CURRENT PARADIGMSin

HER2-Positive Breast Cancer

Neoadjuvant, Adjuvant & Metastatic Settings

Gunter von Minckwitz, MD, PhDChairman of German Breast Group

Germany

NEOADJUVANT SETTING

von Minckwitz et al. J Clin Oncol 2010

Untch M,, J Clin Oncol 2010

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

ER, estrogen receptor; PgR, progesterone receptorLVEF, left ventricular ejection fraction

Untch M,, EBCC 2008 & J Clin Oncol 2010

Von Minckwitz G, J Clin Oncol 2010

Efficacy of TrastuzumabpCR

%

41,4

17,8

0

5

10

15

20

25

30

35

40

45

HER-2 negative HER-2 positive

pCR (ypT0/is ypN0)

Untch M,, J Clin Oncol 2010

Efficacy of Trastuzumabaccording to central HER2

status

%

49,7

16,417,8

0

10

20

30

40

50

60

HER-2 negative HER-2equivocal

HER2 centralpositive

pCR (ypT0/is ypN0)

Long-term LVEF in patients receiving

3xA60T150→3xT175CMFx4 ± Trastuzumab

Gianni L, et al. NOAH study Lancet 2010

PCR predicts survival in HER2-positive disease treated with EC-

P+trastuzumabResults of the TECHNO-study

M. Untch, personal communication

Geparquinto – Decision Tree

HER2 positive?

EC-Doc + Trastuzumabvs. EC-Doc + Lapatinib

no

EC vs. EC + Bev

Response assessment after 4xEC+/-Bev

Doc vs. Doc + Bev2nd randomisation: Pw vs. Pw + RAD001

no

yes

yes

M. Untch, SABCS 2011, G. von Minckwitz SABCS 2011

pCR(no invasive/non-invasive residual in breast

& nodes based on central pathology report review)

M. Untch, SABCS 2011,

Study Design

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 operableHER2+ BCT > 2 cm (inflammatory BC excluded)LVEF 50%N=450

34 weeks

52 weeks of anti-HER2 therapy

lapatinib

trastuzumab

lapatinib

trastuzumab

FEC

X

3

SURGERY

RANDOMIZE

lapatinib

trastuzumab

lapatinib

trastuzumab

paclitaxel

paclitaxel

paclitaxel

+ 12 wks6 wks

J. Baselga, SABCS 2011

Cumulative Incidence of Diarrhea Grade ≥ 3

Safety PopulationJ. Baselga, SABCS 2011

Efficacy – pCR and tpCR

L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumabpCR pathologic complete response

J. Baselga, SABCS 2011

Comparison of pCR-rates

Neo-Sphere Neo-Altto G5 HER2+ G5 TNBC

Duration 12 12+6 24 24

Mono-Tx Doc+H Pw+H EC-Doc+H EC-Doc+B

ypT0/is ypN0 21.5 27.6 45.0 40.1*

Combo-Tx Doc+HP Pw+HL n.a. n.a

ypT0/is ypN0 39.3 46.9

*without pCRs in non-responders

Breast imaging Blood MUGA Tumor Biopsy - required

SURGERY

Paclitaxel x 16 wks

Breast imaging Blood MUGA

Dose-denseAC

(recommended)

Trastuzumab x 1y(recommended)

Endocrine Rx and RT prn

Trastuzumab

Trastuzumab + lapatinib

Lapatinib

N=400HER2+Stage II-III

Paclitaxel x 16 wks

Paclitaxel x 16 wks

Planned cross-validation with NeoALTTO

CALGB 40601: HER2+ Neoadjuvant Trial

R*

Paclitaxel weekly + Myocet weekly

Paclitaxel weekly + Myocet weekly +Carboplatin

Su

rger

yT4 orT3 orT>1cm,Triple neg. orHER2 pos.

*stratified according to HER2/ER and Ki-67

N=600

Trastuzumab+Lapatinib in HER2 positive pts.Bevacizumab in TNBC pts.

18 weeks

GeparSixtoEffect of Carboplatin in

HER2+/triple neg BC

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.

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 ???

Case 1 with Locally Advanced Breast Cancer

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

Case 1 : What is your treatment option?

Treatment approach according to AGO’s perspective:

AC-TH → Surgery → H (up to 1 year)

Case 1 with Locally Advanced Breast Cancer

Any question or contribution?...

