Transcript Advisor Introductions

Optimizing Treatment for Her 2 Positive
Metastatic Breast Cancer Patients
Sunil Verma MD, MSEd, FRCPC
Medical Oncologist
Chair, Breast Medical Oncology
Sunnybrook Odette Cancer Centre
Associate Professor, University of Toronto
Her 2 Story
Poor Prognostic Marker
Outline
•
•
•
•
First Line Treatment
Second Line Treatment and Beyond
Individualized Approach
An Algorithm and Concluding Remarks
Outline
•
•
•
•
First Line Treatment
Second Line Treatment and Beyond
Individualized Approach
An Algorithm and Concluding Remarks
Trastuzumab prolongs overall survival in
HER2-positive MBC
Overall survival (%)
100
Chemotherapy (n = 234)
Chemotherapy + trastuzumab (n = 235)
80
RR = 0.80 (95% CI = 0.64,1.00)
60
p = 0.046
40
20
Median OS:
20.3 months
Median OS:
25.1 months
0
0
5
15
25
Time (months after enrolment)
OS was a secondary endpoint in the study
Chemotherapy = either doxorubicin or epirubicin + cyclophosphamide or paclitaxel
OS, overall survival; RR, relative risk of death
35
45
Adapted from Slamon DJ, et al. N Engl J Med 2001; 344:783–792.
First Line Treatment Approach (20012011)
• A number of effective options with chemo and
anti-her2
– Taxanes and Herceptin
– Vinorelbine and Herceptin
– Capecitabine and Anti-Her2
– Doublet chemo with Her 2 generally not used
• Select group of patients may benefit from an
anti-Her2 and anti-estrogen approach
Recent Achievements in
Her 2 positive MBC
First Line
– MA.31
• Taxane + H vs. Taxane + L
– CLEOPATRA
• Chemo + H vs. Chemo +H+P
7
Gelmon et. al ASCO 2012
8
Gelmon et. al ASCO 2012
9
CLEOPATRA study design
n=406
Patients with
HER2-positive MBC
Placebo + trastuzumab
PD
Docetaxel
≥6 cycles recommended
1:1
centrally confirmed
(N=808)
Pertuzumab + trastuzumab
n=402
PD
Docetaxel
≥6 cycles recommended
Randomization was stratified by geographic region and prior treatment status
(neo/adjuvant chemotherapy received or not)
HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; PD, progressive disease
Swain et al. SABCS 2012 Poster P5-18-26 . 10
CLEOPATRA: Significantly higher response rate
with pertuzumab and trastuzumab
Patients, n (%)
Independently reviewed objective response
HT
PHT
(n = 336)
(n = 343)
233 (69.3)
275 (80.2)
rate
Difference in response rates (95% CI)
Complete response rate
10.8% points (4.2, 17.5)
p = 0.001
14 (4.2)
19 (5.5)
Partial response rate
219 (65.2)
256 (74.6)
Stable disease
70 (20.8)
50 (14.6)
Progressive disease
28 (8.3)
13 (3.8)
Unable to assess or no assessment
5 (1.5)
5 (1.5)
H, trastuzumab; P, pertuzumab; T, docetaxel
Adapted from Baselga J, et al. N Engl J Med 2012; 366:109–119.
