Metastatic HER2 Garcia.pptx

Management of HER2 Positive
Metastatic Breast Cancer

Breast Cancer: Background
• Leading Cause of Cancer for Women
– Risk of developing over lifetime: 1 in 8
– 230,480 new cases estimated for 2011
– Improved public awareness and screening programs
have contributed to early detection and diagnosis
• Metastatic Breast Cancer (MBC)
– 20% with localized disease will develop distant
metastases within 5 years of their initial diagnosis
despite treatment
– 5-year survival rate of 23%
2
American Cancer Society. Cancer Facts & Figures 2011. Atlanta: American Cancer Society; 2011.
American Cancer Society. Breast Cancer Facts & Figures 2009-2010. Atlanta: American Cancer Society; 2009.
Gradishar W. Curr Oncol Rep. 2011;13:11-16.

3
3
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Lancet. 2011.

Factors Associated With Treatment of
Metastatic Breast Cancer
• Incurable
• Treatment is palliative
• ER / PR / HER2 status
• Treatment resistance & adverse effects
– Chemotherapeutic agents may exhibit initial efficacy;
however, the development of resistance to therapy
and tolerability are concerns
4

HER2 POSITIVE BREAST CANCER
• Accounts for 15-20% of breast cancer cases
• Short DFS and OS compared to other subtypes
when treated with conventional therapy
• HER2 targeted therapy dramatically changed
outcome
• Multiple agents available: questions about
optimal sequencing
5

6
Akt
SOS
RAS
RAF
MEK
VEGF
MAPK P
P
P
P
Receptor-specific
ligands HER1, HER2,
HER3, or HER4
HER2
HER1
(EGFR)
HER2 HER4
HER3
Tyrosine kinase
domains
Plasma
membrane
PI3K
Cell proliferation
Cell survival
Cell mobility and invasiveness
Cytoplasm
Nucleus
Transcription
SignalTransduction by the HER Family Promotes
Proliferation, Survival, and Invasiveness
Ross JS, et al. The Oncologist. 2009;14:320-368.

Slamon D, et al. Science 1987;235:177–82.
Pauletti G, et al. J Clin Oncol 2000;18:3651–64.
Shortened median survival*
HER2 positive 3 years
HER2 normal 6–7 years
HER2 protein
overexpression
Targeting HER2: Scientific Rationale
HER2 gene
amplification
*combined metastatic and adjuvant patients

OS of lymph node negative breast cancer by HER2 status

9
Breakdown of the 21%
HER2+
Bauer K., Cancer. 2010;10:228.
ER+/PR+/HER2+
ER+/PR-/HER2+
ER-/PR+/HER2+
ER-/PR-/HER2+
0.5%
N=114,786
~21% HER2+
~79% HER2-
7.1%
10.8%
3.3%

10
Onitilo A. Clin Med Res Opin. 2009;7(2):4-13.
Survival for HER2+ Subtypes

OptimalTesting Algorithm
Immunohistochemistry (IHC)
Breast Cancer Specimen
(invasive component)
Equivocal for HER2
protein expression IHC 2+
Equivocal HER2 gene amplification
(Patients with HER2/CEP17 ratio ≥2.0 were
eligible for the adjuvant trastuzumab trials)
Positive for HER2
protein expression IHC
3+ (defined as uniform
intense membrane
staining of >30% of
invasive tumor cells)
Negative for HER2
protein expression
IHC 0 or 1+
Negative for HER2
gene amplification
Positive for HER2
gene amplification
HER2 testing by validated IHC
assay for HER2 protein
expression
Test with validated assay for
HER2 gene amplification

Breast Cancer Specimen
HER2 testing by validated FISH
assay for HER2 gene
amplification
Equivocal for HER2 gene
amplification (FISH ratio 1.8-2.2 or
HER2 gene copy 4.0-6.0)
Count additional cells for FISH or
retest, or test with HER2 IHC
Equivocal HER2 gene amplification result
(Patients with HER2/CEP17 ratio ≥2.0 were
eligible for the adjuvant trastuzumab trials)
Positive for HER2 gene
amplification (FISH ratio
>2.2 or HER2 gene copy
>6.0)
Negative for HER2 gene
amplification (FISH ratio
<1.8 or HER2 gene copy
<4.0)
HER2 gene no amplification
FISH negative
HER2 gene amplification
FISH positive
OptimalTesting Algorithm FISH

FISH evaluation of HER2 status
based on 2013 ASCO/CAP scoring
criteria.

HER2TargetedAgents
•
•
•
•
•
•

15
© 2013 Genentech, Inc. All rights reserved.
The HER2-Targeted Therapeutic:
Trastuzumab, a Humanized Anti-HER2 mAb
Targets HER2 protein
Selectively binds with high
affinity
HER2 epitopes recognized by
hypervariable murine sequences
Human
IgG1
Carter P, et al. Proc Natl Acad Sci U S A 1992;89:4285-4289. Herceptin® (trastuzumab) [prescribing information]. South San Francisco, CA:
Genentech, Inc.; 2010.
mAb=monoclonal antibody
M1.H.BC.Adv.Ow.17

16
The HER2-Targeted Therapeutic: Trastuzumab MOA
Humanized monoclonal
antibody specific for
HER2
Targets HER2 protein-
overexpressing cells
Proposed MOA based
on preclinical studies
● Extracellular
● Intracellular
Dimerized
HER2
receptors
signal tumor
cells to
proliferate
Extracellular
trastuzumab
binds to subdomain
IV of HER2 receptors
on tumor cells,
flagging them for
destruction by the
immune system
Intracellular
trastuzumab
blocks HER2
signaling to
inhibit
proliferation
of tumor cells
Arnould L, et al. Br J Cancer 2006;94:259-267. Bianco AR. J Chemother
2004;16(suppl 4):52-54. Harari D, Yarden Y. Oncogene 2000;19;6102-6114.
Lewis GD, et al. Cancer Immunol Immunother 1993;37:255-263.
Sliwkowski MX, et al. Semin Oncol 1999;26(suppl 12):60-70. Yakes FM, et al. Cancer Res 2002;62:4132-4141. Yarden Y. Oncology 2001;61(suppl 2):1-13.
Herceptin® (trastuzumab) [prescribing information]. South San Francisco, CA: Genentech, Inc.; 2010.
MOA=mechanism of action

