1. Gunter von Minckwitz, MD, PhD Chairman of German Breast Group Germany
CURRENT PARADIGMS in HER2-Positive Breast Cancer Neoadjuvant, Adjuvant & Metastatic Settings
Gunter von Minckwitz, MD, PhD
Chairman of German Breast Group
Germany

2. NEOADJUVANT SETTING

3. von Minckwitz et al. J Clin Oncol 2010
Untch M,, J Clin Oncol 2010

4. Eligibility Criteria Unilateral or bilateral untreated breast cancer
Tumour 2 cm (palpation) or 1 cm (US)
Given indication for chemotherapy, e.g.:
cT3 or cT4 (including inflammatory)
cT1-3 and ER/PgR negative
cT1-3 and ER/PgR positive and cN+ (for cT2) or pNSLN+(for cT1)
LVEF  55%
No significant cardiac co-morbidity
Untch M,, EBCC 2008 & J Clin Oncol 2010
Von Minckwitz G, J Clin Oncol 2010
ER, estrogen receptor; PgR, progesterone receptor
LVEF, left ventricular ejection fraction

5. Efficacy of Trastuzumab pCR%
Pathologic complete response, according to our primary endpoint definition, was observed in around 21% in all three treatment groups.
If those cases with only DCIS remaining in the breast are also taken into account, this rate increases to 29%.
No statistically significant difference was found for the two comparisons - neither for the effect of capecitabine nor for the effect of treatment duration.
Untch M,, J Clin Oncol 2010

6. Efficacy of Trastuzumab according to central HER2 status%
Pathologic complete response, according to our primary endpoint definition, was observed in around 21% in all three treatment groups.
If those cases with only DCIS remaining in the breast are also taken into account, this rate increases to 29%.
No statistically significant difference was found for the two comparisons - neither for the effect of capecitabine nor for the effect of treatment duration.

7. Long-term LVEF in patients receiving 3xA60T150→3xT175CMFx4 ± Trastuzumab
Gianni L, et al. NOAH study Lancet 2010

8. PCR predicts survival in HER2-positive disease treated with EC-P+trastuzumab Results of the TECHNO-study
M. Untch, personal communication

9. Geparquinto – Decision Tree
HER2 positive? no
yes
EC-Doc + Trastuzumab
vs.
EC-Doc + Lapatinib
EC vs. EC + Bev
Response assessment after 4xEC+/-Bev no
yes
2nd randomisation: Pw vs. Pw + RAD001
Doc vs. Doc + Bev
M. Untch, SABCS 2011, G. von Minckwitz SABCS 2011

10. pCR (no invasive/non-invasive residual in breast & nodes based on central pathology report review)
M. Untch, SABCS 2011,

11. 52 weeks of anti-HER2 therapy
Study Design S U R
G E Y A N D O M I Z E
lapatinib
trastuzumab
paclitaxel
+ 12 wks
6 wks
34 weeks
52 weeks of anti-HER2 therapy
lapatinib
trastuzumab
FEC X 3
Stratification:
T ≤ 5 cm vs. T > 5 cm
ER or PgR + vs.
ER & PgR –
N 0-1 vs. N ≥ 2
Conservative surgery
or not
Invasive operable
HER2+ BC
T > 2 cm
(inflammatory BC
excluded)
LVEF  50%
N=450
J. Baselga, SABCS 2011 11

12. Cumulative Incidence of Diarrhea Grade ≥ 3
J. Baselga, SABCS 2011
Safety Population

13. Efficacy – pCR and tpCR
L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab
pCR pathologic complete response
J. Baselga, SABCS 2011 13

14. Comparison of pCR-rates
Neo-Sphere Neo-Altto G5 HER2+ G5 TNBC Duration Mono-Tx Doc+H Pw+H EC-Doc+H EC-Doc+B ypT0/is ypN * Combo-Tx Doc+HP Pw+HL n.a. n.a ypT0/is ypN
*without pCRs in non-responders

15. CALGB 40601: HER2+ Neoadjuvant Trial
Paclitaxel x 16 wks
Trastuzumab
SURGERY
N=400
HER2+
Stage II-III
Paclitaxel x 16 wks
Dose-dense AC
(recommended)
Trastuzumab x 1y
(recommended)
Lapatinib
Endocrine Rx and RT prn
Paclitaxel x 16 wks
Trastuzumab + lapatinib
Breast imaging
Blood
MUGA
Tumor Biopsy - required
Breast imaging Blood
MUGA
Planned cross-validation with NeoALTTO

16. GeparSixto Effect of Carboplatin in HER2+/triple neg BC
18 weeks
N=600
Paclitaxel weekly + Myocet weekly
T4 or
T3 or T>1cm,
Triple neg. or
HER2 pos. R*
Surgery
Paclitaxel weekly +
Myocet weekly +
Carboplatin
Trastuzumab+Lapatinib in HER2 positive pts.
Bevacizumab in TNBC pts.
*stratified according to HER2/ER and Ki-67

17. Conclusions Trastuzumab (H) doubles pCR-rates
pCR after H is a surrogate for survival
Combination with anthracyclines appears to be safe
Double blockage of HER2 combined with a few CT cycles reaches comparable pCR rates as longer CT+Trastuzumab
Double blockage of HER2 opens the window for CT-free regimen.

