1. Neues aus der (neo) adjuvanten Therapie
Ulrike Nitz
Brustzentrum Niederrhein

2. HER2 +

3. BCIRG 006: anthrazyklinfreie Chemo - Overall Survival
Follow-Up 10.3yrs
Patients
Events
HR (95% CI) p
AC-T
1073
203
1 (reference)
AC-TH
1074
141
0.63 ( )
<0.0001
TCH
1075
167
0.76 ( )
0.0075
85.9%
83.3%
% survival
78.7%
Time (months)
Mod. Slamon DJ et al. SABCS 2015, General Session 5, Abstract No. S5-04

4. Van Ramshorst MS et al. General Session 6 Abstract No. S6-06
The effect of Trastuzumab-based therapy on overall survival in small, node-negative HER2-positive breast cancer: to treat or not to treat?
Van Ramshorst MS et al. General Session 6
Abstract No. S6-06

5. Methods – Data Collection
Population-based cohort study
Netherlands Cancer Registry (NCR)1-2
Stage I HER2+ BC diagnosed between
Linkage with Statistics Netherlands3
1Schouten et al. Int J Epidemiol 1993;22:369 2www.iknl.nl 3www.cbs.nl
Mod. Van Ramshorst MS et al. SABCS 2015, General Session 6, Abstract No. S6-06

6. No chemotherapy no Trastuzumab
Results - Cohort
Chemotherapy +
Trastuzumab
n=1453 (92%)
Chemotherapy and/or
Trastuzumab
n=1567 (45%)
Chemotherapy
n=75 (5%)
Stage I
HER2+ BC
n=3512
Trastuzumab
n=48 (3%)
No chemotherapy no Trastuzumab
n=1936 (55%)
Mod. Van Ramshorst MS et al. SABCS 2015, General Session 6, Abstract No. S6-06

7. Results - Overall Survival
Treated - Untreated
T1a
T1b
T1c
OS Probability
HR 0.05
8-yrs OS 100% vs 85%
p=0.47
HR 0.14
8-yrs OS 99% vs 89%
p=0.05
HR 0.23
8-yrs OS 94% vs 80%
p<0.001
Time (years)
Time (years)
Time (years)
Treated 28
357
356
355 21
294 10
215 8
164 4
111 3 59 2 22
150
650
643
149
635
105
550 79
457 54
354 34
273 15
154 6 75
1398
929
1393
921
1389
899
1142
792
873
682
648
568
413
462
238
297
114
134
Untreated
Mod. Van Ramshorst MS et al. SABCS 2015, General Session 6, Abstract No. S6-06

8. Results – Overall survival
Pts
Events
HR (vs obs.)
95% CI
p-value
2 years
1700
312
0.72
( )
<0.0001
1 year
1702
320
0.74
( )
Observation
1697
405
Number at risk
Observation only
Trastuzumab 1 year
Trastuzumab 2 years
1697
1702
1700
1443
1498
1532
1313
1383
1410
990
1149
1133
143
201
208
Years from randomization
Overall survival (%)
94.4%
92.7%
90.7%
88.7%
86.9%
84.5%
81.0%
80.7%
75.0%
79.5%
79.4%
72.9%
Three patients excluded from the ITT population due to lack of documentation of informed consent
Mod. Jackisch C et al. SABCS 2015, Poster Discussion 5: HER2, Abstract No. PD5-01

9. Chan A et al. General Session 5 Abstract No. S5-02
Neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: 3-year analysis from a phase 3 randomized, placebo-controlled, double-blind trial (ExteNET)
Chan A et al. General Session 5
Abstract No. S5-02

10. ExteNET - Final study design
Part A
Part B
Part C
Primary analysis: invasive DFS (iDFS) in ITT population (n=2840)
iDFS at 2 years: HR=0.67 ( ); p=0.009
Hormone receptor-positive (n=1631; 57.4%); HR=0.51; p=0.001
Centrally-confirmed HER2-positive 60% (n=1463; 51%); HR=0.51; p=0.002
2-year follow-up for iDFS
5-year follow-up for iDFS
Overall survival
HER2+ breast cancer (local)
Prior adjuvant Trastuzumab & chemotherapy
Completed Trastuzumab ≤1 year prior to study entry
Lymph node positive or non- pCR after neoadjuvant therapy
ER/PR status known
Neratinib
x 1 year
240 mg/day R
1:1
Placebo
x 1 year
Chan A et al. Lancet Oncol 2015 in press
Mod. Chan A et al. SABCS 2015, General Session 5, Abstract No. S5-02

