Update on the Management of HER2+ Breast Cancer · In a period of 20 years – HER2 was identified as a bad prognostic factor -Impact on DFS: early recurrences -Impact on OS: distant

Update on the Management of HER2+ Breast Cancer

Christian Jackisch, MD, PhD Sana Klinikum Offenbach

Offenbach, Germany

Outline

• Treatment strategies for HER2-positive metastatic

breast cancer since

– First line

– Second line

– Third line and beyond

• Managing special situations

– Brain metastasis

– Cardiac morbidity

• Future directions

In a period of 20 years

– HER2 was identified as a bad prognostic factor

- Impact on DFS: early recurrences

- Impact on OS: distant mets

- Impact on treatment resistance: endocrine treatment and classical CMF

– HER2 was identified as a target for new treatment approaches

- Definition of the target population: IHC and/or FISH

- Definition of the treatment: humanized monoclonal antibody

- Demonstration of the first clinical results: phase II-III trials

- Demonstration of different modes of application (IV vs SC)

– Trastuzumab clearly changes the prognosis of HER2-positive MBC with

a strong impact on OS in EBC & MBC

Targeting the HER2 Receptor

Approved Treatment Options in HER2+ MBC

Perez EA, et al. Cancer. 2012;118(12):3014-3025. Hernandez-Aya LF, et al. Oncologist. 2011;16(4):404-414.

Other Innovative Targeted Therapies in HER2-Positive Breast Cancer

FLT-3

c-KIT

VEGFR

PDGFR-

Endothelial cell

and pericyte membrane

Cell differentiation

Cell proliferation

Cell survival

(apoptosis inhibition)

Angiogenesis

Cell adhesion/

penetration/metastasis

PI3K

Akt

mTOR

Ras PIP2

IP3 DAG

PKC

RAF

MEK

MAPK

ERK

Src

Nucleus Transcription factors

Tumor cell

membrane

EGFR

IGF-1R HER2

Approved

Under investigation

Pertuzumab*

Everolimus

Afatinib/Neratinib

Trastuzumab emtansine*

Lapatinib*

*Not approved in all countries

Options for Dual Blockade of the HER2 Receptor

L, lapatinib; P, pertuzumab; T, trastuzumab.

2

Downstream signaling pathways1

2 3 2

Lapatinib

Trastuzumab T

L L

2

Downstream signaling pathways2

2 3 2

Pertuzumab T P

Vertical dual blockade Horizontal dual blockade

1. Konecny GE, et al. Cancer Res. 2006;66(3):1630-1639; 2. Nahta R, et al. Cancer Res. 2004;64(7):2343-2346.

Outline


breast cancer since

– First line

Second line

Third line and beyond

Managing special situations

Brain metastasis

Cardiac morbidity

Future directions

CLEOPATRA: Study Design • Primary endpoint: PFS (independently assessed)

• Secondary endpoints: PFS (investigator assessment),

ORR, OS, Safety

Women with

previously untreated,

HER2-positive locally

recurrent/metastatic

breast cancer

(N = 808)

Trastuzumab 6 mg/kg q3w* +

Docetaxel 75-100 mg/m2 q3w† +

Pertuzumab (PTZ) 420 mg q3w‡

(n = 402)

Trastuzumab 6 mg/kg q3w* +

Docetaxel 75-100 mg/m2 q3w† +

Placebo q3w

(n = 406)

Treatment until

disease

progression or

unacceptable

toxicity

*Trastuzumab 8 mg/kg loading dose given †Minimum of 6 docetaxel cycles recommended; <6 cycles permitted for unacceptable toxicity or progressive disease (PD) ‡Pertuzumab 840 mg loading dose given

Baselga J, et al. Cancer Res. 2011;71(24 Suppl): Abstract S5-5.

CLEOPATRA Overall Survival

Swain SM, et al. New Engl J Med. 2015;372(8):724-734.

• 48 patients crossed over from placebo to PTZ arm after previous report of OS benefit

• Long-term cardiac safety profile maintained

PTZ + TRAS + DOC Placebo + TRAS + DOC

56.5 months 40.8 months HR = 0.68, P < .001

Control, 221 events

Hazard ratio, 0.68 (95% CI, 0.56-0.84) P<.001

Months

Pertuzumab, 168 events

Overa

ll S

urv

ival,

%

100 –

90 –

80 –

70 –

60 –

50 –

40 –

30 –

20 –

10 –

0 – 0 10 20 30 40 50 60 70 80

No. at Risk

Pertuzumab 402 371 318 268 226 104 28 1 0

Control 406 350 289 230 179 91 23 0 0

Other Options on the Forefront for First-Line?

