Breast Cancer: Background

(1)

(2)

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2

(3)

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3

(4)

Program Agenda

• Demographics and Background

• Principles of HER2 Testing

• Metastatic and Progressive HER2+ Breast

Cancer

• Early Stage HER2+ Breast Cancer

• Educational Outcomes Post-Assessment

• Question and Answer

(5)

Breast Cancer: Background

• Leading cause of cancer for women

– 2014 estimated new cases of invasive breast

cancer is about 230,000

• Second leading cause of cancer death in women

– Estimated 40,000 deaths in 2014

• Biology is main driver of treatment

• Goal is to provide a more tailored individualized

approach by targeting dysregulated pathways

(6)

HER Family of Receptors as Targets

• Trastuzumab added to chemotherapy:

– Standard of care for HER2-positive breast cancer

– In MBC, improvements in TTP,

ORR, PFS, and OS

– Adjuvant trials demonstrated significant

reductions in the risk of

recurrence, of a magnitude seldom

observed in oncology trials

– Archetype for targeted therapy development in breast cancer

Herbst RS, et al. Int J Radiat Oncol Biol Phys. 2004;59:21; Roskoski R, et al. Biochem Biophys Res Commun. 2004;319:1; Rowinsky E, et al. Annu Rev Med. 2004;55:433; Hortobagyi GN. N Engl J Med. 2005;353:1734-1736.

(7)

HER2-Positive Breast Cancer

Unanswered Questions

• Optimal use in the early disease setting?

• What about dual HER blockade?

• What do we do at progression?

• Are novel agents and combinations

better?

(8)

Program Agenda

• Demographics and Background

• Principles of HER2 Testing

• Metastatic and Progressive HER2+ Breast

Cancer

• Early Stage HER2+ Breast Cancer

• Educational Outcomes Post-Assessment

• Question and Answer

(9)

HER2 Testing Polling Question

• A 48-year-old female presents with a T2,

N1 (1+), M0 infiltrating ductal carcinoma of

the right breast

• The malignancy is ER+, PR-, and HER2

2+

• FISH testing is performed and the ratio is

1.9

(10)

What is the Next Best Course of

Action?

1. Repeat FISH testing using another

specimen and / or perform IHC test on same

specimen

2. Treat patient with chemotherapy +

trastuzumab

3. Treat patient with chemotherapy without

trastuzumab

(11)

NCCN Principles of HER2 Testing

Initial testing by IHC

IHC 0, 1+ HER2-

IHC 2+ Borderline _result ISH testing IHC 3+ HER2+ Initial testing by FISH FISH- HER2- Borderline result IHC testing FISH retest Count additional cells HER2- Borderline result HER2+ FISH+ HER2+

(12)

FDA vs CAP / ASCO Guidelines for

HER2 Testing*

*These definitions depend on laboratory documentation of the following: proof of initial testing validation in which positive and negative HER2 categories are 95% concordant with alternative validated method or same validated

method for HER2; ongoing internal QA procedures; participation in external proficiency testing; current accreditation by valid accrediting agency.

Wolff A, et al. J Clin Oncol. 2013;31(31):3997-4013.

CAP /

ASCO

Result

IHC Score

FISH

Positive

3+

Uniform, intense

membrane staining of

more than

10%

of invasive

tumor cells

FISH HER2 / CEP 17 ratio ≥ 2.0 or

FISH HER2 gene copy number ≥ 6.0

Equivocal

2+

FISH HER2 / CEP 17 ratio < 2.0 and

FISH HER2 gene copy number ≥ 4 and < 6

Negative

0-1+

FISH HER2 / CEP 17 ratio < 2 and

FISH HER2 gene copy number < 4.0

FDA

Result

IHC Score

FISH

Positive

3+

Uniform, intense

membrane staining of

more than

10%

of

invasive tumor cells

(13)

(14)

Program Agenda

• Demographics and Background

• Principles of HER2 Testing

• Metastatic and Progressive HER2+ Breast

Cancer

• Early Stage HER2+ Breast Cancer

• Educational Outcomes Post-Assessment

• Question and Answer

(15)

• A 53-year-old female presents with

inflammatory breast cancer. Her breast

biopsy reveals a poorly differentiated

infiltrating ductal breast cancer

• The tumor is ER(-), PR(-), HER2 amplified

(ratio 4.3)

• Metastatic workup reveals small volume

metastases to both the lung and liver

• Labs reveal only minimal elevation of alkaline

phosphatase

Patient Case

(16)

What Systemic Therapy Will You

Initiate for Her Stage IV Breast

Cancer?