METASTATIC SETTING

Single-Institution Retrospective Analysis

on 2091 patients with MBC

Dawood et al. J Clin Oncol 2010

First Randomized Phase III Study to Investigate Continuation of

Trastuzumab

Capecitabine 2,500 mg/m² d 1–14 q3w

Capecitabine 2,500 mg/m² d 1–14 q3w +

Continuation of trastuzumab 6 mg/kg q3w

R

(n=78)

(n=78)

R, randomizationvon Minckwitz G, et al. J Clin Oncol 27:1999-2006, 2009

Clinical Response (RECIST)

0,0

10,0

20,0

30,0

40,0

50,0

60,0

70,0

80,0

90,0

100,0

X XH

% o

f pts

OR = Overall response = CR+PRCB = Clinical benefit = CR+PR+NC>24wks

OR: 27.0%CB: 54.1%

OR: 48.0%CB: 75.3%

NC: 27.1% NC: 27.2%

OR: 0.0115CB: 0.0068(2-sided p)

CR: 7.7%

CR: 2.7%

PR: 40.4%PR: 24.3%

von Minckwitz G, et al. J Clin Oncol 27:1999-2006, 2009

Time To Progression at median Follow up of 15.6

months

P<0.0467

X : 5.6 (4.2 - 6.3) mosXH : 8.2 (7.3 - 11.2) mos

HR=0.69 (two-sided p=0.034; one-sided p=0.017)

Progression to CNS:X: 8.3% XH: 13.8%

PFSX: 5.6 mos XH: 8.2 mosP=0.026 two sided

von Minckwitz G, et al. J Clin Oncol 27:1999-2006, 2009

Capecitabine + Lapatinib vs Capecitabine

70

Cameron et al, Breast Cancer Res Treat 2008

CapecitabineLapatinib +

Capecitabine

0.00013p-value

102 (51%)82 (41%)Progressed or died*4.36.2Median TTP, months

201198No. of pts

0.57 (0.43, 0.77)Hazard ratio (95% CI)

* due to breast cancer

Final Overall Survival Analysis(N=151)

von Minckwitz G, et al. SABCS 2010 poster presentation

X : 20.6 (18.6 – 27.4) mosXH : 24.9 (20.3 – 30.7) mos

HR=0.94 (two-sided p=0.74)

Overall survival after 2nd progression

cont of trast vs not (N=140)

von Minckwitz G, et al. SABCS 2010 poster presentation

K. L. Blackwell et al, JCO Mar 2010: 1124–1130

….Trastuzumab and lapatinib beyond trastuzumab

34

Phase II Trastuzumab / Pertuzumab Study (BO17929)

Baselga et al. J Clin Oncol 20010

Beyond trastuzumab…T-DM1

Tumor ResponseIRF

(N=110) Investigator

(N=110)

Objective Response Rate, %(95% CI) CR

PRSD*PDUEMissing

32.7(24.1–42.1)

032.746.418.21.80.9

30.0(22.0–39.4)

1.828.252.713.60.92.7

Clinical Benefit Rate, %)(95% CI)

44.5(35.1–54.3)

40.0(31.1–49.3)

IRF - Independent Review Facility *including unconfirmed partial remissions

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 !

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 4xAC4xDocTrastuzumab Trastuzumab

Liver metastases at 5th month after completion of adjuvant Trastuzumab treatment

Treatment ???

Case 2 with Metastatic Breast Cancer

1) Trastuzumab + Paclitaxel

2) Trastuzumab + Vinorelbine

3) Trastuzumab + Capecitabine

4) Lapatinib + Capecitabine

5) Trastuzumab + Lapatinib

6) CT without anti-Her2-agent

Case 2: What is your treatment of choice?

Treatment approach according to AGO’s perspective:

Paclitaxel + Trastuzumab

Case 2 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 ???

Case 3 with Metastatic Breast Cancer

1) Vinorelbine + Trastuzumab

2) Capecitabine + Trastuzumab

3) Capecitabine + Lapatinib

4) Trastuzumab + Lapatinib

Case 3: What is your treatment option in 2nd line?

Treatment approach according to AGO’s perspective:

Capecitabine + Trastuzumab

Case 3 with Metastatic Breast Cancer

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

???

Option 1 2nd Line Treatment for Case 3

WBRT followed by

1) Vinorelbine +Trastuzumab

2) Cisplatin+ Trastuzumab

3) Lapatinib + Capecitabine (if not used as 2nd line)

4) Trastuzumab + Lapatinib

Case 3: What is your treatment option in 3rd line?

Treatment approach according to AGO’s perspective:

Trastuzumab + Lapatinib

Case 3 with Metastatic Breast Cancer

Any question or contribution?...

ADJUVANT SETTING

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 ???

Case 4 with Early Breast Cancer

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

Treatment approach according to AGO’s perspective:

CT+Trastuzumab 52 wks + HT

FEC x6 or EC x4-Pac x12

Case 4 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 ???

Case 5 with Early Breast Cancer

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)

Treatment approach according to AGO’s perspective:

EC-Pac + Trastuzumab 52 wks + HT

Case 5 with Early Breast Cancer

Any question or contribution?...