Lapatinib
Drug Profile
• Belongs to the 4-
anilinoquinazoline class of
tyrosine kinase inhibitors
• Binds reversibly to the
cytoplasmic ATP-binding site of
the kinase, thereby preventing
receptor phosphorylation and
activation
• Works intracellularly
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-
[5-({[2(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-
quinazolinamine
Lapatinib is the first-in-class oral small-molecule
inhibitor HER2 tyrosine kinase:
Xia W, et al. Oncogene. 2002;21:6255-6263.

18
Rusnak DW, et al. Mol Cancer Ther. 2001;1:85-94; Xia W, et al. Oncogene. 2002;21:6255-6263.
PTEN Lapatinib
P13K
pAkt
Ras
Raf
pErk
Shc
Grb2
So8
Phospholipid cell
membrane
Lapatinib: Targeting HER2 and EGFR
• Lapatinib oral tyrosine
kinase inhibitor of ErbB1
and ErbB2
– Blocks signaling through
EGFR and HER2
homodimers and
heterodimers
– May also prevent
signaling between
ErbB1/ErbB2 and other
ErbB family members

19
© 2013 Genentech, Inc. All rights reserved 19
Ligand-activated
HER2:HER3 dimer
HER2 HER3
P
P
P P
Pertuzumab Mechanism of Action: HER2 Dimerizes Preferentially With HER3 to Drive
Downstream Signaling
Baselga, Swain. Nat Rev Cancer 2009 9:463-475. Yarden, Sliwkowski. Nat Rev Mol Cell Biol 2001;2:127-137 Graus-Porta, et al. EMBO J 1997 1647-1655.
Tzahar, et al. Mol Cell Biol 1996;16:5276-5287. Lee-Hoeflich, et al. Cancer Res 2008;68:5878-5887.
Phosphorylation of the HER3 intracellular domain by
HER2 initiates a signaling cascade
M1.P.BC.Adv.Ow.6

20
Pertuzumab Mechanism of Action: HER2:HER3 Dimers Initiate the Strongest Mitogenic
Signaling
Tzahar, et al. Mol Cell Biol 1996;16:5276-5287. Citri, et al. Exp Cell Res 2003;284:54-65. Huang, et al. Cancer Res 2010;70:1204-1214.
Homodimers Heterodimers
HER1:HER1
HER2:HER2
HER3:HER3
HER4:HER4
HER1:HER2 HER1:HER3
HER1:HER4
HER2:HER4
HER3:HER4
Signaling activity
+ + +
+ + + + +
+ + + +
+ + + +
+
HER2:HER3
M1.P.BC.Adv.Ow.7

21
Akt
Shc
Pertuzumab Mechanism of Action: HER2:HER3 Dimerization Initiates Multiple Signaling Pathways,
Including Increased Tumor Cell Proliferation
Downstream PI3K/Akt signaling is
mainly mediated by HER3 after
transphosphorylation by HER2
HER2 HER3
GRb
2
Sos
RAS
PI3K
P P
P
P PDK
1
P
P P
RAF
MEK
MAPK
P
P
mTOR
Cyclin 01
GSK36
NF  B
BAD
p27
Angiogenesis Proliferation
Cell cycle
control
Apoptosis
Survival
Yarden, Sliwokowski. Nat Rev Mol Cell Biol 2001;2:127-137. Olayioye, et al. EMBO J 2000;19:3159-3167. Kim, et al. J Biol Chem 1994;269:24747-24755.
Soltoff, et al. Mol Cell Biol 1994;14:3550-3558. Baselga, Swain. Nat Rev Cancer 2009;7:463-475 Rowinsky. Annu Rev Med 2004;55:433-457.
M1.P.BC.Adv.Ow.8

22
Pertuzumab Mechanism of Action: New Class of Targeted
Anticancer Therapeutic Agents Called HER2 Dimerization Inhibitors
1. Agus, et al. Cancer Cell 2002;2:127-137. 2. Baselga. Cancer Cell 2002;2:93-95. 3. Citri, et al. Exp Cell Res 2003;284:54-65.
4. Franklin, et al. Cancer Cell 2004;5:317-328. 5. Hughes, et al. Mol Cancer Ther 2009;8:1885-1892.
By blocking HER2 dimerization, pertuzumab inhibits key HER signaling
pathways that mediate cancer cell proliferation and survival1-4
Pertuzumab prevents the formation of HER2:HER3 receptor pairs1,5
HER2
Dimerization
domain
Pertuzumab
HER3
M1.P.BC.Adv.Ow.9

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
P
P

Neratinib overview
• Neratinib is an oral, irreversible tyrosine kinase inhibitor
of ERBB1, 2, 4 (HER1, 2, 4 receptors)
x

27
The HER2-Targeted Therapeutic:
Trastuzumab, a Humanized Anti-HER2 mAb
Targets HER2 protein
Selectively binds with high
affinity
HER2 epitopes recognized by
hypervariable murine sequences
Human
IgG1
Carter P, et al. Proc Natl Acad Sci U S A 1992;89:4285-4289. Herceptin® (trastuzumab) [prescribing information]. South San Francisco, CA:
Genentech, Inc.; 2010.
mAb=monoclonal antibody
M1.H.BC.Adv.Ow.17