1. Weekly paclitaxel

2. Weekly paclitaxel + trastuzumab

3. Weekly paclitaxel + trastuzumab + pertuzumab

4. Docetaxel + trastuzumab + pertuzumab

5. TCHP: docetaxel + carboplatin + trastuzumab

+ pertuzumab

(17)

Patient Case

Progressive MBC

• 44-year-old female with metastatic

HER2-positive breast cancer

• Diagnosed 12 months ago with breast cancer

metastatic to the liver

• Liver biopsy demonstrated adenocarcinoma,

ER / PR-negative, HER2-positive

• Treated with pertuzumab, trastuzumab, and

docetaxel with initial partial response

• Progressive disease in liver after 12 months

• Performance status 0

(18)

How Would You Treat This Patient?

1. Trastuzumab-DM1

2. Lapatinib + capecitabine

3. Lapatinib + trastuzumab

4. Trastuzumab + vinorelbine

(19)

Targeted Therapies for HER2+ Breast

Cancer: Trastuzumab, Lapatinib,

Pertuzumab, and T-DM1

(20)

Chemotherapy Plus Trastuzumab

in Metastatic Disease

Slamon et al

n = 469

Marty et al

n = 186

Treatment Arms

AC or T*

vs

AC or T→H

†

Docetaxel

vs

Docetaxel →H

†

Time to Disease

Progression (mos)

_4.6

_7.4

P

value

6.1

11.7 P

value

< 0.001

0.0001

Response Rate

32%

50%

< 0.001

34%

61%

0.0002

Median Overall

Survival (mos)

20

25

0.046

23

31 0.0325

*T = paclitaxel; †H = trastuzumab.

Hudis CA. N Engl J Med. 2007;357:36-51; Slamon DJ, et al. N Engl J Med. 2001;344:783-792; Marty M, et al. J Clin Oncol.

(21)

Phase III Trial Comparing Paclitaxel + Lapatinib

or Trastuzumab as First-Line Therapy for

HER2+ MBC

NCIC CTG MA.31

HER+ MBC

No prior anthracycline

/ taxane-based

chemotherapy in the

metastatic setting

(N = 600)

**Lapatinib 1250 mg PO daily + Taxane* x 24**

weeks → Lapatinib 1500 mg PO daily

until PD

Trastuzumab

†

**+ Taxane* x 24 weeks →**

Trastuzumab 6 mg/kg IV q3wk until PD

R

A

N

D

O

M

I

Z

A

T

I

O

N

_{Primary Endpoint: PFS}

Gelmon K, et al. J Clin Oncol. 2012;(suppl). Abstract LBA671.

(22)

Planned Interim Analysis Nov 2011

Serious Adverse Events

Lapatinib / Taxane → Lapatinib n = 318

Trastuzumab / Taxane → Trastuzumab n = 318

Diarrhea 32 5

Febrile Neutropenia 17 7

Gelmon K, et al. J Clin Oncol. 2012;(suppl). Abstract LBA671.

0

5

10

15

20

25

30

35

40

318 223 110 44 21 8 1 0 0 318 #TTAX/T #LTAX/L 218 85 35 13 2 0 0 0

0

20

40

60

80

100 Perc

ent

ag

e

T

ime (months)

TTAX/T LTAX/L

Progression-Free Survival

Intent to

T

reat

Analysis

Median PFSTTAX/T = 11.4 months Median PFSLTAX/T = 8.8 months

(23)

Phase III CLEOPATRA Study Design

First-Line Pertuzumab for MBC

HER2+ MBC

(N = 800)

R

A

N

D

O

M

I

Z

A

T

I

O

N

Docetaxel 75 mg/m

2*

_q3wk

+ Trastuzumab 8 mg/kg, →

6 mg/kg q3wk

+ PLACEBO

Docetaxel

75 mg/m

2

_q3wk

+

Trastuzumab

8 mg/kg, →

6 mg/kg q3wk

+

Pertuzumab

840 mg cycle 1,

420 mg q3wk

*Docetaxel can be increased to 100 mg/m2_{q3wk if tolerable.}

Primary endpoint: PFS

90% of enrolled

patients

trastuzumab

naïve

Baselga J, et al. N Engl J Med. 2012;366(2):109-119. Swain S, et al. Lancet Oncol. 2013;14(6):461-471. .

(24)

CLEOPATRA: PFS

Independent Assessment

Baselga J, et al. N Engl J Med. 2012;366(2):109-119. .

(25)

CLEOPATRA: OS

O

v

erall

Surv

iv

al

(%

)

100 80 60 40 20 0 0 5 10 15 20 25 30 35 40 45 50 55 402 387 371 342 317 230 143 84 33 9 0 0 406 383 350 324 285 198 128 67 22 4 0 0

Time (m

on

t

h

s)

No. atRisk Ptz + T + D 70 50 30 10 90

HR = 0.66

95% CI 0.52-0.84

P

= 0.0008

Pta + T + D

Ptz + T + D: 113 events; median not reached

Pta + T + D: 154 events; median 37.6 months

1 year

2 years

3 years

89%

69%

50%

94%

81%

66%

Swain S, et al. Lancet Oncol. 2013;14(6):461-471. .