T-DM1: Mechanism of Action

Emtansine

release

Inhibition of

microtubule

polymerization

Internalization

HER2

Adapted from LoRusso PM, et al. Clin Cancer Res. 2011;17(20):6437-6447.

T-DM1

Lysosome

Nucleus

P P

P

• Randomized, phase II, international, open-label studyb

• Stratification factors: World region, prior adjuvant trastuzumab therapy, disease-free interval

• Primary endpoints: PFS by investigator assessment, and safety

• Data analyses were based on clinical data cut of Nov 15, 2010 prior to T-DM1 crossover

• Key secondary endpoints: OS, ORR, DOR, CBR, and QOL

First-Line MBC: TDM4450 Study Design

1:1

HER2-positive,

recurrent locally

advanced breast

cancer or MBC

(N = 137)

Trastuzumab 8 mg/kg loading dose;

6 mg/kg q3w IV

+ Docetaxel 75 or 100 mg/m2 q3w

(n = 70)

Crossover to

T-DM1

(optional)

PDa

T-DM1 3.6 mg/kg q3w IV

(n = 67)

PDa

aPatients were treated until PD or unacceptable toxicity

bThis was a hypothesis-generating study; the final PFS analysis was to take place after 72 events had occurred

Hurvitz SA, et al. J Clin Oncol. 2013;31(9):1157-1163.

DOR, duration of response; CBR, clinical benefit rate; QoL, quality of life

TDM4450 PFS by Investigator: Randomized Patients

Pro

po

rtio

n P

rog

res

sio

n F

ree

1.0

0.8

0.6

0.4

0.2

0.0 0 2 4 6 8 10 12 14 16 18 20

Number of patients at risk

70 66 63 53 43 27 12 4 2 2 0

67 60 51 46 42 35 22 15 6 3 0

Hazard ratio and log-rank P value were from stratified analysis

TRAS+ DOC (n = 70)

T-DM1 (n = 67)

Median PFS,

months

Hazard

ratio

95%

CI

Log-rank

P value

9.2

14.2 0.594 0.364-

0.968 .0353

Time, Months


TRAS + DOC

T-DM1

TDM4450 Duration of Response (DOR): Randomized Patients


1.0 –

0.8 –

0.6 –

0.4 –

0.2 –

0 2 4 6 8 10 12 14 16 18

Pro

gre

ss

ion

-Fre

e S

urv

ival,

Pro

po

rtio

n

Duration of Objective Response, Months No. at Risk

HT 40 40 38 32 19 8 2 1 1 0

T-DM1 43 41 38 33 27 19 12 6 3 0

HT 40 9.5 6.6 to 10.6

T-DM1 43 NR

Median DOR

n Months 95% CI

Outline


breast cancer since

First line

– Second line



Brain metastasis

Cardiac morbidity

EMILIA Trial

LABC, locally advanced breast cancer; MBC, metastatic breast cancer; T-DM1, trastuzumab emtansine; IV, intravenous; PD,

progressive disease; qd, once daily; bid, twice daily; PFS, progression-free survival; OS, overall survival; ORR, objective response

rate.

T-DM1

3.6 mg/kg q3w IV PD

Lapatinib

1250 mg/day orally qd

Capecitabine

1000 mg/m2 orally bid, days 1–

14, q3w

PD

n = 495

n = 496

1:1

HER2-positive

(central) LABC or

MBC (N = 991)

• Prior taxane and

trastuzumab

• Progression on

metastatic therapy

or within 6 months

of adjuvant therapy

Primary endpoint: independently assessed PFS, OS, safety

Key secondary endpoints: investigator-assessed PFS, ORR

Verma S, et al. N Engl J Med. 2012;367(19):1783-1791.