Trastuzumab as First-line Monotherapy for HER2+ MBC:
Response by FISH Analysis
No. of evaluable patients 82 29
CR 7 0
PR 21 2
ORR (%) 28 (34) 2 (7)
95% CI 24–45 1–23
Clinical benefit* 39 (48) 3 (10)
FISH–
n (%)
FISH+
n (%)
* CR + PR + MR + SD > 6 mo.
Update of Vogel et al. Proc Am Soc Clin Oncol. 2001;20:22a. Abstract 86.
IHC 2+/3+ combined

Baselga et al. Cancer Res. 1998;58:2825.
Herceptin/doxorubicin
Tumor
volume
(cm
3
)
Time (days)
5 15 25 35 45
4
0
8
12
16
20
24
Herceptin/paclitaxel
5 25 35 45
15
4
0
8
12
16
20
24
Time (days)
Control
Herceptin Herceptin + chemotherapy
Chemotherapy
Herceptin® + Chemotherapy
in Tumor Xenograft Studies

AC=doxorubicin (60mg/m2) [or epirubicin (75mg/m2)] + cyclophosphamide (600mg/m2) q3w for 6 cycles;
Taxol (175mg/m2 x 3 h) q3w for 6 cycles; Herceptin (4mg/kg) loading dose, 2mg/kg qw until progression;
CT=chemotherapy; KPS=Karnofsky Performance Score; q3w=every three weeks; qw=weekly
No prior adjuvant AC Prior adjuvant AC
Taxol
(n=96)
Herceptin +
Taxol (n=92)
AC
(n=138)
Herceptin +
AC (n=143)
Stratify
Randomize Randomize
Slamon D, et al. N Engl J Med 2001;344:783.
n=469
MBC
HER2+
No prior CT for MBC
Measurable disease
KPS 60%
Herceptin Combination Pivotal Trial in
First-line MBC: Schema

Herceptin Combination Pivotal Trial:
Efficacy Summary
DR=duration of response; H=Herceptin; ORR=overall response rate; T=Taxol; TTP=time to progression;
m=months; Herceptin Package Insert 2002.
Subgroup Overall
Parameter H+AC
(n=143)
AC
(n=138)
H+T
(n=92)
T
(n=96)
H+CT
(n=235)
CT
(n=234)
ORR (%) 56 42 41 17 50 32
P value <0.02 <0.001 <0.001
Median DR (m) 9.1 6.7 10.5 4.5 9.1 6.1
P value 0.005 <0.01 <0.001
Median TTP (m) 7.8 6.1 6.9 3.0 7.4 4.6
P value <0.001 <0.001 <0.001
Median survival (m) 26.8 21.4 22.1 18.4 25.1 20.3
P value 0.16 0.17 0.046
Slamon D, et al. N Engl J Med 2001;344:783.
*
* Study was not powered to show a survival difference in subgroups.

Herceptin Combination Pivotal Trial:
Overall Survival
Update of Mass R, et al. Proc Am Soc Clin Oncol 2001;20;22a:abstract 85.
RR=0.71
p=0.007
20.0 m
26.2 m
RR=1.11
p=NS
19.8 m
24.0 m
FISH–
FISH+
Probability
of
survival
1.0
0.8
0.6
0.4
0.2
0
0 10 20 30 40 50
H+CT (n=176)
CT (n=169)
H+CT (n=50)
CT (n=56)
1.0
0.8
0.6
0.4
0.2
0
0 10 20 30 40 50
Months Months
CT=chemotherapy; NS=not significant; RR=response rate
Survival advantage was demonstrated for first-line H + CT despite 66% of CT group
receiving H in second or later lines of therapy

Taxane + Lapatinib vs Trastuzumab as First-Line
Therapy – Phase III NCIC CTG MA.31
HER+ MBC
No prior
anthracycline /
taxane-based
chemotherapy in
the metastatic
setting
(N = 652)
Lapatinib 1250 mg PO daily +
Taxane*
n = 326
Lapatinib 1500 mg
PO daily until PD
Trastuzumab† + Taxane*
n = 326
Trastuzumab
6 mg/kg IV q3wk
until PD
Primary Endpoint: PFS
Gelmon KA, et al. J Clin Oncol. 2015;33(14):1574-1583.
*Paclitaxel 80 mg/m2 IV q1w, days 1, 8, 15 or docetaxel 75 mg/m2 IV q21d.
†6 mg/kg IV q1w (load 4 mg/kg then 2 mg/kg) or 14 mg/kg q3w (load 8 mg/kg then 6 mg/kg).
R
Maintenance
24 Weeks

Lapatinib + Taxane vs Trastuzumab + Taxane
Progression-Free Survival
Intent-to-treat population
mOS not reached
HR = 1.28
95% CI 0.95-1.71
P = 0.11
0 4 12 20 28 36
40
80
8 16 24 32 40
286
326 125 48 14 2
229 88 25 9 0
287
326
TTax/T
No. at risk
LTax/L 84 28 4 0
207 53 15 1 0
100
20
60
Time (months)
Survival
(%)
TTax/T
LTax/L
TTax/T LTax/L
mPFS, mo 11.3 9.0
Stratified HR,
(95% CI)
1.37 (1.13-1.65)
P value 0.001
Ttax/T = trastuzumab + taxane, trastuzumab maintenance
Ltax/L = lapatinib + taxane, lapatinib maintenance

MA.31 Trial Grade 3/4 Adverse Events
Adverse
Events
Lapatinib/Taxane →
Lapatinib
n = 322
Trastuzumab/Taxane →
Trastuzumab
n = 325
P value
Diarrhea 60 (19%) 4 (1%) < 0.001
Febrile
Neutropenia
17 (5%) 10 (3%) 0.174
Rash 26 (8%) 0 (0%) < 0.001

