Kimberly L. Blackwell MD Professor

Department of Medicine and Radiation Oncology

Duke University Medical Center Director, Breast Cancer Program

Duke Cancer Institute Durham, North Carolina

Evolving Paradigms in HER2+ MBC: Strategies for Individualizing

Therapy with Available Agents

Overview

HER2+ Metastatic Breast Cancer

• Timing

• Special Patient Populations

– ER+

– Brain Metastasis

NCCN: First-line Treatment of HER2+ MBC

• Preferred regimens

– Docetaxel + trastuzumab + pertuzumab (category 1)

– Paclitaxel + trastuzumab + pertuzumab

• Other regimens

– Chemotherapy + trastuzumab

NCCN. Clinical practice guidelines in oncology: breast cancer. v.1.2014.

MA.31/EGF108919: Design

ClinicalTrials.gov. NCT00667251.

Randomize

Experimental Arm

24 Wks: Lapatinib

+ taxane

Until PD:

Lapatinib

Standard Arm

24 Wks: Trastuzumab

+ taxane

Until PD:

Trastuzumab

Primary Outcome: PFS

Sample size: ~ 600 (536 patients centrally confirmed with HER2+)

PFS

(%

)

100

80

60

40

20

0

Mos

0 5 10 15 20 25 30 35 40

TTAX/T LTAX/L

318 318

223 218

110 85

44 35

21 13

8 2

1 0

0 0

0 0

MA.31/EGF108919 : PFS (Intent-to-Treat Analysis)

Gelmon KA, et al. ASCO 2012. Abstract LBA671.

HR: 1.33 (95% CI: 1.06-1.67; P = .01)

Median PFS TTAX/T: 11.4 mos Median PFS LTAX/L: 8.8 mos

TTAX/T

LTAX/L

Pts at Risk, n

• Primary objectives were investigator-assessed PFS and safety. Results are based on a clinical data cutoff date of November 15, 2010

N = 137 MBC patients (never received chemotherapy or HER2-targeted therapy for

locally advanced or metastatic HER2-positive breast cancer)

Randomize

1:1

T-DM1 3.6 mg/kg IV q3wk

Trastuzumab 6 mg/kg IV (8 mg/kg in cycle 1)

+ Docetaxel 75 or 100 mg/m2 IV q3wk

until disease progression or unacceptable toxicity, and then followed for survival

Hurvitz S et al. European Multidisciplinary Cancer Congress; 2011. Abstract 5001.

First-Line Treatment With T-DM1 vs Trastuzumab + Docetaxel

6

Docetaxel

+ Trastuzumab T-DM1 Comparison

No. Patients 70 67

Efficacy

Median PFS (months) 9.2 14.2 HR 0.59

(0.36, 0.97, P = 0.035)

ORR n (%)

(95% CI)

40/69 (58.0%)

(45.5, 69.2)

43/67

(64.2%)

(51.8, 74.8)

Toxicity

Grade 3-4 events 89.4% 46.4%

Treatment discontinuation

due to adverse events 28.8 % 7.2%

First-Line Treatment of HER2-Positive MBC With T-DM1 vs H + T Provides Significant Improvement in PFS

7 ORR = overall response rate. Hurvitz S et al. 2013

MARIANNE: Trial Design

Ellis PA et al. Proc ASCO 2011;Abstract TPS102.

www.clinicaltrials.gov, June 2012.

Eligibility

• Histologically/cytologically

confirmed breast

adenocarcinoma

• Locally recurrent or mBC

• HER2 positivity

• Candidate for chemotherapy

• Measurable or nonmeasurable

disease per RECIST 1.1

• Adequate organ function

Trastuzumab + taxane*

R T-DM1 + pertuzumab

T-DM1 + placebo

Primary endpoint: PFS

* Docetaxel or paclitaxel

Treatment of HER2+ MBC Beyond First Line With Previous Trastuzumab Exposure

• Continued HER2 blockade

– Preferred: T-DM1

– Chemotherapy + trastuzumab

– Trastuzumab + lapatinib

– Capecitabine + lapatinib

– Vinorelbine + trastuzumab + everolimus ?

Randomized Trials of Continuing Anti-HER2 Therapy After Progression on First-Line Anti-HER2 Therapy

Cameron et al EGF100151

Von Minckwitz et al GBG26/BIG3-05

Phase 3 3

No. of patients 399 156

Second-line HER2 therapy Lapatinib vs placebo Trastuzumab vs none

Concurrent chemotherapy Capecitabine Capecitabine

Median PFS 8.4 vs 4.4 mo HR 0.49, P<0.001

8.2 vs 5.6 mo HR 0.69, P = 0.0338

Median OS 75 wk vs 64.7 wk HR 0.87, P = 0.210

24.9 vs 20.6 mo HR 0.94, P = 0.73

Geyer CE et al. N Engl J Med. 2006;355:2733-2743; Cameron D et al. The Oncologist. 2010;15:924-934; Von Minckwitz G et al. Eur J Cancer. 2011;47:2273-2281.