18. Case 1 with Locally Advanced Breast Cancer
Age 30
Menaposual Status
Premenaposual
Surgery -
Tumour size
5.5 cm
Pathology
Diagnosis
Ductal-invasive BREAST CARCINOMA
Grade
Grade III
Lymphatic Nodes
cN2 HR
ER ( + ) , PR ( - )
HER2
IHC +++
Stage
cT3 cN2 cM0
Treatment
???

19. Case 1 : What is your treatment option?
1) Preop AC-T + trastuzumab (9 weeks)
2) Preop AC-T + trastuzumab (T completed up to 52 weeks including adjuvant)
3) Preop TCH
4) Preop AC-T with no trastuzumab
5) Preop trastuzumab without CT
6) Primary surgery

23. Case 1 with Locally Advanced Breast Cancer
Treatment approach according to AGO’s perspective:
AC-TH → Surgery → H (up to 1 year)

24. Any question or contribution?...

25. METASTATIC SETTING

26. Single-Institution Retrospective Analysis on 2091 patients with MBC
Dawood et al. J Clin Oncol 2010

27. First Randomized Phase III Study to Investigate Continuation of Trastuzumab
Capecitabine 2,500 mg/m² d 1–14 q3w
(n=78) R
Capecitabine 2,500 mg/m² d 1–14 q3w + Continuation of trastuzumab 6 mg/kg q3w
(n=78)
von Minckwitz G, et al. J Clin Oncol 27: , 2009
R, randomization

28. Clinical Response (RECIST)
OR: 27.0%
CB: 54.1%
OR: 48.0%
CB: 75.3%
NC: 27.1%
NC: 27.2%
OR:
CB:
(2-sided p)
CR: 7.7%
CR: 2.7%
PR: 40.4%
PR: 24.3%
von Minckwitz G, et al. J Clin Oncol 27: , 2009
OR = Overall response = CR+PR
CB = Clinical benefit = CR+PR+NC>24wks 28

29. Time To Progression at median Follow up of 15.6 months
X : 5.6 ( ) mos
XH : 8.2 ( ) mos
HR=0.69 (two-sided p=0.034; one-sided p=0.017)
Progression to CNS:
X: 8.3% XH: 13.8%
PFS
X: 5.6 mos XH: 8.2 mos
P=0.026 two sided
von Minckwitz G, et al. J Clin Oncol 27: , 2009 29

30. Capecitabine + Lapatinib vs Capecitabine
Lapatinib + Capecitabine
p-value
102 (51%)
82 (41%)
Progressed or died*
4.3
6.2
Median TTP, months
201
198
No. of pts
0.57 (0.43, 0.77)
Hazard ratio (95% CI) 70
* due to breast cancer
Cameron et al, Breast Cancer Res Treat 2008

31. Final Overall Survival Analysis (N=151)
X : 20.6 (18.6 – 27.4) mos
XH : 24.9 (20.3 – 30.7) mos
HR=0.94 (two-sided p=0.74)
von Minckwitz G, et al. SABCS 2010 poster presentation 31

32. Overall survival after 2nd progression cont of trast vs not (N=140)
von Minckwitz G, et al. SABCS 2010 poster presentation 32

33. ….Trastuzumab and lapatinib beyond trastuzumab
K. L. Blackwell et al, JCO Mar 2010: 1124–1130

34. Phase II Trastuzumab / Pertuzumab Study (BO17929)
Reference
1. Gelmon KA, Fumoleau P, Verma S. Results of a phase II trial of trastuzumab (H) and pertuzumab (P) in patients (pts) with HER2-positive metastatic breast cancer (MBC) who had progressed during trastuzumab therapy. J Clin Oncol. 2008;26(15S): Abstract 1026.
Baselga et al. J Clin Oncol 20010 34

35. Beyond trastuzumab…T-DM1
Tumor Response
IRF
(N=110)
Investigator
Objective Response Rate, %
(95% CI) CR PR
SD* PD UE
Missing
32.7
(24.1–42.1)
46.4
18.2
1.8
0.9
30.0
(22.0–39.4)
28.2
52.7
13.6
2.7
Clinical Benefit Rate, %)
44.5
(35.1–54.3)
40.0
(31.1–49.3)
IRF - Independent Review Facility *including unconfirmed partial remissions 35

36. Conclusion
ADCC is an antibody specific key mechanism for the action of trastuzumab
Trastuzumab is synergistic to various other agents
In vivo data and clinical evidence support the concept of “trastuzumab beyond progression”; representing a paradigm shift
HER2 blockade throughout all stages of MBC should be considered !