Phase III CLEOPATRA Study Design
First-Line Pertuzumab for MBC
HER2+
MBC
(N = 800)
Docetaxel 75 mg/m2* q3wk
+ Trastuzumab 8 mg/kg, →
6 mg/kg q3wk
+ PLACEBO
Docetaxel 75 mg/m2 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 SM, et al. N Engl J Med. 2015;372(8):724-734.
R

37

38

CLEOPATRA: PFS
Investigator Assessment
100
90
80
70
60
50
40
30
20
10
0
PFS
(%)
Time (months)
HR 0.68, 95% CI [0.58, 0.80], P < 0.001
Pertuzumab + T + D: median = 18.7 months
Placebo + T + D: median = 12.4 months
6.3
Months
80
70
60
50
40
30
20
10
0
402
406
284
223
179
110
121
75
87
51
37
21
6
6
0
0
0
0
n at risk
T, trastuzumab; D, docetaxel.
Pertuzumab
Placebo

CLEOPATRA: OS
Pertuzumab +Trastuzumab + Docetaxel
Median OS: 56.5 months
Placebo + Trastuzumab + Docetaxel
Median OS: 40.8 months
HR = 0.68, 95% CI [0.56-0.84],P < 0.001
Median follow-up: 50 months (range, 0-70 months)
100
90
80
70
60
50
40
30
20
10
0
Time (months)
OS
(%)
70
60
50
40
30
20
10
0
1
28
104
226
268
318
371
402
0
23
91
179
230
289
350
406
n at risk
Δ = 15.7 months
Pertuzumab
Placebo

CLEOPATRA: Safety Profile
Grade ≥ 3 Events Placebo + Trastuzumab
+ Docetaxel
n = 396
Pertuzumab + Trastuzumab
+ Docetaxel
n = 408
Neutropenia 46.2% 49.0%
Febrile neutropenia 7.6% 13.7%
Leukopenia 14.9% 12.3%
Diarrhea 5.1% 9.3%
Peripheral neuropathy 1.8% 2.7%
Anemia 3.5% 2.5%
Asthenia 1.8% 2.7%
Fatigue 3.3% 2.2%
Granulocytopenia 2.3% 1.5%
Left ventricular dysfunction 3.3% 1.5%
Dyspnea 2.0% 1.0%
Hypertension 1.8% 2.0%
Pneumonia 2.0% 1.0%
Swain SM, et al. Oncologist. 2014;19(7):693-701; Swain SM, et al. N Engl J Med. 2015;372(8):724-734.
Serious AE

Phase III MARIANNE Study Design
T-DM1 +/- Pertuzumab
HER2+
Progressive or
recurrent
locally
advanced or
chemotherapy
-naïve MBC
(N = 1092)
T-DM1 + PERTUZUMAB q3wk
T-DM1 + PLACEBO q3wk
Primary endpoint: PFS
TRASTUZUMAB q3wk +
DOCETAXEL q3wk OR
PACLITAXEL qwk
Ellis P, et al. J Clin Oncol. 2015;33(suppl). Abstract 507.
R

R
A
N
D
O
M
I
Z
E
German Breast Group 26/Breast International Group 03-05 Study:
Trastuzumab Beyond Progression in HER2 Positive Advanced
Breast Cancer
Patients on treatment until progression
or unacceptable toxicity, then followed
for survival
•Trastuzumab + Capecitabine 2000
mg/m2/d po days 1-14 q 3 wk
•Capecitabine 2500 mg/m2/d po
days 1-14 q 3 wk
•Progressive, HER2+
MBC or LABC
•Previously treated
with trastuzumab*
•1 prior
chemotherapy
regimen
N=156
*Trastuzumab must have been administered for metastatic disease.
von Minckwitz G et al. J Clin Oncol 2009.

German Breast Group 26/Breast
International Group 03-05: Results

R
A
N
D
O
M
I
Z
E
EGF100151 Study
Study Design
Patients on treatment until progression
or unacceptable toxicity, then followed
for survival
•Lapatinib 1250 mg po qd
continuously + Capecitabine 2000
mg/m2/d po days 1-14 q 3 wk
•Capecitabine 2500 mg/m2/d po
days 1-14 q 3 wk
•Progressive, HER2+
MBC or LABC
•Previously treated
with anthracycline,
taxane and
trastuzumab*
•No prior
capecitabine
Stratification:
•Disease sites
•Stage of disease N=528
*Trastuzumab must have been administered for metastatic disease.
Geyer C, et al. NEJM. 2006;355:2733-2743.

Therapy with Lapatinib Resulted in a Significant
Improvement in Time to Progression (1 of 2)
Capecitabine
Lapatinib +
Capecitabine
0.00013
P value (log-rank, 1-sided)
102
82
Progressed or died
18.6
27.1
Median TTP, wk
201
198
No. of pts
0.57 (0.43, 0.77)
Hazard ratio (95% CI)
Independent Assessment

50
Overall Survival:
Capecitabine ± Lapatinib
0.800
P-value (log-rank, 2-sided)
29 (18%)
29 (18%)
Deaths
0.93 (0.55, 1.59)
Hazard ratio (95% CI)
NR
NR
Median OS
161
160
No. of pts
Time (weeks)
0 10 20 30 40 50 70 90
Cumulative
Survival
(%)
0
10
20
30
40
50
60
70
80
90
100
60 80
Geyer C, et al. N Engl J Med. 2006;355:2733-2743.
Capecitabine
Lapatinib +
Capecitabine
Capecitabine
Lapatinib + Capecitabine

Not For Affirmative Use
A Randomized Study of Lapatinib (Tykerb/Tyverb®) in
Combination with Trastuzumab versus Lapatinib
Monotherapy in Patients with Heavily-Pretreated HER2+
Metastatic Breast Cancer Progressing on Trastuzumab
Therapy
J. O’Shaughnessy1, K. Blackwell2, H. Burstein3, AM. Storniolo4, G. Sledge4, S.
Vukelja5 J. Baselga6, M. Koehler7, S. Laabs7,
A. Florance7, D. Roychowdhury7
1Baylor Sammons Cancer Center, 5Texas Oncology, PA, US Oncology, Dallas, TX;
2Duke University Medical Center, Durham, NC; 3Dana-Farber Cancer Institute, Boston, MA;
4I.U. Simon Cancer Center, Indianapolis, IN; 6Vall d'Hebron University Hospital, Barcelona, Spain; 7Medicine
Development Center Oncology, GlaxoSmithKline, Collegeville, PA.
Presented at the American Society of Clinical Oncology Annual Meeting, 2008.