(26)

CLEOPATRA: Safety Profile

Grade ≥ 3 Events

Placebo + Trastuzumab

+ Docetaxel

(n = 397)

Pertuzumab + Trastuzumab

+ Docetaxel

(n = 407)

Neutropenia

46%

49%

Febrile neutropenia

8%

14%

*Febrile neutropenia in Asian patients

11.7%

25.6%

Leukopenia

15%

12%

Mucosal Inflammation

20%

28%

Diarrhea

5%

9%

Peripheral neuropathy

2%

3%

Anemia

4%

3%

Asthenia

2%

3%

Fatigue

3%

2%

Granulocytopenia

2%

LVSD

8%

4%

Symptomatic LVSD

1%

2%

Decline ≥ 10 pts from baseline & to < 50%

7%

4%

Dyspnea

2%

1%

Swain S, et al. Oncologist. 2013;18(3):327-264.

LVSD = Left ventricular systolic dysfunction Baselga J, et al. N Engl J Med. 2012;366(2):109-119.

Swain S, et al. Lancet Oncol. 2013;14(6):461-471.

(27)

T-DM1: Mechanism of Action

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

Emtansine

release

Inhibition of

microtubule

polymerization

Internalization

HER2

T-DM1

Lysosome

Nucleus

P

(28)

Phase III Trial: Trastuzumab-DM1 vs

Capecitabine + Lapatinib (EMILIA)

Study Design

Patients with HER2+

locally advanced or

MBC previously tx

with a taxane and

trastuzumab

(N = 980)

Trastuzumab-DM1

3.6 mg/kg q3wk

Continue until

disease progression

or unacceptable

toxicity occurs

Lapatinib

+

Capecitabine

Continue until

disease progression

or unacceptable

toxicity occurs

R

A

N

D

O

M

I

Z

A

T

I

O

N

Verma S, et al. N Engl J Med. 2012;367:1783-9128.

Co-Primary Endpoints: OS and PFS

61% of patients in each group had 0-1 prior chemo

regimens for locally advanced or metastatic disease.

(29)

EMILIA: Progression-Free Survival

Independent Review

Proport

ion

Progres

s

ion

-F

re

e

Unstratified HR = 0.66 (P < 0.0001)

(30)

EMILIA: Overall Survival

Ov era ll Sur v iv al (%) 100 80 60 40 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Months Stratifiedhazardratio,0.68 (95%CI,0.55-0.85) P<0.001 Efficacystoppingboundary, P=0.0037 No.at Risk Lapatinib– capecitabine T-DM1 496 495 471 485 453 474 435 457 403 439 368 418 297 349 240 293 204 242 159 197 133 164 110 136 86 111 45 62 63 86 27 38 17 28 7 13 32 34 36 4 5 Lapatinib–Capecitabine T-DM1 182 149 25.1 30.9 Median No. of Months No. of Events 85.2%(95% CI, 82.0-88.5) 64.7%(95%CI,59.3-70.2) Lapatinib–Capecitabine T-DM1 78.4%(95%CI,74.6-82.3) 51.8%(95%CI,45.9-57.7)

(31)

EMILIA: Safety Profile

Capecitabine +

Lapatinib

(n = 488)

T-DM1

(n = 490)

Adverse Event

All Grades

Grade ≥ 3

All Grades

Grade ≥ 3

Diarrhea

80%

21%

23%

2%

Hand-Foot Syndrome

58%

16%

1%

0%

Vomiting

29%

5%

19%

1%

Hypokalemia

9%

4%

9%

2%

Fatigue

28%

4%

35%

2%

Nausea

45%

3%

39%

1%

Mucosal

Inflammation

19%

2%

7%

< 1%

Increased AST

9%

1%

22%

4%

Increased ALT

9%

1%

17%

3%

Thrombocytopenia

3%

< 1%

28%

13%

(32)

TDM-4450 Phase II

First-Line Study Design

Patients with

HER2+ locally

advanced or

MBC

(N = 137)

Trastuzumab-DM1

3.6 mg/kg q3wk

Continue until

disease progression

or unacceptable

toxicity occurs

Trastuzumab

6 mg/kg q3wk

+

Docetaxel 75 or 100 mg/m

2

q3wk

Continue until

disease progression

or unacceptable

toxicity occurs →

crossover to

T-DM1

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

(33)

TDM-4450

Progression-Free Survival

Hurvitz SA, et al. J Clin Oncol. 2013;31(9):1157-1163. _{HT = trastuzumab + docetaxel}

Progre

ss

io

n

-Free

Surv

iv

al

(

prop

ortio

n)

0

0.2

0.4

0.6

0.8

1.0

4

2

6

8

10

12

14

16

18

20

No. at risk HT T-DM1 66 70 63 53 43 27 12 4 2 2 0 60 67 51 46 42 35 22 15 6 3 0 Median PFS n months HR 95% CI Log-rankP 70 9.2 67 HT T-DM1 14.2 0.59 0.36 to 0.97 0.035

