IDFS
1400 patients; recruitment ongoing
-
KAITLIN
122
HER2+
Node+
or
Node-, ER-
and T>2cm
R
AC x 4
or
FEC x3
AC x 4
or
FEC x3
TAXANE
TRASTUZUMAB
PERTUZUMAB
T-DM1
PERTUZUMAB
IDFS
HO
89,5%
93,1%
1300/2500 women recruited…
PUT ON HOLD AFTER MARIANNE TRIAL RESULTS
-
MANAGEMENT OF HER-2 + EBC: Unanswered questions
• Optimal duration for all patients
• Neoadjuvant or adjuvant setting
• Optimal anti-HER-2 agent and optimal combination with CT
Dual blockade in the adjuvant setting•
• Without CT in certain cases? Small N0 tumors; elderly pts; minor cardiac problems??
• Mechanisms of resistance & predictive markers (beyond HER-2)
The role of BIOSIMILARS•
-
BACK-UP
-
The magnitude of improvement in pCR ratedid not predict EFS and OS effect
Cortazar P et al. Pathological complete response and long-term clinical
benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014
-
Association between pCR and EFS by BC subtype
Cortazar P et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBCpooled analysis. Lancet. 2014