A Randomized Study of Lapatinib (Tykerb/Tyverb®) in
Combination with Trastuzumab versus Lapatinib
Monotherapy in Patients with Heavily-Pretreated HER2+
Metastatic Breast Cancer Progressing on Trastuzumab
Therapy
Blackwell K, et al J Clin Oncol 2012

Total Blockade of HER2 May Provide Greater Anti-tumor
Activity and Overcome Resistance
HER2 - HER2
PTEN
SOS
RAS
RAF
MEK
MAPK
Cell proliferation
Cell survival
Cell mobility and invasiveness
PI3K
Akt
MUC4
PI3K
Akt
SOS
RAS
RAF
MEK
MAPK
Transcription
Hudis C. N Eng J Med 2007;357(1):39-51.
Nahta R, Esteva F. Breast Cancer Res 2006;8(6):215.
Slide developed by LifeBrand for GSK

Lapatinib in HER2+ Breast Cancer Lines
Trastuzumab-Conditioned BT474 Cells
Lapatinib inhibits growth of BC cell
lines that acquire resistance to a
therapeutically relevant dose of
trastuzumab
Lapatinib in combination with
trastuzumab is synergistic in HER2+ BC
cell lines
Konecny et al. Cancer Res. 2006;66:1630-1639
0
10
20
30
40
50
60
70
80
90
100
Fraction
unaffected
(%)
500
250
125
62
39
15
7
3
13
0.05
Nmol lapatinib
Nmol trastuzumab
1.5
trastuzumab
lapatinib
MDA-MB-361 Cells
0
10
20
30
40
50
60
70
80
90
100
lapatinib
Combination
trastuzumab
Fraction
unaffected
(%)
0.014 µmol trastuzumab
1 µmol lapatinib
4 nmol
0.05 nmol
x

Tykerb in Combination with Trastuzumab
Phase III Study to Test if Total HER2 Blockade
Improves Clinical Outcome
R
A
N
D
O
M
I
Z
A
T
I
O
N
Tykerb 1000 mg/day PO
Trastuzumab 4→ 2 mg/kg IV qw
N=148
Tykerb 1500 mg/day PO
N=148
Stratification Factors
• Visceral Disease
• Hormone Receptor
Key Inclusion
• HER2+(FISH+/ IHC3+) MBC
• Progression on
• Anthracycline
• Taxane
• Trastuzumab
• Progression on most recent
trastuzumab regimen
Crossover if PD after
4wk therapy (N=73)

Tykerb in Combination with Trastuzumab Treatment
Efficacy
*Confirmed CR+PR
†CR+PR+SD ≥ 6 mo
Tykerb
N=145
Tykerb +
Trastuzumab
N=146
Response Rate, %*
(95% CI)
6.9
(3.4, 12.3)
10.3
(5.9, 16.4)
Odds Ratio (95% CI) 1.5 (0.6, 3.9)
P=0.46
Clinical Benefit Rate, %†
(95% CI)
12.4
(7.5, 18.9)
24.7
(17.9, 32.5)
Odds Ratio (95% CI) 2.2 (1.2, 4.5)
P=0.01

63
ado-Trastuzumab Emtansine (T-DM1) Background:
Dual Mechanism of Action (MOA)
Emtansine
release
Inhibition of
microtubule
polymerization
Internalization
HER2
Lysosome
Nucleus
P
P
P
Trastuzumab-specific MOA
maintained
Antibody:
Trastuzumab
Emtansine
Cytotoxic: DM1
Stable linker:
MCC
Antibody–drug
conjugate:
T-DM1
Highly potent
DM1a
is internalized
within HER2(+)
cancer cells
Junttila T, et al. Breast Cancer Res Treat 2011;128:347-356.
aDM1 is 24- to 270-fold more potent than taxane in cytotoxic assays
M3.K.BC.Adv.Ow.8

64
Carter PJ, Senter PD. Cancer J 2008;14:154-169. Chari RV. Acc Chem Res 2008;41:98-107. Lewis Phillips GD, et al. Cancer Res 2008;68:9280-9290.
A Novel Antibody-Drug Conjugate (ADC) (cont.)
Monoclonal antibody
trastuzumab
Target Expression: HER2
Highly potent cytotoxic agent
(DM1, a tubulin destabilizer)
Cytotoxic Drug: DM1
Systemically stable
Thioether Linker
T-DM1
M3.K.BC.Adv.Ow.7

65
Combines 2 Approaches to Target HER2(+) Cancer
Targeted Intracellular
Delivery of DM1
• ado-trastuzumab emtansine
binds to the HER2 receptor
and is internalized
• DM1 is released inside the cell
• DM1 kills tumor cells by
inhibiting microtubule
assembly
Trastuzumab
Biologic Properties
• Blocks downstream HER2
signaling to inhibit proliferation
of tumor cells
• Flags HER2-positive tumor
cells for destruction via
antibody-dependent cell-
mediated cytotoxicity
• Inhibits HER2 shedding
Combined Mechanism of Action
Lewis Phillips GD, et al. Cancer Res 2008;68:9280-9290. Junttila T, et al. Breast Cancer Res Treat 2011;128:347-356.
M3.K.BC.Adv.Ow.9