Time (months)

(34)

TDM-4450: Select Adverse Events

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

Trastuzumab + Docetaxel

(n = 66)

T-DM1

(n = 69)

All Grades

Grade 3-4

All Grades

Grade 3-4

Neutropenia

65%

62%

16%

5.8%

Thrombocytopenia

6%

3%

28%

7%

Leucopenia

26%

24%

10%

0%

Febrile Neutropenia

14%

0%

Alopecia

67%

0%

4%

0%

Fatigue

46%

5%

49%

0%

Diarrhea

46%

3%

16%

0%

Peripheral Edema

44%

6%

10%

0%

Increased AST

6%

0%

44%

9%

Headache

18%

0%

41%

0%

Arthralgias

30%

2%

23%

0%

Pneumonia

2%

0%

9%

6%

(35)

T-DM1 vs Physician’s Choice in Patients

Who Have Received at Least 2 Prior

Regimens of HER2-Targeted Therapy

(TH3RESA)

Available at: http://clinicaltrials.gov/NCT014191971.

Metastatic or

unresectable locally

advanced HER2+ BC

Prior trastuzumab,

taxane and lapatinib

R

A

N

D

O

M

I

Z

A

T

I

O

N

T-DM1

3.6 mg/kg IV every 21

days

Physician’s choice:

chemo, hormone

therapy, biologic,

HER2-targeted

Primary Endpoints: PFS, OS

(36)

TH3RESA

Progression-Free Survival

Wildiers H, et al. ESMO 2013. LBA 15.

0

2

4

6

8

10

12

14

0.0

0.2

0.4

0.6

0.8

1.0 P

ro

p

o

rt

io

n

P

ro

g

re

s

io

n

-F

re

e

T

ime (months)

CI = confidence interval; HR = hazard ratio; TPC = treatment of physician’s choice *Median follow-up: TPC = 6.5 months; trastuzumab emtansine = 7.2 months.

Median (months) Number of events 3.3 129 6.2 219 TPC* (n = 198) Trastuzumab emtansine* (n = 404) Stratified HR = 0.528 (95% CI: 0.422-0.661) P < 0.0001

(37)

TH3RESA

Overall Survival

Wildiers H, et al. ESMO 2013. LBA 15.

0

2

4

6

8

10

12

14

0.0

0.2

0.4

0.6

0.8

1.0 P

ro

p

o

rt

io

n

S

u

rv

iv

in

g

T

ime (months)

CI = confidence interval; HR = hazard ratio; NE = not established; TPC = treatment of physician *Observed 21% of target events.

Median (months) Number of events 14.9 44 NE 61 TPC* (n = 198) Trastuzumab emtansine* (n = 404) Stratified HR = 0.552 (95% CI: 0.369-0.826) P < 0.0034

(38)

Phase III MARIANNE Study Design

HER2+

Progressive or

recurrent

locally

advanced or

chemotherapy-naïve MBC

(N = 1092)

R

A

N

D

O

M

I

Z

A

T

I

O

N

T-DM1 + PERTUZUMAB q3wk

T-DM1 + PLACEBO q3wk

Primary endpoint: PFS

TRASTUZUMAB q3wk +

DOCETAXEL q3wk OR

PACLITAXEL qwk

(39)

Lu CH. Clin Cancer Res. 2007;13:5883-5888.

PI3K / AKT / mTOR Pathway

IRS1

P

r

oli

f

e

r

a

t

ion

S

u

r

v

i

v

al

R

e

s

i

st

ance

t

o

t

r

a

st

u

z

um

a

b

?

p

A

K

T

=

s

u

r

og

a

t

e

o

f

an ac

t

i

v

a

t

ed

p

a

t

h

w

ay

GDP GDP GTP GTP SOS GRB2 SCH MAPK ERK PI3K Ras Raf MEK AK T PTEN P1P2 P1P3 PDK1 LKB1 AMPK TSC2 RSK FOXO GSK3 IKK BAD RHEB mTOR 4EBP1 S6K eIF4E S6 eIF4B

mutation of PIK3CA

loss of PTEN

GF

(40)

Phase I / II Everolimus Experience

Everolimus 10 mg qday

and

Trastuzumab 6 mg/kg q3wk

Best Response

N (%)

N = 47

Complete response

(CR)

-

Partial response (PR)

7 (15%)

Stable disease ≥ 24

weeks (SD)

9 (19%)

Overall response rate

7 (15%)

Clinical benefit rate

16 (34%)

Median PFS

4.1 months

Most frequent grade

3 / 4 adverse events

(> 10%)

Lymphopenia,

hyperglycemia,

mucositis

Everolimus 10 mg qday,

Paclitaxel 80 mg/m

2

_{days 1, 8, and 15 q4wk}

+ Trastuzumab 2 mg/kg qwk

Best Response

N (%)

N = 48

Complete response

(CR)

-Partial response (PR)

9 (19%)

Stable disease (SD)

30 (62%)

Overall response rate

9 (19%)

Clinical benefit rate

19 (40%)

Progressive disease

9 (19%)

Most frequent grade

3 / 4 adverse events

(> 10%)

Neutropenia,

lymphopenia,

stomatitis

Hurvitz SA, et al. Breast Cancer Res Treat. 2013;141:437-446. Morrow PK, et al. J Clin Oncol. 2011;29(23):3126-3123.