EMILIA: OS

0 2 4 6 8 10 12 14 16

Time, Months

Ove

rall

Su

rviv

al,

%

18 20 22 24 26 28 30 32 34 36

496

495

471

485

453

474

435

457

403

439

368

418

297

349

240

293

204

242

159

197

133

164

1 10

136

86

11 1

63

86

45

62

27

38

17

28

7

13

4

5

CAP + L

T-DM1

78.4% (95% CI, 74.6-82.3)

51.8% (95% CI, 45.9-57.7)

85.2% (95% CI, 82.0-88.5)

64.7% (95% CI, 59.3-70.2)

No. at risk:

1.0

0.8

0.6

0.4

0.2

0.0

Stratified HR: 0.68; (95% CI, 0.55-0.85); P<.001

Efficacy stopping boundary, P = .0037 HR: 0.73

Verma S, et al. N Engl J Med. 2012;367(19):1783-1791.

Median,

Months

No.

Events

CAP + L 25.1 182

T-DM1 30.9 149

Outline


breast cancer since

First line

Second line

– Third line and beyond


Brain metastasis

Cardiac morbidity

Future directions

2

T-DM1c (optional

crossover)

TH3RESA Study Schema

• Stratification factors: World region, number of prior regimens for advanced BC,d

presence of visceral disease

• Co-primary endpoints: PFS by investigator and OS

• Key secondary endpoints: ORR by investigator and safety

PD

PD T-DM1

3.6 mg/kg q3w IV (n = 400)

Treatment of

physician’s choice

(TPC)b

(n = 200)

HER2-positive (central)

advanced BCa

(N = 600)

≥2 prior HER2-directed

therapies for advanced BC

Prior treatment with

trastuzumab, lapatinib,

and a taxane

a Advanced BC includes MBC and unresectable locally advanced/recurrent BC

b TPC could have been single-agent chemotherapy, hormonal therapy, or HER2-directed therapy, or a combination of a HER2-directed therapy with

a chemotherapy, hormonal therapy, or other HER2-directed therapy c First patient in: Sep 2011. Study amended Sep 2012 (following EMILIA 2nd interim OS results) to allow patients in the TPC arm to receive

T-DM1 after documented PD d Excluding single-agent hormonal therapy

BC, breast cancer; IV, intravenous; ORR, objective response rate; PD, progressive disease; q3w, every 3 weeks

1

Krop IE, et al. Lancet Oncol. 2014;15(7):689-699.

TH3RESA Overall Survival

Krop IE, et al. Lancet Oncol. 2014;15(7):689-699.

Stratified HR 0.552 (95% CI 0.369-0.826); P<.0034

Efficacy stopping boundary; HR 0.370; P<.0000016

Unstratified HR* 0.570 (95% CI 0.386-0.840); P<.0040

Physician’s

choice

(n = 198)

Trastuzumab

emtansine

(n = 404)

Median OS

(95% CI), months

14.9 (11.27-NE) NE

Events 44 61

Physician’s choice

Trastuzumab emtansine

Number at risk

Physician’s choice

Trastuzumab

emtansine

Months since randomization

198

404

169

381

125

316

80

207

51

127

30

65

9

30

3

7

0

0

0 2 4 6 8 10 12 14 16 0

20

40

60

80

100

Overa

ll S

urv

ival, %

EGF104900 trial

MBC, metastatic breast cancer; qd, once daily; PFS, progression-free survival; OS, overall survival; ORR, overall response rate; CBR,

clinical benefit rate.

Lapatinib

1000 mg qd

Trastuzumab

4 mg/kg load, then 2 mg/kg

weekly

Lapatinib*

1500 mg qd

n = 148

n = 148

1:1

HER2-positive

MBC (central)

(N = 296)

• Prior taxane,

anthracyclines and

trastuzumab

• Progression on

trastuzumab within

most recent regimen

for MBC

• Patients were

stratified by hormone

receptor and visceral

disease status

Primary endpoint: PFS

Key secondary endpoints: OS, ORR, CBR, safety

*Lapatinib is not approved for use as a single agent.

Blackwell KL, et al. J Clin Oncol. 2010;28(7):1124-1130.

Blackwell KL, et al. J Clin Oncol. 2012;30(21):2585-2592.

Overall Survival in ITT O

vera

ll S

urv

ival,

%

0

20

40

60

80

100

5 10 15 20 25 30

Time Since Random Assignment, months

35

L

n = 145

L + TRAS

n = 146

Died, n (%) 113 (78) 105 (72)

Median, months 9.5 14

HR (95% CI) 0.74 (0.57 to 0.97)

Log-rank P .026

80%

56% 70%

41%

6-month OS

12-month OS

L + T

L

Outline

Treatment strategies for HER2-positive metastatic

breast cancer since

First line

Second line


• Managing special situations

– Brain metastasis

Cardiac morbidity

Future directions

Taking Care of CNS Metastases Postponing WBRT

Bachelot T , et al. Lancet Oncol. 2013;14:64-71.