Updated Kaplan-Meier curves of
investigator-assessed PFS
Progression-free survival (%)
100
Ptz + T + D: median 18.7 months
Pla + T + D: median 12.4 months
90
∆=6.3 months
80
70
60
HR=0.69
95% CI 0.58−0.81
50
40
30
20
10
0
0
5
10
15
20
25
30
35
40
45
50
Time (months)
n at risk
Ptz + T + D
402
341
284
218
178
108
67
34
8
0
0
Pla + T + D
406
329
223
148
110
72
42
26
8
0
0
D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab
Swain et al. SABCS 2012 Poster P5-18-26 . 12
Kaplan-Meier curves of the
confirmatory overall survival analysis
1 year
100
94%
Overall survival (%)
90
2 years
89%
80
81%
70
66%
69%
60
HR=0.66
95% CI 0.52−0.84
p=0.0008
3 years
50
50%
40
30
20
Ptz + T + D: 113 events; median not reached
Pla + T + D: 154 events; median 37.6 months
10
0
0
5
10
15
20
25
30
35
40
45
50
55
Time (months)
n at risk
Ptz + T + D
402
387
371
342
317
230
143
84
33
9
0
0
Pla + T + D
406
383
350
324
285
198
128
67
22
4
0
0
Stopping boundary for concluding statistical significance at this second interim analysis was p≤0.0138
D, docetaxel; Pla, placebo; Ptz, pertuzumab; T, trastuzumab
Swain et al. SABCS 2012 Poster P5-18-26 . 13
Breast cancer therapies following
discontinuation of study treatment in patients
who had withdrawn from study treatment
n (%)
Placebo
+ trastuzumab + docetaxel
(n=338)
Pertuzumab
+ trastuzumab + docetaxel
(n=298)
Any
260 (76.9)
225 (75.5)
In patients receiving subsequent breast cancer treatment
n=260
n=225
Any HER2-targeted treatment
178 (68.5)
160 (71.1)
Trastuzumab
104 (40.0)
106 (47.1)
Lapatinib
114 (43.8)
93 (41.3)
Trastuzumab emtansine
26 (10.0)
21 (9.3)
Capecitabine
140 (53.8)
113 (50.2)
Vinorelbine
70 (26.9)
51 (22.7)
Cyclophosphamide
43 (16.5)
30 (13.3)
Doxorubicin
46 (17.7)
29 (12.9)
Paclitaxel
32 (12.3)
21 (9.3)
Docetaxel
11 (4.2)
13 (5.8)
Swain et al. SABCS 2012 Poster P5-18-26 . 14
Adverse events (all grades) with ≥25%
incidence or ≥5% difference between arms
Placebo + trastuzumab + docetaxel
(n=396)
Pertuzumab + trastuzumab + docetaxel
(n=408)
Diarrhea
191 (48.2)
278 (68.1)
Alopecia
240 (60.6)
248 (60.8)
Neutropenia
197 (49.7)
216 (52.9)
Nausea
168 (42.4)
179 (43.9)
Fatigue
148 (37.4)
155 (38.0)
Rash
95 (24.0)
149 (36.5)
Decreased appetite
105 (26.5)
121 (29.7)
Mucosal inflammation
79 (19.9)
112 (27.5)
Asthenia
121 (30.6)
110 (27.0)
Vomiting
97 (24.5)
104 (25.5)
Peripheral edema
122 (30.8)
101 (24.8)
Pruritus
40 (10.1)
68 (16.7)
Constipation
101 (25.5)
63 (15.4)
Febrile neutropenia
30 (7.6)
56 (13.7)
Dry skin
23 (5.8)
44 (10.8)
n (%)
Highlighted are adverse events with ≥5% higher incidence
Swain et al. SABCS 2012 Poster P5-18-26 . 15
Cardiac adverse events
Placebo
+ trastuzumab + docetaxel
Pertuzumab
+ trastuzumab + docetaxel
Data cutoff date
May 2011
(n=397)
May 2012
(n=396)
May 2011
(n=407)
May 2012
(n=408)
LVSD (all grades)
33 (8.3)
34 (8.6)
18 (4.4)
22 (5.4)
Symptomatic LVSD
7 (1.8)
7 (1.8)
4 (1.0)
5 (1.2)
LVEF decline to <50% and by
≥10% points from baseline*
25/379 (6.6)
28/378 (7.4)
15/393 (3.8)
18/394 (4.6)
LVEF recovery to ≥50%*
18/25 (72.0)
25/28 (89.3)
13/15 (86.7)
16/18 (88.9)
n (%)
* In patients with post-baseline assessment
LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction
Swain et al. SABCS 2012 Poster P5-18-26 . 16
T-DM1
Mechanism of Action
KADCYLA is a HER2-targeted antibody and microtubule inhibitor conjugate
consisting of
• HERCEPTIN, a humanized anti-HER2 IgG1 monoclonal antibody
• DM1, a cytotoxic microtubule inhibitor derived from maytansine
− on average, KADCYLA has 3.5 DM1 molecules per antibody
• MCC, a stable thioether linker, covalently linking HERCEPTIN to
DM1
Antibody
(HERCEPTIN)
Stable linker
Cytotoxic
agent (DM1)
DM: derivative of maytansine
MCC: 4-[N-maleimidomethyl] cyclohexane-1carboxylate
KADCYLA Product Monograph. Hoffmann-La Roche Limited. September 11, 2013.
Swanton C, Johnston SR, editors. Handbook of Metastatic Breast Cancer, 2nd ed. Informa Healthcare, New York, 2012.