(41)

Phase III Trial of Everolimus in Combination

With Trastuzumab and Paclitaxel as Frontline

Therapy for HER2+ MBC (BOLERO-1)

HER+ MBC

No prior anthracycline

/ taxane-based

chemotherapy in the

metastatic setting

(N = 719)

Everolimus 10 mg PO +

Paclitaxel 80 mg/m

2

_{qwk d 1, 8, 15}

+ Trastuzumab 2 mg/kg d 1, 8, 15, 22

Placebo +

Paclitaxel 80 mg/m

2

_{qwk d 1, 8, 15}

+ Trastuzumab 2 mg/kg d 1, 8, 15, 22

R

A

N

D

O

M

I

Z

A

T

I

O

N

_{Primary Endpoint: PFS}

(42)

Phase III Trial of Daily Everolimus in

Combination With Trastuzumab and

Vinorelbine in Pretreated HER2+ MBC

(BOLERO-3)

HER+ MBC

Prior trastuzumab

and taxane-based

chemotherapy

(No more than 3

prior lines of tx

for MBC)

(N = 569)

Everolimus 5 mg PO +

Vinorelbine 25 mg/m

2

_weekly

+ Trastuzumab 2 mg/kg weekly

(n = 284)

Placebo +

Vinorelbine 25 mg/m

2

_weekly

+ Trastuzumab 2 mg/kg weekly

(n = 285)

R

A

N

D

O

M

I

Z

A

T

I

O

N

_{Primary Endpoint: PFS}

Andre F, et al. Lancet Oncology. 2014;15(6):580-591.

(43)

BOLERO-3: Primary Endpoint

Progression-Free Survival by Local Assessment

285 253 202 177 138 109 85 64 49 38 26 23 19 16 12 10 7 4 Placebo

Hazard ratio = 0.78; 95% CI 0.65-0.95

P

value = 0.0067

Median PFS

Everolimus: 7.00 months; 95% CI 6.74-8.18

Placebo: 5.78 months; 95% CI 5.49-6.90

Everolimus (n/N = 196 / 284)

Placebo (n/N = 219 / 285)

Censoring times

100

80

60

40

20

0

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Time, weeks 90 96 102 284 259 233 200 161 126 98 78 54 40 35 26 18 14 14 9 5 4 Everolimus

Number of Patients Still at Risk

(44)

BOLERO-3:

Subgroup Analyses by Local Assessment

Andre F, et al. Lancet Oncology. 2014;15(6):580-591.

Favors PBO Favors EVE 0.25 0.5 1 2 4

Subgroup

N

All

569 Age

< 65 years

472 ≥ 65

97 Region

Europe

223 North America

123 Asia

166 Latin America

36 Other

21 Prior lapatinib

Yes

161 No

408 Prior adj/neo

trastuzumab

Yes

251 No

318 Baseline ECOG PS

0

382 1 or 2

186 Hormonal status

ER

–

/PgR

–

250 ER

+

_/PgR

+

₃₁₇

Visceral involvement

Yes

439 No

130 Hazard Ratio

(95% CI)

0.78 (0.65-0.95)

0.77 (0.62-0.95)

0.93 (0.56-1.57)

0.72 (0.53-0.99]

0.86 (0.55-1.32)

0.83 (0.59-1.18)

0.61 (0.27-1.38)

1.28 (0.48-3.45)

0.79 (0.56-1.11)

0.78 (0.62-0.99)

0.65 (0.48-0.87)

0.92 (0.71-1.18)

0.79 (0.63-1.00)

0.75 (0.53-1.05)

0.65 (0.48-0.87)

0.93 (0.72-1.20)

0.89 (0.72-1.10)

0.48 (0.30-0.76)

(45)

BOLERO-3: Safety Profile

Everolimus Arm

(n = 280)

Placebo Arm

(n = 282)

All Grades

Grade 3-4

All Grades

Grade 3-4

Stomatitis

63%

13%

28%

1%

Pyrexia

39%

3%

23%

1%

Decreased Appetite

33%

1%

17%

1%

Fatigue

43%

12%

42%

4%

Diarrhea

38%

4%

31%

1%

Nausea

35%

3%

37%

1%

Constipation

30%

< 1%

31%

< 1%

Rash

25%

0%

18%

1%

Noninfectious

Pneumonitis

6%

< 1%

3%

1%

Hyperlipidemia

2%

0%

1%

0%

Hyperglycemia

9%

6%

5%

3%

(46)