Time to Progression by CNS Response Survival (Dashed lines Are 95% CI)

Patients who did not respond to treatment

Patients who responded to treatment

100 –

90 –

80 –

70 –

60 –

50 –

40 –

30 –

20 –

10 –

0 –

100 –

90 –

80 –

70 –

60 –

50 –

40 –

30 –

20 –

10 –

0 –

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Number at risk No response 15 13 9 5 4 3 1 0 Response 29 29 29 29 26 21 13 10 9 7 2 2 2 2 1 No. at risk 44 44 44 43 42 41 40 37 37 36 35 34 31 30 26 23 22 17 14 13 13 11 8 7 7 5 4

Time, Months

Time, Months

Pro

ba

bil

ity o

f P

rog

res

sio

n, %

Su

rviv

al

Pro

ba

bil

ity,

%

Trastuzumab 6 mg/kg q21 days

+

Capecitabine 2500 mg/m2/day, days 1-14 q21 days

R

A

N

D

O

M

I

Z

E

D

Key eligibility

• HER2+ MBC*

• Prior anthracyclines or taxanes

• Any line therapy

• No CNS metastases**

• Evaluable systemic dx

Phase III Planned N = 650

*FISH+/IHC 3+

**No CNS metastases at baseline confirmed by independently reviewed MRI scan

Stratification

• Prior trastuzumab

– yes vs no

• Prior MBC tx

– 0 vs >1

Lapatinib 1250 mg/day

+

Capecitabine 2000 mg/m2/day, days 1-14 q21 days

Taking Care of CNS Metastases CEREBEL: Optimizing Systemic Therapy

Pivot X , et al. J Clin Oncol. 2015 Jan 20 [Epub ahead of print].

Progression-Free Survival Survival

• Trial was terminated early (n = 540/650)

• Incidence of CNS-mets as first site of relapse was 3% (Tras + Cap) vs 5% (Lap + Cap)

• PFS & OS & SAE were in favor of Tras + Cap over Lap + Cap

• Different result according to pretreatment with trastuzumab

Taking Care of CNS Metastases CEREBEL: Optimizing Systemic Therapy

Pivot X , et al. J Clin Oncol. 2015 Jan 20 [Epub ahead of print].

Time Since Random Assignment, Months Time Since Random Assignment, Months

Pro

gre

ss

ion

-Fre

e S

urv

iva

l, %

Ove

rall

Su

rviv

al,

%

Number at risk Lap + Cap 271 147 49 20 20 7 4 Tras + Cap 269 154 56 26 26 15 7

Number at risk Lap + Cap 271 194 79 48 27 7 7 Tras + Cap 269 207 97 61 29 15 6 1

100 –

80 –

60 –

40 –

20 –

0 5 10 15 20 25 30 35 40

100 –

80 –

60 –

40 –

20 –

0 5 10 15 20 25 30 35 40

Lap + Cap

Tras + Cap

Lap + Cap

Tras + Cap

Lap + Cap

n = 271

Tras + Cap

n = 269

Events, n 160 (59%) 134 (50%)

PFS, months (95% CI)

First quartile 3.9 (2.8 to 5.4) 5.5 (4.8 to 5.6)

Median 6.6 (5.7 to 8.1) 8.1 (6.1 to 8.9)

Third quartile 12.2 (9.0 to 13.8) 18.2 (12.0 to 25.1)

Hazard ratio (95% CI) 1.30 (1.04 to 1.64)

Stratified log-rank P .021

Lap + Cap n = 271

Tras + Cap n = 269

Events, n 70 (26%) 58 (22%)

OS, mos (95% CI)

1st quartile 14.5 (12.8 to 15.4) 16.2 (14.3 to 19.7)

Median 22.7 (19.5 to NR) 27.3 (23.7 to NR)

3rd quartile NR 33.6 (33.6 to NR)

HR (95% CI) 13.34 (1.04 to 1.64)

Stratified log-rank P .095

Survival

Taking Care of CNS Metastases EMILIA: Retrospective Analysis of CNS-Mets

• In the EMILIA trial, 95/991 patients had CNS mets at baseline

• CNS progression: No CNS mets @ baseline (2% T-DM1; 0.7% XL)

CNS mets @ baseline (22.2% T-DM1; 16.0% XL)

• Patients with CNS @ baseline had significantly improved survival (26.8 mos vs 12.9 mos)

Krop IE, et al. Ann Oncol. 2015;26(1):113-119.

