•William J. Gradishar MD, FACP•Betsy Bramsen Professor of Breast Oncology

•Director, Maggie Daley Center For Women's Cancer Care•Robert H. Lurie Comprehensive Cancer Center

•Northwestern University Feinberg School of Medicine•Chicago, IL

Therapeutic options forrelapsed / refractory HER2 positive

metastatic breast cancer

Lapatinib added to capecitabine for patients with HER2 MBC progressing on trastuzumab: PFS

Geyer et al, N Engl J Med. 2006;355:2733-43.

No. of patients at risk: L + C C

163161

9678

5233

2114

104

41

Weeks

Patients Free of Disease Progression (%)100

80

60

40

20

00 10 20 30 40 50 60

P<0.001

Lapatinib + capecitabine (49 events; median time to progression, 8.4 mo)

Capecitabine alone ( 72 events; median time to progression, 4.4 mo)

30

Lapatinib added to capecitabine for patients with HER2 MBC progressing on trastuzumab: Efficacy

Geyer et al, N Engl J Med. 2006;355:2733-43.

Lapatinib + capecitabine

(n=163)Capecitabine

(n=161)HR

(95% CI) PMedian TTP (months) 8.4 4.4 0.49

(0.34–0.71) <0.001

Median PFS (months) 8.4 4.1 0.49

(0.33–0.67) <0.001

Overall response (%) 22 14 0.09

Death (%) 22 22

Lapatinib added to capecitabine for patients with HER2 MBC progressing on trastuzumab: Adverse events

Geyer et al, N Engl J Med. 2006;355:2733-43.

Lapatinib + capecitabine(n=164)

Capecitabine(n=152)

P(incidence

- any grade)

Grade 1 2 3 4 Any 1 2 3 4 Any

Diarrhea (%) 27 20 12 1 60 14 14 11 0 39 <0.001

Dyspepsia (%)8 3 0 0 18 3 <1 0 0 5 0.014

Rash (%) 20 7 1 0 27 9 5 7 0 15 0.011

Lapatinib ± trastuzumab in patients with trastuzumab refractory MBC: PFS

Blackwell et al, J Clin Oncol. 2010;28:1124-30.

No. of patients at risk: L L + T

148148

5373

2142

1327

58

02

Time from random assignment (weeks)

Alive without progression (cumulative %)100

80

60

40

20

00 10 20 30 40 50 60

13

28 6-month PFS

p=0.008

Lapatinib + trastuzumab

(n=146)Lapatinib(n=145)

Progressed or died (n) 127 128

Median (weeks) 12.0 8.1

Hazard ratio (95% CI) 0.73 (0.57–0.93)

Lapatinib ± trastuzumab for trastuzumab refractory MBC: OS (updated analysis)

Blackwell et al, J Clin Oncol 2012;30:2585-92.

No. of at risk: L+T L

146145

120100

8764

6346

4228

1

Time since random assignment (months)

Overall Survival (%)100

80

60

40

20

00 5 10 15 20 25 35

6 month OS

41%

Lapatinib + trastuzumab

(n=146)Lapatinib(n=145)

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

Median (weeks) 14 9.5

Hazard ratio (95% CI)

0.74 (0.57–0.97)

Log-rank P .026

12-month OS

56%

80%

70%

30

2513

Current standards of care for HER2 positive MBC: patients progressing on trastuzumab (NCCN)

Agents for trastuzumab-exposed HER2-positive diseaseCapecitabine + lapatinibCapecitabine + trastuzumabLapatinib + trastuzumab

NCCN Category 2A

NCCN 2012; Breast cancer V3.2012

Single arm phase II trials of trastuzumab emtansine

Burris et al, J Clin Oncol. 2011;29:398-405.Krop et al, J Clin Oncol. 2012;30(26):3234-41.

Burris et al Krop et alPatients Patients with MBC progressing

after HER2 therapy with chemotherapy (n=112)

Patients with MBC previously treated with trastuzumab and lapatinib, anthracylines, capecitabine and taxane(n=110)

Treatment Trastuzumab emtansine 3.6 mg/kg q3w

Trastuzumab emtansine 3.6 mg/kg q3w

Objective response rate (%)

25.9 (all PR)(33.8% in HER2 positive tumors tested centrally)

35 (all PR)

PFS N/R 6.9 months

Results from a randomized phase II trial of trastuzumab emtansine

Hurvitz et al, Eur J Cancer. 2011;47(Suppl 1):#5001.

Series10

24

14.2

9.2

Trastuzumab emtansine(n=67)

Trastuzumab + taxane(n=70)

HR: 0.59 (0.36–0.97) p=0.0035

PFS (months)

EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine in patients progressing after trastuzumab: Study design Entry criteria

Centrally confirmed HER2+ locally advanced or metastatic, progressive breast cancerPrior taxane and trastuzumab ECOG PS 0–1

Secondary endpointsORR and clinical benefit, duration of responseTime to symptom progression

Verma et al, N Engl J Med. 2012; 367: 1783-91.