HER2 Beyond Progression

Author

Agents

N

TTP

PFS

OS

Von Minckwitz

et al

Capecitabine

+ trastuzumab

vs

capecitabine

156 8.2 months vs

5.6 months,

P

= 0.03

NR

25.5 months vs

20.4 months,

P

= 0.257

Geyer

et al

Capecitabine

+ lapatinib

vs

capecitabine

324 8.4 months vs

4.4 months,

P

< 0.001

8.4 months vs

4.1 months,

P

< 0.001

19 months vs

16 months,

P

= 0.206

Blackwell

et al

Lapatinib +

trastuzumab

vs lapatinib

296 NR

12 weeks vs

8.1 weeks,

P

= 0.008

14 months vs

9.5 months,

P

= 0.026

Blackwell K, et al. J Clin Oncol. 2010;28(7):1124-1130; Blackwell K, et al. J Clin Oncol. June 11, 2012. Epub;

Geyer CE, et al. N Engl J Med. 2006;355:2733-2743; Cameron D, et al. Oncologist. 2010;15(9):924-934; Von Minckwitz G, et al. J Clin Oncol. 2009;27(12):1999-2006.

(47)

Program Agenda

• Demographics and Background

• Principles of HER2 Testing

• Metastatic and Progressive HER2+ Breast

Cancer

• Early Stage HER2+ Breast Cancer

• Educational Outcomes Post-Assessment

• Question and Answer

(48)

• A 42-year-old female presents with new

right breast mass

• Examination demonstrates a 3 cm mass in

the right breast with a palpable right

axillary lymph node

• Mammogram: suspicious mass right

breast

• Ultrasound: 2.8 cm mass right breast with

suspicious right axillary node

Patient Case

Frontline Therapy

(49)

Patient Case Continued

• Biopsy: IDC, ER-35%, PR-negative, HER2

3+, Ki67 82%

• Lymph node aspirate: positive for

malignant cells

• Systemic staging demonstrates 4 cm right

breast mass, right axillary nodes, but no

distant disease

(50)

How Would You Approach This

Patient?

1. Pertuzumab + trastuzumab + docetaxel

x 4 cycles pre-operatively with FEC x

3 cycles post-operatively

2. Pertuzumab, trastuzumab, carboplatin,

and docetaxel for 6 cycles pre-operatively

3. Surgery followed by adjuvant

(51)

pCR Correlates With Better EFS in Subsets

of BC, Including HER2+ BC:

a FDA Led Meta-Analysis

(N = 11,955 / 1,989 HER2+)

Cortazar P, et al. Lancet. 2014. Epub ahead of print. 0 20 40 60 80 100 120 0.0 0.2 0.4 0.6 0.8 1.0 E v en t-Free S urv iv al P rob ab ili ty

Months Since Randomization HR = 0.39,P < 0.001 pCR (n = 586) no pCR (n = 1403) 0 20 40 60 80 100 120 0.0 0.2 0.4 0.6 0.8 1.0 E v en t-Free S urv iv al P rob ab ili ty

Months Since Randomization HR = 0.58,P = 0.001

pCR (n = 247) no pCR (n = 839)

HER2+

HER2+ HR+

HER2+

HR-0 20 40 60 80 100 120 0.0 0.2 0.4 0.6 0.8 1.0 E v en t-F ree S urv iv al P rob ab ili ty

Months Since Randomization HR = 0.25,P < 0.001

pCR (n = 325) no pCR (n = 510)

(52)

Phase III NeoALTTO Study Design

B

A

S

E

L

I

N

E

Lapatinib

Trastuzumab

Lapatinib +

trastuzumab

6 weeks

Lapatinib + paclitaxel

Trastuzumab +

paclitaxel

Lapatinib +

trastuzumab +

paclitaxe

l

12 weeks

S

U

R

G

E

R

Y

F

E

C

x

3 9 weeks

Lapatinib

Trastuzumab

Lapatinib +

trastuzumab

34 weeks

tumor biopsy blood sample PET / CT scan Week 2 tumor biopsy blood sample PET / CT Week 8 PET / CT scan

1. Blood for translational studies 2. Blood for CTC analysis centers only

3. In selected sites only

CTC analysis to be also performed at start and completion of adjuvant therapy (W1 and Month 12 FU)

Tumor biopsy blood sample Blood sample Blood sample

Radiotherapy (if indicated)

(53)

NeoALTTO Primary Outcome Measure:

pCR*

*Pathologic complete response (pCR) rate defined as the absence of invasive cancer in the breast at the

time of surgery.