37. Case 2 with Metastatic Breast Cancer
Age 56
Menaposual Status
Postmenaposual
Surgery
TM-AD
Tumour size
4 cm
Pathology
Diagnosis
INVASIVE LOBULAR CARCINOMA
Grade
Grade II
Lymphatic Nodes
6/22 HR
ER 0%, PR 0%
HER2
IHC 2+, FISH pos.
Stage
T2 N2 M°
Previous Treatment
4xAC4xDocTrastuzumab  Trastuzumab
Liver metastases at 5th month after completion of adjuvant Trastuzumab treatment
Treatment
???

38. Case 2: What is your treatment of choice?
1) Trastuzumab + Paclitaxel
2) Trastuzumab + Vinorelbine
3) Trastuzumab + Capecitabine
4) Lapatinib + Capecitabine
5) Trastuzumab + Lapatinib
6) CT without anti-Her2-agent

40. Case 2 with Metastatic Breast Cancer
Treatment approach according to AGO’s perspective:
Paclitaxel + Trastuzumab

41. Case 3 with Metastatic Breast Cancer
Age 50
Menaposual Status
Postmenaposual
Surgery
mod. Rad mastectomy
Tumour size
3.5 cm
Pathology
Diagnosis
INVASIVE DUCTAL CARCINOMA
Grade
Grade III
Lymphatic Nodes
7/21 HR
ER 60%, PR 30%
HER2
IHC 3+
Stage
T2 N2 M1 (lung)
1st line treatment
DocH trastuzumab
(liver metastases during trastuzumab monotherapy at 9th months )
2nd line treatment
???

42. Case 3: What is your treatment option in 2nd line?
1) Vinorelbine + Trastuzumab
2) Capecitabine + Trastuzumab
3) Capecitabine + Lapatinib
4) Trastuzumab + Lapatinib

45. Case 3 with Metastatic Breast Cancer
Treatment approach according to AGO’s perspective:
Capecitabine + Trastuzumab

46. 2nd Line Treatment for Case 3
Option 1
2nd Line Treatment for Case 3
Stage
T² N² M¹ (lung)
1st line treatment
DocH Trastuzumab
Liver metastases during Trastuzumab monotherapy at 9th months
2nd line treatment
Capecitabine + Trastuzumab
CNS metastasis after 6 months
3rd line treatment
???

47. Case 3: What is your treatment option in 3rd line?
WBRT followed by
1) Vinorelbine +Trastuzumab
2) Cisplatin+ Trastuzumab
3) Lapatinib + Capecitabine (if not used as 2nd line)
4) Trastuzumab + Lapatinib

48. Case 3 with Metastatic Breast Cancer
Treatment approach according to AGO’s perspective:
Trastuzumab + Lapatinib

49. Any question or contribution?...

50. ADJUVANT SETTING

51. Case 4 with Early Breast Cancer
Age 45
Menaposual Status
Premenopausal
Surgery
BCS-SNL
Tumour size
1,2 cm
Pathology
Diagnosis
INVASIVE DUCTAL CARCINOMA
Grade,
Ki-67
Grade I,
24%
Lymphatic Nodes
0/2 HR
ER 60%, PR 60%
HER2
IHC +++
Stage
cT¹ cN° M°
Treatment
???

52. Case 4: What is your treatment option?
1) CT + HT + Trastuzumab (9 weeks)
2) CT + HT + Trastuzumab (52 weeks)
3) CT + HT
4) HT + Trastuzumab (9 weeks)
5) HT + Trastuzumab (52 weeks)
6) HT

56. Case 4 with Early Breast Cancer
Treatment approach according to AGO’s perspective:
CT+Trastuzumab 52 wks + HT
FEC x6 or EC x4-Pac x12

57. Case 5 with Early Breast Cancer
Age 38
Menaposual Status
Premenaposual
Surgery
BCT-SNL
Tumour size
2,3 cm
Pathology
Diagnosis
INVASIVE DUCTAL CARCINOMA
Grade
Grade III
Lymphatic Nodes
0/1 HR
ER ( - ) , PR ( - )
HER2
IHC %100 (+++)
Stage
pT2 pN° M°
Treatment
???

58. Case 5: What is your treatment option?
1) CT + Trastuzumab (9 weeks)
2) CT + Trastuzumab (52 weeks)
3) CT
4) Trastuzumab (9 weeks)
5) Trastuzumab (52 weeks)

62. Case 5 with Early Breast Cancer
Treatment approach according to AGO’s perspective:
EC-Pac + Trastuzumab 52 wks + HT

63. Any question or contribution?...