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.

TPC Treatment Category

TPC treatment category

TPC

(n=184a)

Combination with HER2-directed agent, %

Chemotherapyb + trastuzumab

Lapatinib + trastuzumab

Hormonal therapy + trastuzumab

Chemotherapyb + lapatinib

83.2

68.5

10.3

1.6

2.7

Single-agent chemotherapy,b % 16.8

a Includes patients who received study treatment. b The most common chemotherapy agents used were vinorelbine, gemcitabine, eribulin, paclitaxel, and docetaxel.

T-containing 80.4

PFS by Investigator Assessment

Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months.

Unstratified HR=0.521 (P<0.0001).

198 120 62 28 13 6 1 0

404 334 241 114 66 27 12 0

TPC

T-DM1

No. at risk:

Time (months)

14 12 10 8 6 4 2

0.0

0.2

0.4

0.6

0.8

1.0

0

Pro

po

rtio

n p

rog

res

sio

n-f

ree

TPC

(n=198)

T-DM1

(n=404)

Median (months) 3.3 6.2

No. of events 129 219

Stratified HR=0.528 (95% CI, 0.422, 0.661)

P<0.0001

PFS Subgroup Analyses TPC T-DM1

T-DM1 Better

TPC Better

Baseline characteristic

Total n n Event

Median (months) n Event

Median (months) HRa

All patients 602 198 129 3.3 404 219 6.2 0.52 (0.42, 0.65)

World region

United States

Western Europe

Other

147

256

199

48

85

65

24

61

44

4.1

3.2

3.1

99

171

134

58

91

70

5.8

6.9

5.8

0.71

0.44

0.53

(0.44, 1.14)

(0.32, 0.61)

(0.36, 0.78)

0.2 0.5 1 2 5

Age group

<65 years

65–74 years

≥75 years

509

74

19

164

28

6

108

17

4

3.4

3.2

3.0

345

46

13

191

25

3

5.8

6.9

NE

0.55

0.42

0.14

(0.44, 0.70)

(0.22, 0.80)

(0.02, 0.79)

a Unstratified HR.

NE, not estimable.

Baseline ECOG PS

0

1

2

262

301

37

82

101

15

48

68

13

3.6

3.1

1.6

180

200

22

84

120

13

7.0

5.4

6.9

0.44

0.63

0.41

(0.31, 0.64)

(0.47, 0.85)

(0.19, 0.92)

Race

White

Asian

Other

488

81

35

161

24

13

104

17

8

3.4

2.8

3.3

325

57

22

177

30

12

6.3

5.4

6.6

0.50

0.63

0.57

(0.39, 0.64)

(0.35, 1.14)

(0.23, 1.41)

(95% CI)

First Interim OS Analysis

198

404

169

381

125

316

80

207

51

127

30

65

9

30

0

0

TPC

T-DM1

No. at risk:

3

7

Time (months)

44 patients in the TPC arm received crossover T-DM1 treatment after documented progression.

Unstratified HR=0.57 (P=0.004).

16 12 10 8 6 4 2

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n s

urv

ivin

g

0 14

Observed 21% of targeted events

TPC

(n=198)

T-DM1

(n=404)

Median (months) 14.9 NE

No. of events 44 61

Stratified HR=0.552 (95% CI, 0.369, 0.826); P=0.0034

Efficacy stopping boundary HR<0.363 or P<0.0000013

BOLERO-3: Study Design

*Following a 4-mg/kg loading dose on day 1, cycle 1 (1 cycle = every 21 days). AE = adverse event; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; PD = progressive disease; PO = oral; PS = performance status; QoL = quality of life http://www.clinicaltrials.gov/ct2/show/NCT01007942?term=BOLERO3&rank=1 2013 ASCO Annual Meeting. Oral Abstract 505. Presented by: Ruth M. O’Regan, MD.

Everolimus (5 mg PO daily) + Vinorelbine (25 mg/m2 weekly) + Trastuzumab (2 mg/kg weekly*)

(n = 284)

Therapy until PD or intolerable toxicity

Placebo (PO daily) + Vinorelbine (25 mg/m2 weekly) + Trastuzumab (2 mg/kg weekly*)

(n = 285)

R 1:1

• Stratification by prior lapatinib use (yes/no)

Key Endpoints:

• Primary: PFS

• Secondary: OS, ORR, time to

deterioration of ECOG PS, safety,

DoR, CBR, and QoL

Treatment Groups Follow-up/Survival

N = 569

• Locally advanced or

metastatic HER2+ breast

cancer

• Prior taxane required

• Resistance to trastuzumab

required

BOLERO-3: Primary Endpoint Progression-Free Survival by Local Assessment

2013 ASCO Annual Meeting. Oral Abstract 505. Presented by: Ruth M. O’Regan, MD.

100

80

60

40

20

0

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84

Time (weeks) 90 96 102 108 1 14 120 126 132 138 144 150 156 162 168 174

284

285

259

253

233

202

200

177

161

138

126

109

98

85

78

64

54

49

40

38

35

26

26

23

18

19

14

16

14

12

9

10

5

7

4

4

2

3

2

3

1

1

1

1

1

1

1

0

1

0

1

0

1

0

1

0

1

0

0

0

Everolimus

Placebo

No. of Patients Still at Risk

Pro

ba

bil

ity (

%)