11. 3-year iDFS analysis (ITT: n=2840)
97.8%
94.1%
92.0%
95.6%
90.5%
Disease-free survival (%)
91.6%
89.9%
88.6%
Two-sided *p-value=0.023
HR (95% CI)=0.74 ( )
Neratinib
Placebo
Months after randomization
No. at risk
Neratinib Placebo
*p value descriptive
Mod. Chan A et al. SABCS 2015, General Session 5, Abstract No. S5-02

12. Harbeck N et al. General Session 5 Abstract No. S5-03
Final analysis of the WSG-ADAPT HER2+/HR+ phase II trial Efficacy, safety, and predictive markers for 12-weeks of neoadjuvant T-DM1 with or without endocrine therapy versus Trastuzumab + endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer
Harbeck N et al. General Session 5 Abstract No. S5-03

13. ADAPT HER2+/HR+ – Trial design
Endpoint 1 2 3 4 5 6 7 8 9 10 11 12
pCR
T-DM1 3.6 mg/kg
VS.
Surgery*
T-DM1
3.6 mg/kg R
pCR
Endocrine therapy
Trastuzumab
pCR
EOT
Endocrine therapy
Prognosis
3 weeks therapy
Efficacy e.g. KI-67
BIOPSY
>
>
Hofmann et al., Trials 2013
*Standard chemotherapy recommended after surgery/ 12-week biopsy (in case of clinical non-pCR); Trastuzumab to be completed, for a total of one year.
Mod. Harbeck N et al. SABCS 2015, General Session 5, Abstract No. S5-03

14. ADAPT HER2+/HR+ – pCR (no invasive tumor in breast and nodes)
48/117
51/123
pCR rate
18/119
41.0%
41.5%
15.1%
A (T-DM1)
B (T-DM1+ET)
C (Trastuzumab+ET) 14
Mod. Harbeck N et al. SABCS 2015, General Session 5, Abstract No. S5-03

15. ADAPT HER2+/HR+ – Conclusions
More than 40% pCR (breast and nodes) in T-DM1 treated patients after 12 weeks without systemic chemotherapy:
41% T-DM1 and 41.5% T-DM1 + ET
15.1% Trastuzumab + ET
Adding endocrine therapy to T-DM1 does not increase pCR; effect independent of menopausal status
Very low overall toxicity; no new safety signals
Early tumor response (low cellularity or Ki67 drop ≥30%) significantly associated with increased pCR (OR 2.2)
Mod. Harbeck N et al. SABCS 2015, General Session 5, Abstract No. S5-03

16. von Minckwitz G et al. General Session 2 Abstract No. S2-04
HER+, HER2-/HR-, Carboplatin
Early survival anaylsis of the randomized phase II trial investigating the addition of Carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto)
von Minckwitz G et al. General Session 2
Abstract No. S2-04

17. Main Study Design R Surgery n=595 centrally confirmed TNBC or
HER2-positive breast cancer
cT2, cT3, or cT4a-d
cT1 and cN+ or pNSLN+ PM
PMCb
Surgery R
Paclitaxel (P) 80 mg/m2 q1w
Non-pegylated
liposomal Doxorubicin (M)
20 mg/m2 q1w
Carboplatin (Cb) q1w
Dose of AUC 2 was reduced to AUC 1.5 after enrolment of 330 patients
von Minckwitz et al. Lancet Oncology 2014
Mod. von Minckwitz G et al. SABCS 2015, General Session 2, Abstract No. S2-04