1.0 –

0.8 –

0.6 –

0.4 –

0.2 –

0.0 –

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Pro

po

rtio

n S

urv

ivin

g

Time, Months No. at Risk

XL 50 47 45 41 36 30 21 15 13 7 6 5 4 1 0 0 0 0 0

T-DM1 45 43 42 40 38 34 32 27 21 18 16 11 8 6 4 2 2 1 1

XL n = 50

T-DM1 n = 45

Median, months

12.9 26.8

Stratified HR = .382 (95% CI 0.184-0.795)

P = .0081

Progression-Free Survival Survival

Taking Care of CNS Metastases EMILIA: Retrospective Analysis

Krop IE, et al. Ann Oncol. 2015;26(1):113-119.

Outline


breast cancer since

First line

Second line



Brain metastasis

– Cardiac morbidity

Future directions

Cardiac Dysfunction Secondary to HER2 Treatment Strategies in the Metastatic Setting

Study, n Median

Age, Years

Previous Treatment LVEF Drop <50%

and >10–20 Points

Chronic Heart

Failure

Trastuzumab+ docetaxel1

(First line)

CLEOPATRA

(406)

54 40% Anthracyclines

23% Taxanes

10% Trastuzumab

6.6% 0%

Lapatinib + capecitabine2

(Mainly second and third

line)

EMILIA

(496)


100% Taxanes

100% Trastuzumab

1.6% NR

T-DM12

(Mainly second and third

line)

EMILIA

(495)


100% Taxanes

100% Trastuzumab

1.7% NR

Trastuzumab+

pertuzumab+ docetaxel1

(First line)

CLEOPATRA

(402)


23% Taxanes

12% Trastuzmab

3.8% <1%

Lapatinib+ trastuzumab3

(Second line onwards)

EGF104900

(148)


100% Taxanes

100% Trastuzumab

2.5% <1%

1. Baselga J, et al. N Engl J Med. 2012;366(2):109-119; 2. Verma S, et al. N Engl J Med. 2012;367(19):1783-1791; 3. Tyverb Assessment Report. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000795/WC500147870.pdf. Accessed 10 March 2015.

LVEF, left ventricular ejection fraction; NR, not reported; T-DM1, trastuzumab emtansine

OF/LPD/0005/14. Date of preparation: March 2014.

Outline


breast cancer since

First line

Second line



Brain metastasis

Cardiac morbidity

• Future directions

OF/LPD/0005/14. Date of preparation: March 2014.

MARIANNE trial Challenging first-line treatment (recruitment complete)

MARIANNE trial. Available at http://clinicaltrials.gov/ct2/show/NCT01120184 (accessed March 2014).

T-DM1, trastuzumab emtansine; IV, intravenous; PD, progressive disease; LD, loading dose; PFS, progression-free survival; OS,

overall survival.

1:1:1

HER2-positive locally

recurrent or advanced

breast cancer

(N=1095)

Stratified by: •World region

•Neo/adjuvant therapy (Y/N)

•Trastuzumab- and/or

lapatinib-based therapy

(Y/N)

•Visceral disease (Y/N)

Primary endpoints: PFS, AEs

Key secondary endpoints: OS

PD

PD

T-DM1 (3.6 mg/kg IV q3w)

Pertuzumab

(840 mg LD, 420 mg IV q3w)

T-DM1 (3.6 mg/kg IV q3w)

Placebo

Trastuzumab

Taxane (docetaxel or paclitaxel)

PD

Open label

Blinded

Blinded

Future Directions in HER2+ MBC for Biosimilars

• First line: Pertuzumab-Trastuzumab-Taxane

– Future: T-DM1+pertuzumab?

• Second line: T-DM1

• Third line: Many options…optimal timing unknown

– Lapatinib-trastuzumab

– Lapatinib-capecitabine

– Trastuzumab-other chemo

Documents

Update on the Management of HER2+ Breast Cancer · In a period of 20 years – HER2 was identified as a bad prognostic factor -Impact on DFS: early recurrences -Impact on OS: distant