Therapeutic options for
relapsed / refractory HER2 positive
metastatic breast cancer
•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
Lapatinib added to capecitabine for patients with
HER2 MBC progressing on trastuzumab: PFS
Patients Free of Disease Progression (%)
100
Lapatinib + capecitabine (49 events;
median time to progression, 8.4 mo)
Capecitabine alone ( 72 events; median
time to progression, 4.4 mo)
80
60
40
P<0.001
20
0
0
No. of patients at risk:
L+C
163
C
161
10
20
30
40
50
60
10
4
4
1
3
0
Weeks
96
78
52
33
21
14
Geyer et al, N Engl J Med. 2006;355:2733-43.
Lapatinib added to capecitabine for patients with
HER2 MBC progressing on trastuzumab: Efficacy
Lapatinib +
capecitabine
(n=163)
Capecitabine
(n=161)
HR
(95% CI)
Median 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
22
22
Death (%)
P
0.09
Geyer et al, N Engl J Med. 2006;355:2733-43.
Lapatinib added to capecitabine for patients with HER2 MBC
progressing on trastuzumab: Adverse events
Lapatinib + capecitabine
(n=164)
Grade
Diarrhea (%)
Dyspepsia (%)
Rash (%)
1
P
(incidence
- any grade)
Capecitabine
(n=152)
2
3
4
Any
27
20
12
1
60
8
3
0
0
20
7
1
0
1
2
3
4
Any
14
14
11
0
39
<0.001
18
3
<1
0
0
5
0.014
27
9
5
7
0
15
0.011
Geyer et al, N Engl J Med. 2006;355:2733-43.
Lapatinib ± trastuzumab in patients with
trastuzumab refractory MBC: PFS
Alive without progression (cumulative %)
100
80
60
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)
p=0.008
40
28
6-month PFS
20
13
0
0
10
20
30
40
50
60
Time from random assignment (weeks)
No. of patients at risk:
L
148
L+T
148
53
73
21
42
13
27
5
8
0
2
Blackwell et al, J Clin Oncol. 2010;28:1124-30.
Lapatinib ± trastuzumab for trastuzumab
refractory MBC: OS (updated analysis)
Overall Survival (%)
100
80%
80
Died, n (%)
Median (weeks)
70%
60
56%
6 month OS
40
Lapatinib +
trastuzumab
(n=146)
Lapatinib
(n=145)
105 (72)
113 (78)
14
9.5
Hazard ratio
(95% CI)
0.74
(0.57–0.97)
Log-rank P
.026
41%
12-month OS
20
0
0
No. of at risk:
L+T
L
5
10
15
20
25
30
35
Time since random assignment (months)
146
145
120
100
87
64
63
46
42
28
25
13
1
Blackwell et al, J Clin Oncol 2012;30:2585-92.
Current standards of care for HER2 positive MBC:
patients progressing on trastuzumab (NCCN)
 Agents for trastuzumab-exposed HER2-positive
disease
 Capecitabine + lapatinib
 Capecitabine + trastuzumab
 Lapatinib + trastuzumab
NCCN Category 2A
NCCN 2012; Breast cancer V3.2012
Single arm phase II trials of
trastuzumab emtansine
Burris et al
Krop et al
Patients
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
Burris et al, J Clin Oncol. 2011;29:398-405.
Krop et al, J Clin Oncol. 2012;30(26):3234-41.
Results from a randomized phase II trial of
trastuzumab emtansine
PFS (months)
24
HR: 0.59 (0.36–0.97)
p=0.0035
Trastuzumab emtansine
(n=67)
14.2
9.2
Trastuzumab + taxane
(n=70)
0
Hurvitz et al, Eur J Cancer. 2011;47(Suppl 1):#5001.
EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine
in patients progressing after trastuzumab: Study design
 Entry criteria
 Centrally confirmed HER2+ locally advanced or metastatic, progressive breast cancer
 Prior taxane and trastuzumab
 ECOG PS 0–1
 Secondary endpoints
 ORR and clinical benefit, duration of response
 Time to symptom progression
Trastuzumab emtansine
(3.6 mg/kg q21d)
HER2 + MBC
Prior T failure
(Target n=978)
R
Primary endpoints:
OS, PFS and safety
Lapatinib (1250mg/d)
+ capecitabine
(1000 mg/m2 q12 hr x 14/21d)
Verma et al, N Engl J Med. 2012; 367: 1783-91.
EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine
in patients progressing after trastuzumab: PFS
Progression-free survival (%)
100
Trastuzumab emtansine
(265 events; median time, 9.6 mo)
80
Lapatinib + capecitabine
(304 events; median time, 6.4 mo)
60
Stratified hazard ratio
0.65 (95% CI, 0.55-0.77)
40
p<0.001
20
0
0
No. at risk:
Lapatinib +
capecitabine
Trastuzumab
emtansine
2
4
6
8
10
12
14
16 18
20
22
24
26
28
30
Months
496
404
310
176
129
73
53
35
25
14
9
8
5
1
0
0
495
419
341
236
183
130
101
72
54
44
30
18
9
3
1
0
Verma et al, N Engl J Med. 2012; 367: 1783-91.
EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine
in patients progressing after trastuzumab: OS
Overall survival (%)
Trastuzumab emtansine
(149 events; median time, 30.9 mo)
100
Lapatinib + capecitabine
(182 events; median time, 25.1 mo)
85.2%
80
78.2%
Stratified hazard ratio,
0.68 (95% CI, 0.55–0.85)
p<0.001
64.7%
60
51.8%
40
20
0
0
No. at risk:
Lapatinib +
capecitabine
Trastuzumab
emtansine
2
4
6
8
10 12 14 16 18 20 22 24 26 28 30 32 34 36
Months
496 471 453 435 403 368 297 240 204 159 133 110 86
63
45
27
17
7
4
495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5
Verma et al, N Engl J Med. 2012; 367: 1783-91.
EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine
in patients progressing after trastuzumab: ORR
Patients (%)
50
p<0.001
43.6
30.8
CR
PR
25
0
Trastuzumab emtansine
(n=397)
Duration of
response (mo): 12.6
Lapatinib + capecitabine
(n=389)
6.5
Verma et al, N Engl J Med. 2012; 367: 1783-91.
EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine
in patients progressing after trastuzumab: Dose reduction
Dose reduction
(patients, %)
Median daily dose
Discontinued due to
adverse events
(patients, %)
Trastutumab
emtansine (n=495)
Lapatinib +
capecitabine (n=496)
16.3
L: 27.3
C: 53.4
3.5 mg/kg/21d
L:1250 mg/d
C: 1730 mg/m2/d
5.9
L: 7.6
C: 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
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
(%)
470 (95.9)
200 (40.8)
477 (97.7)
278 (57.0)
114 (23.3)
8 (1.6)
389 (79.7)
101 (20.7)
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)
Any event
Specific events†
Diarrhea
Palmar-plantar erythrodysesthesia
Verma et al, N Engl J Med. 2012; 367: 1783-91.
Summary
 For patients with relapsed / refractory metastatic
breast cancer lapatinib + capecitabine is the current
standard of care
 Based 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
setting
 The EMILIA trial demonstrated improved PFS and OS with
less dose reduction due to AEs