Hazard ratio = 0.78; 95% CI [0.65, 0.95]

Log-rank P value: 0.0067

Median PFS

Everolimus: 7.00 months

Placebo: 5.78 months

Everolimus (n/N = 196/284)

Placebo (n/N = 219/285)

Censoring times

CI = confidence interval.

BOLERO-3: Most Common Adverse Events (Hematologic)

2013 ASCO Annual Meeting.

Oral Abstract 505.

Presented by: Ruth M.

O’Regan, MD.

Everolimus Arm (N = 280) Placebo Arm (N = 282)

AE, % All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4

Neutropenia 81 35 38 70 32 30

Anemia 49 17 2 29 6 <1

Leukopenia 46 30 8 37 25 4

Febrile neutropenia 17 11 5 4 3 1

Thrombocytopenia 14 3 1 2 <1 0

Special Populations

Randomized Trials of Endocrine Therapy ± Anti-HER2 Therapy as First-Line Therapy in HER2

Positive Metastatic Disease

Kaufman et al Johnston et al

Endocrine therapy Anastrozole Letrozole

Anti-HER2 therapy Trastuzumab – open label

Lapatinib (1500 mg PO qd) vs placebo

Phase 3 3

No. of patients 207 219

Crossover 70% None

Progression assessment Reconciled between treating physician and independent review

Based on treating physician

Median PFS 4.8 vs 2.4 mo HR 0.63, P = 0.0016

8.2 vs 3.0 mo HR 0.74, P = 0.013

Median OS 28.5 vs 23.9 mo P = 0.325

32.3 vs 33.3 mo P = 0.188

Kaufman B et al. J Clin Oncol. 2009;27:5529-5537. Johnston S et al. J Clin Oncol. 2009;27:5538-5546.

The Clinical Problem of Her2+

Breast Cancer Brain Metastases (BCBM)

Devastating, feared consequence of advanced breast cancer

Incidence of ~30% among women with HER2+

metastatic disease

Current SOC: radiotherapy (WBRT vs. focused radiation),

systemic therapy

Post-XRT: Lapatinib/capecitabine, ORR 18 – 38%; PFS 3.5 –

5.1 months

XRT-naïve: Lapatinib/capecitabine, ORR 67%; PFS 5.5 mos

Bendell 2003; Lin 2009; Lin 2011; Boccardo 2008; Sutherland 2010; Metro 2011; Bachelot 2011.

EMILIA Patients with CNS Brain Metastasis at Enrollment

Krop, ASCO, 2013

Consent and Screening (n = 60)

Neratinib (240 mg orally once daily) and

capecitabine 750 mg/m2 BID for

14 days followed by 7 days rest

Baseline brain MRI (≥ 1 measurable lesion)

CT Chest/Abdomen/Pelvis, CTCs

Follow-up every 3 weeks

Brain MRI & body CT

re-staging at week 6

PD (CTCs)

• If CNS PD – Off study

•If non CNS PD– extension with

trastuzumab offered

CR, PR, SD – Continue therapy

Cohorts 3a and 3b – Progressive CNS Disease

Prior lapatinib (cohort 3b)

n=25 No prior lapatinib (cohort 3a)

n=35

Evidence for Everolimus BBB penetration

Preclinical Evidence:

Athymic mouse brain everolimus concentrations above the IC50 values for

PTEN-/- glioblastoma cells ~ 24 hours following administration of

everolimus 5 mg/kg orally

Clinical Evidence:

Clinical study of everolimus to treat 28 patients with SEGA (subependymal

giant cell astrocytomas) tumors in patients with TSC (tuberous sclerosis)

illustrates 78% of patients achieved ≥30% reduction in tumor burden at 6

months further supporting BBB penetration

Novartis, data on file. Franz et al. ASCO 2010.

(Note: MW = 958.2 daltons)

LCCC 1025 Phase II Study Schema

N = 11 – 35

Two-stage design

Current Accrual, n = 18/28

Open at UNC, UVA, MD Anderson-Orlando, UAB

U of Chicago;

PI: CK Anders

Conclusions

• Evidence supports continue HER2 based therapy after progression

• T-DM1 has activity in the first, second and third line setting.

• In endocrine sensitive tumors, endocrine therapy + HER2 targeted therapy is an option

• After Pertuzumab and T-DM1 strategies, small molecule inhibitors of HER2 should be considered, especially in patients with brain metastasis.

Thanks!