Emtansine
T-DM1
Retains Activity of Herceptinf
In vitro studies in human breast cancer cells that overexpress HER2
have shown that, like HERCEPTIN, KADCYLA
• Binds subdomain IV of the HER2 extracellular domain
• Inhibits HER2 signaling
• Mediates antibody-dependent cell-mediated cytotoxicity (ADCC)
• Inhibits shedding of the HER2 extracellular domain
KADCYLA Product Monograph. Hoffmann-La Roche Limited. September 11, 2013.
T-DM1
Intracellular Delivery of DM1
HER2
KADCYLA
Internalization
DM1
release*
Lysosomal
degradation
Inhibition of
tubulin
polymerizatio
n
KADCYLA has the additional MOA of DM1. Upon binding to HER2, KADCYLA
undergoes
•
•
•
•
Receptor-mediated internalization
Subsequent lysosomal degradation
Intracellular release of DM1-containing cytotoxic catabolites
DM1 binding to tubulin, disrupting microtubule networks in the cell, resulting in
cell cyclecytotoxic
arrestcatabolite
and apoptotic
death
*The primary DM1-containing
released iscell
lysine-MCC-DM1.
KADCYLA Product Monograph. Hoffmann-La Roche Limited. September 11, 2013.
LoRousso PM, et al. Clin Cancer Res 2011.
PHASE II STUDY
T-DM1 vs. Docetaxel and Trastuzumab
Trastuzumab
HER2-positive,
recurrent locally
advanced breast
cancer or MBC
(N=137)
1:1
8 mg/kg loading dose;
6 mg/kg q3w IV
PDa
+ Docetaxel
75 or 100 mg/m2 q3w
(n=70)
T-DM1
3.6 mg/kg q3w IV
(n=67)
PDa
Crossover to
T-DM1
(optional)
Objective Response by Investigator
Patients With Measurable Disease at Baseline
Trastuzumab +
docetaxel
a
(n=69)
T-DM1
(n=67)
40 (58.0)
43 (64.2)
45.5–69.2
51.8–74.8
3 (4.3)
7 (10.4)
Partial response
37 (53.6)
36 (53.7)
Stable disease
23 (33.3)
13 (19.4)
Progressive disease
4 (5.8)
8 (11.9)
Unable to evaluate or missing
2 (2.9)
3 (4.5)
56 (81.2)
50 (74.6)
70.7–89.1
63.2–84.2
Patients with an objective response,b n (%)
95% CI
Objective responses, n (%)
Complete response
Patients with clinical benefit,c n (%)
95% CI
aOne
patient was not included in the efficacy analysis due to study site withdrawal.
as complete or partial response based on RECIST 1.0 determined on 2 consecutive tumor assessments at least 4
weeks apart.
cDefined as objective response any time during the study or maintained stable disease for at least 6 months
from randomization.
Hurvitz, et al., JCO, 2013
bDefined
Hurvitz SA, et al. Abstract 5.001. ESMO 2011.
Progression-Free Survival by Investigator
Randomized Patients
Median
PFS, mos
Proportion progression-free
1.0
Trastuzumab
+ docetaxel
T-DM1
0.8
(n=70)
(n=67)
Hazard
ratio
95% CI
Log-rank P
value
0.59
0.36 –
0.97
0.035
9.2
14.2
0.6
0.4
0.2
0.0
0
2
4
Number of patients at risk
T+D 70
66
63
T-DM1 67
60
51
6
53
46
Hazard ratio and log-rank P value were from stratified analysis.