25%

30%

51%

0%

20%

40%

60%

80%

100%

pCR

Lapatinib n = 154

Trastuzumab n = 149

Lapatinib + Trastuzumab n = 152

Lapatinib

n = 154

Trastuzumab

n = 149

Lapatinib +

Trastuzumab

n = 152

P

Value

pCR

HR+ Subset

16%

23%

42%

0.03 pCR

HR- Subset

34%

37%

61%

0.005

(54)

NeoALTTO: Does pCR Translate Into

Improved EFS and OS?

• Found correlation

between pCR and

EFS and OS

• 3-year EFS was 86%

for those who

achieved pCR, 72%

for those who did not

(

P

= 0.0003)

• OS was 94% for

those who achieved

pCR,

87% for those

who did not

(P

= 0.005)

• Most notable in

HR-negative disease

• Not powered to detect

difference in survival

between study arms

Piccart-Gebhart M, et al. Presented at the 2013 San Antonio Breast Cancer Symposium. Abstract S1-01.

0

1

2

3

4 0%

20%

40%

60%

80%

100%

O

v

erall

Surv

iv

al

Y

ears Since Landmark Date (30 wks after randomization)

pCR no pCR

pCR status No. patients No. deaths 3 yr OS rate Hazard ratio P value

pCR no pCR 137 262 9 42 95% 0.35 (0.15, 0.70) 0.005 87%

(55)

NeoALTTO Safety Outcomes

Number of Patients With Grade ≥ 3 Adverse Events

Lapatinib

(n = 154)

Trastuzumab

(n = 149)

Lapatinib +

Trastuzumab

(n = 152)

Diarrhea

23%

2%

21%

Hepatic

13%

1%

9%

Neutropenia

16%

3%

9%

Skin Disorders

7%

3%

7%

• No major cardiac dysfunction noted

• One death in the lapatinib + trastuzumab arm

immediately after end of treatment

(56)

Phase III Adjuvant Lapatinib and / or

Trastuzumab Treatment Optimization

(ALTTO)

Surgery

____________

At least 4 cycles

of (neo) adjuvant

chemotherapy

Trastuzumab

Lapatinib

Trastuzumab

Break

Lapatinib

Lapatinib + Trastuzumab

12 weeks 6 weeks 34 weeks

Design 1

no concurrent

taxane

____________

Design 2

concurrent taxane

(12 weeks)

R

A

N

D

O

M

I

Z

A

T

I

O

N

(57)

ALLTO: Disease-Free Survival

Piccart-Gebhart M, et al. Presented at the 2014 ASCO Annual Meeting.

0

1

2

3

4

5 2093

1938

1832

1672

1256

474 2091

1957

1822

1684

1261

476 2097

1959

1838

1658

1246

448 0%

20%

40%

60%

80%

100%

Pc

t

o

f

Pa

ti

e

n

ts

A

liv

e

a

n

d

Dis

e

a

s

e

F

re

e

Y

ears Since Randomization

Lap+

T

ras

T

ras->Lap

T

ras

MFU = 4.5 yrs

Lap+

T

ras

T

ras->Lap

T

ras

2093 254 2091 284 2097 301 88% 87% 0.048† 0.610 86% 0.84 (0.70, 1.02) 0.96 (0.80, 1.15) *97.5% CI Lap+Tras

No. Patients No. Events 4 yr DFS rate Hazard Ratio P value c.f.Tras*

Arm Tras->Lap

Tras

(58)

ALLTO: DFS by Chemotherapy

Timing

0 1 2 3 4 5 1155 1057 995 935 875 399 1143 1060 985 941 891 409 1147 1060 990 913 846 382 0% 20% 40% 60% 80% 100% P c t o f P a ti e n ts A liv e a n d Di s e a s e Fr e e

Years Since Randomization

Lap+Tras Tras->Lap Tras MFU = 4.9 yrs Lap+Tras Tras->Lap Tras 1155 168 1143 184 1147 207 86% 85% 0.034 0.317 83% 0.80 (0.65, 0.98) 0.90 (0.74, 1.10) *95% CI Lap+Tras No. Patients No. Events 4 yr DFS rate P value Hazard Ratio c.f.Tras* Arm Tras->Lap Tras 0 1 2 3 4 5 938 881 837 737 381 75 948 897 837 743 370 67 950 899 848 745 400 66

Years Since Randomization

Lap+Tras Tras->Lap Tras MFU = 3.9 yrs 938 86 948 100 950 94 90% 89% 0.680 0.593 90% 0.94 (0.70, 1.26) 1.08 (0.81, 1.43) *95% CI Lap+Tras No. Patients No. Events 4 yr DFS rate P value Hazard Ratio c.f.Tras* Arm Tras->Lap Tras

Sequential (Design 1)

Sequential (Design 2 & 2B)

Interaction

T

ests

P

= 0.41 L+

T

(59)