18. Test for interaction p=0.015
pCR Rates by Subtype
ypT0 ypN0
OR 0.84; p=0.6
OR 1.94; p=0.005
Test for interaction p=0.015
P = Paclitaxel, M = Non-pegylated liposomal Doxorubicin, Cb = Carboplatin von Minckwitz et al. Lancet Oncology 2014
Mod. von Minckwitz G et al. SABCS 2015, General Session 2, Abstract No. S2-04

19. DFS: Effect of Carboplatin in all Patients
3 yrs DFS 84.7%
3 yrs DFS 81.0%
Logrank p=0.3105
HR PMCb to PM = 0.81, 95% CI (0.54,1.21), p=0.3115
PM 54/293 events
PMCb 43/295 events
Proportion disease-free
DFS, months
PM PMCb
104 95
0 0
P = Paclitaxel, M = Non-pegylated liposomal Doxorubicin, Cb = Carboplatin
Mod. von Minckwitz G et al. SABCS 2015, General Session 2, Abstract No. S2-04

20. DFS: Effect of Carboplatin in TNBC
3 yrs DFS 85.8%
3 yrs DFS 76.1%
Logrank p=0.0325
HR PMCb to PM = 0.56, 95% CI (0.33,0.96), p=0.0350
PM 36/157 events
PMCb 21/158 events
Proportion disease-free
DFS, months
50 50
0 0
PM PMCb
P = Paclitaxel, M = Non-pegylated liposomal Doxorubicin, Cb = Carboplatin
Mod. von Minckwitz G et al. SABCS 2015, General Session 2, Abstract No. S2-04

21. Research biopsies- frozen and fixed
CALGB Schema
Randomized Phase II
ARM
Paclitaxel 80 mg/m2 wkly x12
ddAC x 4 A
ddAC x 4
Paclitaxel 80 mg/m2 wkly x12
Bevacizumab 10 mg/kg q2wks x 9 B
Surgery&*
XRT*
No adjuvant systemic treatment planned
2x2 R
Carboplatin AUC 6 q3wks x 4
Paclitaxel 80 mg/m2 wkly x 12
ddAC x 4 C
Carboplatin AUC 6 q3wks x 4
Paclitaxel 80 mg/m2 wkly x 12
Bevacizumab 10 mg/kg q2wks x 9
ddAC x 4 D
Research biopsies- frozen and fixed
&Research biopsies if residual tumor; *MD discretion
Mod. Sikov WM et al. SABCS 2015, General Session 2, Abstract No. S2-05

22. CALGB 40603 - EFS for Carboplatin vs. not
Proportion Event-Free
HR=0.84 ( ), p=0.36
No Cb
3-yr=71% Cb
3-yr=76%
Number at Risk
Years from Study Entry
No Cb Cb
94 101
31 37
2 2
0 0
Mod. Sikov WM et al. SABCS 2015, General Session 2, Abstract No. S2-05

23. ADAPT HR-/HER2- – Trial Design1 2 3 4 5 6 7 8 9 10 11 12
Endpoint
vs.
pCR R
Surgery or biopsy*
EOT
Nab-Paclitaxel
125 mg/m²
Gemcitabine
1000 mg/m²
Carboplatin
AUC2
Prognosis
3 weeks therapy
Efficacy
BIOPSY
BIOPSY
Standard chemotherapy (4xEC) recommended after surgery / 12-week biopsy (in case of clinical non-pCR)
Mod. Gluz O et al. SABCS 2015, General Session 6, Abstract No. S6-07

24. ADAPT HR-/HER2- – Pathological complete response
pCR rate
A (nab-Pac+Gem)
p<0.001
67/146
51/178
ypT0/is, ypN0
28,7%
45,9%
B (nab-Pac+Carbo)
Mod. Gluz O et al. SABCS 2015, General Session 6, Abstract No. S6-07

25. Denosumab adjuvant

26. Gnant M et al. General Session 2 Abstract No. S2-02
The impact of adjuvant Denosumab on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial
Gnant M et al. General Session 2
Abstract No. S2-02