8
10
Time (months)
43
42
27
35
12
12
22
14
4
15
16
18
2
6
2
3
20
0
0
Hurvitz, et al., JCO, 2013
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MARIANNE: A clinical trial of pertuzumab and
T-DM1 in first-line metastatic breast cancer
Pertuzumab + T-DM1
HER2-positive,
progressive or
recurrent, locally
advanced or
untreated MBC
(N = 1092)
R
Placebo + T-DM1
Trastuzumab + taxane (docetaxel or paclitaxel)
T-DM1 ± pertuzumab: blinded, placebo-controlled
Trastuzumab + taxane: open-label
2010
First patient in
July 2010
2011–2012
Last patient in
Q2 2012
2013
Figure adapted from:
http://clinicaltrials.gov/ct2/show/NCT01120184;
Roche. Data on file
Summary
First Line
• The standard of care should consist of
pertuzumab and trastuzumab along with
docetaxel (?other taxane alternative)
• T-DM1 looks very promising in the first line
and may be suited for selected patients
– Not candidates for chemotherapy
– DFI < 6 months
– Contraindication to taxanes
24
Future Questions
First Line
• Can we combine Pertuzumab and
Herceptin with other partners
– Other taxanes
– Other chemotherapies
(Vinorelbine/Capecitabine)
– Other biologics – T-DM1/Bevacizumab
• Developing effective drugs that can target
brain metastases
• Duration of targeted therapy for those
responding
25
Outline
•
•
•
•
First Line Treatment
Second Line Treatment and Beyond
Individualized Approach
An Algorithm and Concluding Remarks
Second Line
(2006-2010)
• There is continued benefit of trastuzumab
beyond progression
– Capecitabine and Trastuzumab
• There is benefit of Lapatinib in combination with
Capecitabine upon progression on Trastuzumab
Recent Achievements in
Her 2 positive MBC
Second Line and Beyond
– EGF 104900
• L+ H vs L alone
– EMILIA
• T-DM1 vs Cape + L
– Bolero-3
• Vinorelbine + H + Everolimus vs. Vinorelbine + H
28
Trastuzumab and Lapatinib
Trastuzumab and Lapatinib
Overall Survival
EMILIA Study Design
HER2-positive LABC
or MBC (N=980)
• Prior taxane and
trastuzumab
• Progression on
metastatic treatment
or within 6 months of
adjuvant treatment
T-DM1
3.6 mg/kg q3w IV
PD
Capecitabine
1000 mg/m2 PO bid, days 1–14, q3w
+
Lapatinib
1250 mg/day PO qd
PD
1:1
Verma et al NEJM 2012
Verma et al NEJM 2012
EMILIA: Overall Survival
Verma et al NEJM 2012
EMILIA
Adverse Events
Verma et al NEJM 2012
34
TH3RESA Study Schema
HER2-positive (central)
advanced BCa
(N=600)
≥2 prior HER2-directed
therapies for advanced BC
Prior treatment with
trastuzumab, lapatinib,
and a taxane
T-DM1
3.6 mg/kg q3w IV
2
(n=400)
1
Treatment of
physician’s choice
(TPC)b
PD
PD
T-DM1c
(optional
crossover)
(n=200)
• 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
a Advanced
BC includes MBC and unresectable locally advanced/recurrent BC.
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.
b TPC
Wildiers H, et al. ECC 2013; Abstract 15LBA.
PFS by Investigator Assessment
TPC
T-DM1
(n=198)
(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
Proportion progression-free
1.0
0.8
0.6
0.4
0.2
0.0
0
2
4
6
8
10
12
14
Time (months)
No. at risk:
TPC
198
120
62
28
13
6
1
0
T-DM1
334
241
114
66
27
12
0
404
Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months.
Unstratified HR=0.521 (P<0.0001).
Wildiers H, et al. ECC 2013; Abstract 15LBA.
First Interim OS Analysis
1.0
Observed 21% of targeted events
Proportion surviving
0.8
0.6
TPC
T-DM1
(n=198)
(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
0.4
0.2
0.0
0
2
4
6
8
10
12
14
16
Time (months)
No. at risk:
TPC
198
169
125
80
51
30
9
3
0
404
381
316
207
127
65
30
7
0
T-DM1
44 patients in the TPC arm received crossover T-DM1 treatment after documented progression.
Unstratified HR=0.57 (P=0.004).
Wildiers H, et al. ECC 2013; Abstract 15LBA.
The PI3K pathway and Breast
Cancer
HER2/HER3
PTEN
TORC2
PI3K
Ras
PIP3
Raf
Akt
PDK1
MEK
Tuberin
Erk
Rheb
Rsk
TORC1
S6K
S6
4EBP1
• Constitutive activation of the
PI3K pathway is frequent.
• PI3K pathway activation
conveys malignant
transformation, cell growth and
invasion, tumor neoangiogensis
and resistance towards anticancer treatments.
• Known mechanisms of PI3K
pathway activation include
activating mutations of RTKs,
gain-of-function mutation of the
PIK3CA gene, and loss-offunction mutations of PTEN.
O’Regan R, et al. ASCO 2013; Abstract 505. Not for distribution.
O Regan ASCO 2013
39
O’Regan R, et al. ASCO 2013; Abstract 505. Not for distribution.