ALLTO: Overall Survival

0

1

2

3

4

5 2093

1979

1930

1795

1362

533 2091

2005

1933

1805

1368

521 2097

2023

1949

1804

1373

508 0%

20%

40%

60%

80%

100%

Perc

entage of

Pati

ents

Al

iv

e

Y

ears Since Randomization

Lap+

T

ras

T

ras->Lap

T

ras

MFU = 4.5 yrs

Lap+

T

ras

T

ras->Lap

T

ras

2093 106 2091 119 2097 135 95% 95% 0.078 0.433 94% 0.80 (0.62, 1.03) 0.91 (0.71, 1.16) *95% CI Lap+Tras

No. Patients No. Deaths 4 yr OS rate Hazard Ratio P value c.f.Tras*

Arm Tras->Lap

(60)

ALLTO: Adverse Events

Note: Primary CE: cardiac death or severe CHF NYHA Class III-IV; Secondary CE: asymptomatic (NYHA I) or mildly symptomatic (NYHA II) significant confirmed drop in LVEF. A significant LVEF drop is defined as an absolute decrease of > 10 points below the baseline LVEF and to < 50%.

0 20 40 60 80 100 % o f A E s b y Trea tm e n t A rm 75 50 20 23 24 ₁₆ 55 49 20 (15) (5) ₍₁₎ (3) (3) ₍₁₎ (4) ₍₁₎

Diarrhea Hepatobiliary Rash or Erythema

AEs L+T L T incidence for all armsP < 0.001 for when compared to T (5) 0 2 4 6 8 10 % o f Card iac E v e n ts 3.7 2.4 4.5 0.97 0.25 0.86

Any Cardiac Event Primary Cardiac Event

CARDIAC SAFETY

(61)

Phase II NeoSphere Study Design

FEC = 5-fluorouracil, epirubicin, and cyclophosphamide. Gianni L, et al. Lancet Oncol. 2012;13(1):25-32.

Docetaxel

q3wk x 4 →

FEC

q3wk x 3 +

(62)

NeoSphere Primary Outcome Measure:

pCR*

29%

46%

17%

24%

0%

20%

40%

60%

80%

100%

pCR

TH n = 107

THP n = 107

HP n = 107

TP n = 96

P

= 0.003

P

= 0.014

P

=

0.019

*Pathologic complete response (pCR) rate defined as the absence of invasive cancer in the breast at the time of surgery. T = docetaxel; H = trastuzumab, P = pertuzumab.

(63)

NeoSphere Safety Outcomes

Most Common Grade ≥ 3 Adverse Events

TH

(n = 107)

THP

(n = 107)

HP

(n = 108)

TP

(n = 94)

Neutropenia

57%

44.9 1%

55.3 Febrile Neutropenia

8%

-

7%

Leukopenia

12%

5%

-

7%

Diarrhea

4%

6%

-

4%

Asthenia

-

2%

-

2%

Granulocytopenia

1%

-

2%

Rash

2%

-

1%

Menstruation

Irregularity

1%

-

4%

Drug Hypersensitivity

-

1%

2%

-

ALT Increase

3%

-

1%

One case of CHF developed in the trastuzumab + pertuzumab (HP) arm. Gianni L, et al. Lancet Oncol. 2012;13(1):25-32.

(64)

Phase II TBCRC 006

• 66 patients with HER2+ tumors > 3 cm or > 2 cm with palpable nodes

Rimawi MF, et al. J Clin Oncol. 2013;31(14):1726-1731.

Lapatinib 1000 mg po

daily

Trastuzumab 2 mg/kg

qwk

S U R G E R Y

8

12

2

0 Bx

Plus letrozole or goserelin

(pre-menopausal patients)

if ER+

28.0%

21.0%

40.0%

0%

20%

40%

60%

80%

100%

All

Patients

ER +

ER -

pCR Breast

• Increased pCR in the absence of cytotoxic chemotherapy

• Addition of estrogen blockade in ER+ patients led to increased

efficacy when compared to NeoSphere (ER+ pCR 6%)

(65)

Chemotherapy + Dual Targeted Therapy

Evidence of Benefit

NeoALTTO

(N = 455)

NSABP

B-41

(N = 529)

NeoSphere

(N = 417)

TBCRC 006

(N = 66 )

Phase

III

II

Chemo + T

30%

53%

22%

-

Chemo + L

25%

53%

-

Chemo + TL

51%

62%

-

Dual Targeted

Therapy Alone

17%

(Trastuzumab + Pertuzumab)

28%

(Trastuzumab + Lapatinib)

All show an increased pCR rate in ER- tumors

pCR Breast

Baselga J, et al. Lancet. 2012;379(9816):633-640; Robidoux A, et al. J Clin Oncol. 2012;30(suppl). Abstract LBA506; Gianni L, et al. Lancet Oncol. 2012;13(1):25-32; Chang JCN, et al. J Clin Oncol. 2011;29(suppl). Abstract 505.