Trastuzumab emtansine(3.6 mg/kg q21d)

Primary endpoints: OS, PFS and safetyR

HER2 + MBCPrior T failure(Target n=978)

Lapatinib (1250mg/d)+ capecitabine

(1000 mg/m2 q12 hr x 14/21d)

EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine in patients progressing after trastuzumab: PFS

Verma et al, N Engl J Med. 2012; 367: 1783-91.

Months

Progression-free survival (%)

p<0.001

0 6 12 18 24 30

100

80

60

40

20

0

No. at risk:Lapatinib +capecitabineTrastuzumabemtansine

496

495

176

236

28262220161410842

404

419

310

341

5

9

0

0

1

3

0

1

129

183

35

72

73

130

53

101

25

54

8

18

14

44

9

30

Trastuzumab emtansine (265 events; median time, 9.6 mo)

Lapatinib + capecitabine (304 events; median time, 6.4 mo)

Stratified hazard ratio0.65 (95% CI, 0.55-0.77)

EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine in patients progressing after trastuzumab: OS

Verma et al, N Engl J Med. 2012; 367: 1783-91.

Months

Overall survival (%)

0

100

80

60

40

20

0

496

495

435

457

471

485

453

474

27

38

4

5

17

28

7

13

403

439

240

293

368

418

297

349

110

136

45

62

86

111

63

86

204

242

159

197

133

164

6 12 18 24 3028262220161410842 363432

78.2%

51.8%

85.2%

64.7%

Trastuzumab emtansine (149 events; median time, 30.9 mo)

Lapatinib + capecitabine (182 events; median time, 25.1 mo)

Stratified hazard ratio,0.68 (95% CI, 0.55–0.85) p<0.001

No. at risk:Lapatinib +capecitabineTrastuzumabemtansine

EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine in patients progressing after trastuzumab: ORR

Trastuzumab emtansine(n=397)

Lapatinib + capecitabine(n=389)

0

25

50

CRPR

30.8

Verma et al, N Engl J Med. 2012; 367: 1783-91.

Patients (%)43.6

p<0.001

Duration ofresponse (mo): 12.6 6.5

EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine in patients progressing after trastuzumab: Dose reduction

Trastutumab emtansine (n=495)

Lapatinib + capecitabine (n=496)

Dose reduction (patients, %)

16.3 L: 27.3C: 53.4

Median daily dose 3.5 mg/kg/21d L:1250 mg/dC: 1730 mg/m2/d

Discontinued due to adverse events (patients, %)

5.9 L: 7.6C: 9.4

Verma et al, N Engl J Med. 2012; 367: 1783-91.

EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine in patients progressing after trastuzumab:

Grade 3 or 4 events in ≥2% in either arm

Verma et al, N Engl J Med. 2012; 367: 1783-91.

Adverse Event Trastuzumab emtansine(n=490)

Lapatinib + capecitabine(n=488)

Events of any grade

(%)

Grade 3 or 4 events

(%)

Events of any grade

(%)

Grade 3 or 4 events

(%)

Any event 470 (95.9) 200 (40.8) 477 (97.7) 278 (57.0)

Specific events†

Diarrhea 114 (23.3) 8 (1.6) 389 (79.7) 101 (20.7)

Palmar-plantar erythrodysesthesia 6 (1.2) 0 283 (58.0) 80 (16.4)

Vomiting 93 (19.0) 4 (0.8) 143 (29.3) 22 (4.5)

Neutropenia 29 (5.9) 10 (2.0) 42 (8.6) 21 (4.3)

Hypokalemia 42 (8.6) 11 (2.2) 42 (8.6) 20 (4.1)

Fatigue 172 (35.1) 12 (2.4) 136 (27.9) 17 (3.5)

Nausea 192 (39.2) 4 (0.8) 218 (44.7) 12 (2.5)

Mucosal inflammation 33 (6.7) 1 (0.2) 93 (19.1) 11 (2.3)

Anemia 51 (10.4) 13 (2.7) 39 (8.0) 8 (1.6)

Elevated ALT 83 (16.9) 14 (2.9) 43 (8.8) 7 (1.4)

Elevated AST 110 (22.4) 21 (4.3) 46 (9.4) 4 (0.8)

Thrombocytopenia 137 (28.0) 63 (12.9) 12 (2.5) 1 (0.2)

Summary For patients with relapsed / refractory metastatic

breast cancer lapatinib + capecitabine is the current standard of careBased on a comparison with capecitabine alone

improvements in PFS and OS Studies have shown that dual HER2 inhibition with

lapatinib and trastuzumab also has clinical activity in this setting and may be considered

The novel drug-antibody conjugate trastuzumab emtansine is now approved by the FDA in this settingThe EMILIA trial demonstrated improved PFS and OS with

less dose reduction due to AEs