O Regan ASCO 2013
40
Summary
Second Line and Beyond
• T-DM1 offers significant clinical benefit and superior
toxicity profile and is very effective for second line Her 2
+ treatment
• Patients progressing on T-DM1 still may derive a benefit
from ongoing systemic tx with chemo with anti-Her 2
approaches
• The role of Lapatinib has evolved and now is generally
considered in third or later lines of treatment. One may
consider earlier use if:
– Progressive brain metastases despite radiation
– Lack of response to first/second line of herceptin
– ? Biomarkers – p95 still needs to be validated
41
Future Questions
• Is there a benefit of Pertuzumab or T-DM1 (along with
other partners) beyond progression?
• What is the effect on tumor biology once patients
progress on Pertuzumab/T-DM1?
– What are potential targeted agents that may help
overcome resistance?
• What will be the role of PI3K inhibitors in second line +
treatment?
• Who are the ideal patients for dual targeted treatment
alone?
42
Outline
•
•
•
•
First Line Treatment
Second Line Treatment and Beyond
Individualized Approach
An Algorithm and Concluding Remarks
Personalized Factors to Consider
•
•
•
•
Hormone Receptor Status
Prior Adjuvant Trastuzumab
CNS Metastases
Biomarkers
Hormone Receptor Status
CLEOPATRA
Overall survival in predefined subgroups
Favors
pertuzumab
n
HR
95% CI
All
808
0.66
0.52‒0.84
No
Yes
432
376
0.66
0.66
0.47‒0.93
0.46‒0.94
Europe
North America
South America
Asia
306
135
114
253
0.72
0.68
0.55
0.64
0.48‒1.07
0.36‒1.28
0.31‒0.98
0.41‒1.00
<65 years
≥65 years
<75 years
≥75 years
681
127
789
19
0.70
0.51
0.66
0.72
0.53‒0.91
0.27‒0.95
0.52‒0.85
0.15‒3.50
White
Black
Asian
Other
480
30
261
37
0.70
0.52
0.66
0.29
0.51‒0.95
0.14‒1.91
0.43‒1.03
0.06‒1.43
Visceral disease
Non-visceral disease
630
178
0.57
1.42
0.44‒0.74
0.71‒2.84
Positive
Negative
388
408
0.73
0.57
0.50‒1.06
0.41‒0.79
IHC 3+
FISH-positive
721
767
0.66
0.67
0.51‒0.85
0.52‒0.86
Prior (neo)adjuvant chemotherapy
Region
Age group
Race
Disease type
ER/PgR status
HER2 status
Favors
placebo
0
1
2
3
4
5
ER, estrogen receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; PgR, progesterone receptor
Swain et al. SABCS 2012 Poster P5-18-26 . 45
Hormone Receptor Status
EMILIA
Overall Survival Subgroup Analyses
Cap + Lap
T-DM1
Total
n
Median
(mos)
Median
(mos)
HR
(95% CI)
991
25.1
30.9
0.70 (0.56, 0.87)
<65 years
853
24.6
30.9
0.66 (0.52, 0.83)
65–74 years
113
27.1
NR
0.74 (0.37, 1.47)
25
NR
11.1
3.45 (0.94, 12.65)
545
25.3
31.9
0.62 (0.46, 0.85)
426
23.7
27.1
0.75 (0.54, 1.03)
First-line
118
27.9
NR
0.61 (0.32, 1.16)
Second-line
361
NR
27.1
0.88 (0.61, 1.27)
Third- and later-line
512
23.3
33.9
0.62 (0.46, 0.84)
Baseline
characteristic
All patients
T-DM1 Cap + Lap
Better
Better
Age group
≥75 years
ER and PR status
ER+ and/or PR+
ER– and PR–
Line of therapya
aDefined
Hazard ratio 0.2
as any systemic therapy including endocrine and chemotherapy.
NR, not reached.
From confirmatory OS analysis; data cut-off July 31, 2012.
Verma et al. ESMO 2012; Oral Abstract #LBA12
0.5
1
2
5
Prior Trastuzumab
CLEOPATRA: Independently assessed
PFS by prior trastuzumab therapy in
patients with (neo)adjuvant therapy
HT
Median PFS, months
PHT
Median PFS, months
Hazard ratio
(CI)
Prior (neo)adjuvant trastuzumab
treatment
(n = 88)
10.4
16.9
0.62
(0.35, 1.07)
No prior (neo)adjuvant
trastuzumab treatment
(n = 288)
12.6
21.6
0.60
(0.43, 0.83)
CI, confidence interval; PFS, progression-free survival
Adapted from Baselga J, et al. N Engl J Med 2012; 366:109–119.