27. randomized Placebo-controlled double-blind
ABCSG-18 – Trial Design
Prospective randomized placebo-controlled double-blind multicenter phase-3 trial
Recruitment 2006–2013 (3,425 postmenopausal patients)
Primary endpoint: Time to first clinical fracture (reached March 2014)
Secondary endpoints:
Fracture related secondary endpoints (Primary Analysis March 2015)
Disease outcome related endpoints
DFS – time driven analysis of disease free survival
OS, BMFS (will be analyzed at EoS)
Inclusion criteria:
Postmenopausal women with non-metastatic adenocarcinoma of the breast
ER+ and/or PR+; adjuvant non-steroidal aromatase inhibitor therapy
Exclusion criteria:
Prior or concurrent treatment with SERMs
Current or prior IV bisphosphonate administration
Known history of:
Paget’s disease
Cushing’s disease
hyperprolactinemia
hypercalcaemia or hypocalcaemia
other active metabolic bone disease
randomized Placebo-controlled double-blind
1:1
(n=3,425)
Denosumab 60 mg SC Q6M
Placebo SC Q6M
Gnant et al, Lancet 2015; 386: 433–43
Mod. Gnant M et al. SABCS 2015, General Session 2, Abstract No. S2-02

28. ABCSG-18 – Primary Endpoint Results (ASCO 2015)
Number of Fractures/Patients
Hazard ratio vs Placebo
p value
Placebo
176/1,709
0.50 (0.39–0.65)
<0.0001
Denosumab
92/1,711
Patients at risk
Placebo
Denosumab
1709
1711
1660
1665
1470
1488
1265
1297
1069
1118
921
965
785
823
637
688
513
549
384
432
275
305
185
221
112
Risk of fracture, %
Time since randomization, months 26 43 45
105 65
129 80
157 87
167 92
174
stratified by hospital type, use of prior aromatase inhibitor, and baseline lumbar spine bone mineral density Gnant et al, Lancet 2015; 386: 43
Mod. Gnant M et al. SABCS 2015, General Session 2, Abstract No. S2-02

29. ABCSG-18 – Results of the DFS ITT Analysis
Number of Events/Patients
HR (95% CI) vs Placebo
p value
Placebo
203/1,709
0.816 (0.66–1.00)
Cox
Denosumab
167/1,711
Log-rank
93.8%
88.9%
92.6%
83.5%
86.8%
Disease-free survival, %
80.4%
Time since randomization, months
Patients at risk
Placebo
Denosumab
1709
1711
1663
1676
1626
1623
1578
1584
1443
1424
1289
1296
1086
1102
958
984
779
693
714
534
548
454
479
289
300
241
252
115 73 66
stratified by hospital type, use of prior aromatase inhibitor, and baseline lumbar spine bone mineral density
Mod. Gnant M et al. SABCS 2015, General Session 2, Abstract No. S2-02

30. ABCSG-18 – Sensitivity Analysis DFS (cross-over censored*)
Number of Events/Patients
HR (95% CI) vs Placebo
p value
Placebo
199/1,709
0.807 (0.66–0.99)
Cox
Denosumab
164 /1,711
Log-rank
93.8%
88.9%
84.3%
92.7%
86.9%
80.3%
Disease-free survival, %
Patients at risk
Placebo
Denosumab
1709
1711
1661
1673
1616
1619
1562
1580
1424
1418
1269
1291
1066
1095
757
773
675
708
523
543
443
475
279
296 69 66
935
976
231
250
109
115
Time since randomization, months
*Patients (n=54) who went EoT because of alternate bone-active therapy (BIS, D-Mab) according to the protocol were censored at EoT stratified by hospital type, use of prior aromatase inhibitor, and baseline lumbar spine bone mineral density
Mod. Gnant M et al. SABCS 2015, General Session 2, Abstract No. S2-02

31. ABCSG-18 – Schlussfolgerung
Frakturrate bei postmenopausalen Frauen unter Aromatasehemmer höher als vermutet (rund 10% in der Kontrollgruppe)
Signifikante Reduktion Frakturrate durch Denosumab
Frühe Analyse positiv für krankheitsfreies Überleben („borderline significance“), ähnlicher Effekt wie Bisphosphonate in der Metaanalyse
Keine relevanten Nebenwirkungen
Mod. Gnant M et al. SABCS 2015, General Session 2, Abstract No. S2-02