TDM4258g* Phase II Single-Arm ado-Trastuzumab Emtansine (T-DM1) in MBC: Study Design
1:1
HER2-Positive MBC
• Progressed on HER2-
directed therapy or
within 60 days after
receiving trastuzumab
• ≥1 prior chemotherapy
agent for MBC
(N=112)
T-DM1
3.6 mg/kg q3w
up to 1 year
A single-arm phase II US study
aPatients who were still achieving clinical benefit after 1 year were eligible to transfer to an extension study
Option of
continued
treatmenta
Primary endpoint: ORR by
independent review, safety and
tolerability
Burris HA III, et al. J Clin Oncol 2011;29:398-405.
Key secondary endpoints: ORR
by investigator assessment, DOR,
PFS by independent and
investigator assessment, and PK
66
M5.K.BC.Early.Ow.13
*Roche Sponsored Study

Demographics (N=112)
Median age (range), years 54.5 (33-82)
Race, n (%)
White
Black/Asian or Pacific Islander
101 (90.2)
9 (8.0)/2 (1.8)
ECOG PS, n (%)
0
1
2/3
60 (53.6)
43 (38.4)
8 (7.1)/1 (0.9)
ER positive or PR positive, n (%)
ER negative and PR negative, n (%)
53 (47.3)
56 (50)
Median time since metastatic diagnosis (range), months 33.1 (2-258)
≥3 distinct metastatic sites, n (%) 84 (75)
Metastatic sites, ≥50% of patients, n (%)
Lung
Liver
Bone
63 (56.3)
63 (56.3)
59 (52.7)
Median number of systemic agents for metastatic disease (range) 5 (1-17)
Prior lapatinib therapy, n (%) 67 (59.8)
TDM4258g* Phase II Single-Arm ado-Trastuzumab Emtansine (T-DM1) in MBC: Baseline
Demographics and Disease Characteristics
ER=estrogen receptor; PR=progesterone receptor
67
M5.K.BC.Early.Ow.14

TDM4258g* Phase II Single-Arm ado-Trastuzumab Emtansine (T-DM1) in MBC: Efficacy
Overview
Efficacy Endpoints IRF Investigator
ORR,a %
All treated patients (n=112) 25.9b 37.5c
Prior lapatinib (n=66) 24.2 34.8
Centrally confirmed HER2 positive (n=74) 33.8 47.3
Centrally confirmed HER2 negative (n=21) 4.8 9.5
Median DOR (95% CI), months
Responders (n=29) NR (6.2-NE) 9.4 (7.0-NE)
Median PFS (95% CI), months
Efficacy-evaluable patients (n=108) 4.6 (3.9-8.6) 4.6 (4.1-6.0)
Prior lapatinib (n=66) 5.3 (3.6-8.9) 4.2 (2.8-6.8)
Centrally confirmed HER2 positive (n=74) 8.2 (4.4-NE) --
Centrally confirmed HER2 negative (n=21) 2.6 (1.4-3.9) --
68
aDifferences between the IRF- and investigator-determined ORR are attributed to the independent selection of
different lesions by the reviewers and alternative interpretations of nontarget lesions; bAll partial responses;
c4 (3.6%) complete responses and 38 (33.9%) partial responses
IRF=independent review facility; NE=not estimable; NR=not reached
M5.K.BC.Early.Ow.15

TDM4374g* Phase II Single-Arm ado-Trastuzumab Emtansine (T-DM1) in Previous Trastuzumab- and
Lapatinib-Treated MBC: Study Design
A single-arm phase II study
Krop IE, et al. J Clin Oncol 2012;30:3234-3241.
69
Data cutoff for analysis was June 21, 2010. Median follow-up was 17.4 months
CBR=clinical benefit rate; H=trastuzumab; L=lapatinib; X=capecitabine
1:1 T-DM1
3.6 mg/kg q3w
HER2-Positive MBC
• Prior exposure to an anthracycline,
a taxane, X, L, and H
• ≥2 HER2-directed therapy regimens
for LABC or MBC
• Progression on most recent HER2-
directed therapy regimen
(N=110)
Primary endpoint: ORR by
independent review, safety and
tolerability
Key secondary endpoints: CBR
(CR + PR + SD ≥6 months), DOR,
PFS, and PK
M5.K.BC.Early.Ow.19

Lapatinib-Treated MBC: Baseline Characteristics
Characteristic
Median age (range), years 52.5 (34-77)
Median time since metastatic diagnosis (range), months 42.8 (4.6-148.9)
ECOG PS, n (%)
0/1
2
54 (49.1)/53 (48.2)
3 (2.7)
ER positive and/or PR positive,a n (%)
ER negative and PR negative,a n (%)
55 (50.0)
51 (46.4)
≥3 distinct metastatic sites, n (%) 81 (73.6)
Sites of metastasis, n (%)
Locoregional
Lung
Bone
Liver
CNS
70 (63.6)
69 (62.7)
57 (51.8)
49 (44.5)
19 (17.3)
Median number of agents for metastatic disease (range)b 7.0 (3-17)
Patients who received all 5 prior agents,
c
n (%) 109 (99.1)
aInformation on ER/PR status was unknown for 4 patients; bExcluding hormonal therapies; c1 patient received
prior ixabepilone instead of a taxane
ER=estrogen receptor; PR=progesterone receptor
Krop IE, et al. J Clin Oncol 2012;30:3234-3241.
70
M5.K.BC.Early.Ow.20