Prior Trastuzumab
CLEOPATRA:Overall survival subgroup
analyses
• An exploratory subgroup analysis was
performed for patients who had received
prior neoadjuvant and/or adjuvant
trastuzumab therapy (88 patients).
– The observed hazard ratio of 0.68 (95% CI
0.30−1.55) indicates overall survival benefit in
the pertuzumab arm
Swain et al. SABCS 2012 Poster P5-18-26 . 48
Prior Trastuzumab
EMILIA: Progression-Free Survival Subgroup Analyses
Cap + Lap T-DM1
Baseline
characteristic
Total
n
All pts
991
6.4
9.6
0.66 (0.56, 0.78)
Age
<65 yrs
≥65 yrs
853
138
6.0
8.1
9.8
7.0
0.62 (0.52, 0.74)
1.06 (0.68, 1.66)
ER and PR status
ER+ and/or PR+ 545
ER− and PR−
426
7.1
5.6
9.0
10.3
0.72 (0.58, 0.91)
0.56 (0.44, 0.72)
Line of therapya
First
Second
Third
5.7
6.8
6.5
10.8
9.6
9.0
0.51 (0.30, 0.85)
0.69 (0.53, 0.91)
0.69 (0.55, 0.86)
118
361
512
Median, Median,
mos
mos
HR
(95% CI)
Hazard ratio 0.2
T-DM1 Cap + Lap
better
better
0.5
1
2
Data cut-off Jan 14, 2012
HRs were from unstratified analysis.
aDefined as any systemic therapy, including endocrine or chemotherapy.
Verma et al. N Eng J Med 2012 (incl. supplementary appendix)
Blackwell et al. ASCO 2012; Abst #LBA1
5
Prior Trastuzumab
EMILIA: Overall Survival Subgroup Analyses
Cap + Lap
T-DM1
Total
n
Median
(mos)
Median
(mos)
HR
(95% CI)
991
25.1
30.9
0.70 (0.56, 0.87)
<65 years
853
24.6
30.9
0.66 (0.52, 0.83)
65–74 years
113
27.1
NR
0.74 (0.37, 1.47)
25
NR
11.1
3.45 (0.94, 12.65)
545
25.3
31.9
0.62 (0.46, 0.85)
426
23.7
27.1
0.75 (0.54, 1.03)
First-line
118
27.9
NR
0.61 (0.32, 1.16)
Second-line
361
NR
27.1
0.88 (0.61, 1.27)
Third- and later-line
512
23.3
33.9
0.62 (0.46, 0.84)
Baseline
characteristic
All patients
T-DM1 Cap + Lap
Better
Better
Age group
≥75 years
ER and PR status
ER+ and/or PR+
ER– and PR–
Line of therapya
aDefined
Hazard ratio 0.2
as any systemic therapy including endocrine and chemotherapy.
NR, not reached.
From confirmatory OS analysis; data cut-off July 31, 2012.
Verma et al. ESMO 2012; Oral Abstract #LBA12
0.5
1
2
5
CNS Metastases
EMILIA
CNS metastases at baseline and
Progression
51
CNS Metastases
EMILIA
OS Analysis for Patients with CNS mets at baseline
52
Outline
•
•
•
•
First Line Treatment
Second Line Treatment and Beyond
Individualized Approach
An Algorithm and Concluding Remarks
HISTORY – 30 YEARS IN THE MAKING
Milestones in the Management of HER2-positive MBC
Overall Survival
First Line
Second
Line +
Abbreviations: Ana, anastrozole; Cape, capecitabine; CT, chemotherapy; Doc, docetaxel; Lap, lapatinib; Let, letrozole; OS, overall survival; Pac, paclitaxel;
Pert, pertuzumab; T-DM1, trastuzumab emtansine; Tras, trastuzumab.
Verma et. al The Oncologist
2013
An Algorithm to Manage Her 2 positive MBC
Verma et. al The Oncologist 2013
An Algorithm to Manage Her 2 positive MBC
Can we
consider
Pertuzumab
for DFI 6m1year?
Can we consider
another taxane with
P + H?
Is there still activity of
Trastuzumab/Lapatini
b post T-DM1?
Verma et. al The Oncologist 2013
Conclusion
Raising the Bar
• The outcome of patients with Her 2 positive
breast cancer has significantly improved in the
past two decades
• Novel targeted drugs are improving survival and
reducing toxicity for patients with advanced
breast cancer
• The future looks quite bright as we can now
envision a total targeted approach for some of
these patients…..and an overall survival in
excess of five years for some of our patients!