Lapatinib-Treated MBC: Efficacy Overview
Efficacy Endpoints IRF1 Investigator
1,2
ORR,a %
All treated patients (n=110) 34.5b 32.7
c
Progressed on H + CT and L + CT (n=73) 34.2 --
Centrally confirmed HER2 positive (n=80) 41.3 40.0
Centrally confirmed HER2 negative (n=15) 20.0 13.3
Median DOR (95% CI), months
Responders (n=38) 7.2 (4.6-NE) 9.7 (7.1-NE)
Median PFS (95% CI), months
All treated patients (n=110) 6.9 (4.2-8.4) 5.5 (4.2-7.9)
Centrally confirmed HER2 positive (n=80) 7.3 (4.6-12.3) --
Centrally confirmed HER2 negative (n=15) 2.8 (1.3-NE) --
71
1. Krop IE, et al. J Clin Oncol 2012;30:3234-3241. 2. Krop IE, et al. Presented at: ESMO. 2010 (abstr 2770).
aObjective response rate = CR or PR determined by 2 consecutive tumor assessments ≥4 weeks apart;
bAll partial responses; c4.5% complete responses
CT=chemotherapy; H=trastuzumab; IRF=independent review facility; L=lapatinib; NE=not estimable
M5.K.BC.Early.Ow.21

Phase III Trial: T-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
Verma S, et al. N Engl J Med. 2012;367(19):1783-1791.
Co-Primary Endpoints: OS and PFS
61% of patients in each group had 0-1 prior chemo regimens for locally advanced or metastatic disease.
39% had > 1 prior regimen.
R

EMILIA* (TDM4370g) Phase III ado-Trastuzumab Emtansine (T-DM1) vs Capecitabine + Lapatinib in HER2-Positive MBC:
Progression-Free Survival (PFS) by Independent Review
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
Cap + Lap
T-DM1
Patients at risk by independent review:
Median, Months Events, n
Cap + Lap 6.4 304
T-DM1 9.6 265
0.0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Proportion
Progression
Free
Time, Months
Verma S, et al. N Engl J Med 2012;367:1783-1791 [including supplementary appendix].
Unstratified HR=0.66 (95% CI, 0.56-0.78; P<0.0001)
Cap=capecitabine; Lap=lapatinib
Median PFS by investigator review:
9.4 for T-DM1 vs 5.8 months for Cap + Lap;
HR=0.66; P<0.001
73
Stratified HR=0.65 (95% CI, 0.55-0.77)
P<0.001
M5.K.BC.Early.Ow.46

EMILIA: Overall Survival
Overall
Survival
(%)
100
80
60
40
20
0
0 6 12 18 24 30
4 10 16 22 28
2 8 14 20 26
Months
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
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)
Median No.
of Months
No. of
Events
Lapatinib-Capecitabine 25.1 182
T-DM1 30.9 149
Stratified hazard ratio 0.68 95% CI [0.55-0.85]
P < 0.001
Efficacy stopping boundary P = 0.0037

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%
Serious AE

T-DM1 vs Physician’s Choice – Beyond
Second-Line HER2 Therapy (TH3RESA)
Krop IE, et al. Lancet Oncol. 2014;15(7):689-699.
Metastatic or
unresectable locally
advanced HER2+ BC
Prior trastuzumab,
taxane, and lapatinib
(N = 602)
T-DM1
3.6 mg/kg IV every
21 days
n = 404
Physician’s choice:
chemo, hormone
therapy, biologic,
HER2-targeted
n = 198
Primary Endpoints: PFS, OS
R
2
1

TH3RESA* (BO25734) Phase III ado-Trastuzumab Emtansine (T-DM1) vs Treatment of Physician’s Choice in HER2-Positive MBC:
Progression-Free Survival (PFS) by Investigator Assessment
198
404
120
334
62
241
28
114
13
66
6
27
1
12
0
0
TPC
T-DM1
Patients at risk:
Time, Months
14
12
10
8
6
4
2
0.0
0.2
0.4
0.6
0.8
1.0
0
Proportion
Progression
Free
Krop IE, et al. Lancet Oncol 2014;15:689-699.
77
Events,
n
Median,
Months
TPC (n=198) 129 3.3
T-DM1 (n=404) 219 6.2
Stratified HR=0.528 (95% CI, 0.422-0.661)
P<0.0001
M5.K.BC.Early.Ow.96
Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months. Unstratified HR=0.521 (P<0.0001)
TPC=treatment of physician’s choice

TH3RESA* (BO25734) Phase III ado-Trastuzumab Emtansine (T-DM1) vs Treatment of Physician’s Choice in HER2-Positive
MBC: Final Overall Survival (OS) Analysis
Time, Months
Proportion
Surviving
78
TPC
T-DM1
Patients at risk:
M5.K.BC.Early.Ow.101
40
34
28
22
16
12
2
0.0
0.2
0.4
0.6
0.8
1.0
0 4 6 8 10 14 18 20 24 26 30 32 36 38
0
6
39
62
80
107
168
198 150 131 122 115 93 68 66 59 51 28 16 1 0
0
25
132
179
226
280
388
404 368 347 321 298 251 207 192 167 164 84 54 12 2
Wildiers H, et al. Presented at: SABCS. 2015 (abstr S5-05). *Roche Sponsored Study
TPC=treatment of physician’s choice
Stratified HR=0.68 (95% CI, 0.54-0.85)
P=0.0007
(Prespecified crossing boundary: HR<0.748;
P<0.012)
Median, Months
TPC (n=198) 15.8
T-DM1 (n=404) 22.7

MARIANNE* (BO22589) Phase III ado-Trastuzumab Emtansine (T-DM1) + Pertuzumab vs Trastuzumab + Taxane in First-
line MBC: Study Design
Ellis P, et al. Presented at: ASCO. 2015 (abstr 507).
Trastuzumab + docetaxel
(8 mg/kg LD then 6 mg/kg + 100 or 75 mg/m2 q3w)
OR
Trastuzumab + paclitaxel
(4 mg/kg LD then 2 mg/kg + 80 mg/m2 qw)
T-DM1 + placebob
(3.6 mg/kg + 840 mg LD then 420 mg q3w)
R
HER2-Positive (Central)
LABCa or MBC
• No prior chemotherapy
for LABC/MBC
• >6 months from prior
(neo)adjuvant vinca
alkaloid or taxane
chemotherapy
(N=1095)
Primary endpoint: PFS by IRF,
non-inferiority and superiority assessed
Stratification factors: World region,
prior neo-/adjuvant therapy (if yes: prior
trastuzumab/lapatinib), visceral disease
Key secondary endpoints: OS,
PFS by investigator, ORR, safety,
patient-reported outcomes
T-DM1 + pertuzumab
(3.6 mg/kg + 840 mg LD then 420 mg q3w)
aLocally progressive or recurrent and not amenable to resection with curative intent; bPertuzumab placebo
IRF=independent review facility; LD=loading dose
79

80

Progression-Free Survival
MARIANNE Trial
Ellis P, et al. J Clin Oncol. 2015;33(suppl 15). Abstract 507.
Time (mo.)
0 6 18 30 42 54
40
80
12 24 36 48
365 265 107 50 5
163 75 21
363 261 135 75 5
177 109 25
367
HT
T-DM1 + P
T-DM1 257 133 67 3
176 104 28
1
100
20
0
60
Progression-Free
Survival
(%)
HT
T-DM1 + P
T-DM1
HR, hazard ratio; HT, trastuzumab + taxane; P, pertuzumab; PFS, progression-free survival; T-DM1, trastuzumab emtansine.
Median PFS (mo)
Events (no.)
Stratified HR
(97.5% CI) vs HT
Stratified HR
(97.5% CI) vs T-DM1
13.7
231
-
15.2
217
14.1
HT T-DM1 + P
T-DM1
236
0.87 (0.69-1.08)
P = 0.14
0.91 (0.73-1.13)
P = 0.31
0.91 (0.73-1.13)
-

MARIANNE* (BO22589) Phase III ado-Trastuzumab Emtansine (T-DM1) + Pertuzumab vs Trastuzumab + Taxane in First-
line MBC: Overall Survival (OS) (First Interim Analysis)
100
80
60
40
20
0
Survival,
%
0 6 12 18 24 30 36 42 48 54
Time, Months
365
367
363
335
345
341
303
321
309
273
291
282
250
263
257
218
224
231
98
104
106
25
37
28
1
3
1
82
HT=trastuzumab + taxane; NR=not reached; Pert=pertuzumab
Events,
n
Median OS,
Months
Stratified HR
(97.5% CI) vs HT
HT 123 NR –
T-DM1 116 NR 0.86 (0.64-1.16)
T-DM1 + Pert 115 NR 0.82 (0.61-1.11)
HT
T-DM1
T-DM1 + Pert
Patients at risk:

MARIANNE* (BO22589) Phase III ado-Trastuzumab Emtansine (T-DM1) + Pertuzumab vs Trastuzumab + Taxane in First-line MBC:
Maintenance of HRQOL
● The FACT-Breast Trial Outcome Indexa evaluates
– Physical well-being
– Functional well-being and
– Breast cancer subscale
83
Time to Eventb HT
(n=327)
T-DM1
(n=352)
T-DM1 +
Pertuzumab
(n=338)
Median, months 3.6 7.7 9.0
HR
95% CI (vs HT)
–
0.70
(0.57-0.86)
0.68
(0.55-0.84)
aHRQOL measured by the Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) of the Functional
Assessment of Cancer Therapy-Breast (FACT-B) questionnaire; bEvent was defined as ≥5-point decrease
from the baseline HRQOL score (Eton, J Clin Epidemiol, 2004)
HRQOL=health-related quality of life; HT=trastuzumab + taxane

MARIANNE* (BO22589) Phase III ado-Trastuzumab Emtansine (T-DM1) + Pertuzumab vs Trastuzumab + Taxane in First-line MBC:
Overview of AEs
HT, %
(n=353)
T-DM1, %
(n=361)
T-DM1 +
Pertuzumab, %
(n=366)
Any AE 98.6 98.9 98.6
Grade ≥3 AE 54.1 45.4 46.2
AE leading to death 1.7 1.1 1.9
AE leading to
discontinuation of any
treatment component
29.7 18.3 19.1
LVEF <50% and ≥15%
points decrease from
baseline
4.5 0.8 2.5
84
HT=trastuzumab + taxane; LVEF=left ventricular ejection fraction

ExteNET: Phase III Study Design
 Primary endpoint: iDFS in ITT population at 2 yrs
 Results of primary analysis: 2-yr iDFS improved with neratinib vs
placebo (93.9% vs 91.6%, HR: 0.67; P = .009)
– Hormone receptor+ (n = 1631): HR: 0.51; P = .001
– HER2+ 60% (n = 1463): HR: 0.51; P = .002
Slide credit: clinicaloptions.com
Chan A, et al. SABCS 2015. Abstract S5-02.
Pts with HER2+
local BC; adj.
trastuzumab
completed ≤ 1 yr
before study entry plus
chemo; lymph node+
disease or no pCR;
known ER and PgR
status
(N = 2840)
iDFS: 2- and 5-yr F/U
OS: 5-yr F/U
Neratinib 240 mg/day
Placebo
1 yr

100
90
80
70
60
50
0
Neratinib
(n = 1420)
Placebo
(n = 1420)
48
ExteNET Current Analysis: 3-Yr iDFS
Chan A, et al. SABCS 2015. Abstract S5-02. Reproduced with permission. Slide credit: clinicaloptions.com
2-sided P = .023
HR: 0.74 (95% CI: 0.56-0.96)
97.8%
95.6%
94.1%
91.6%
94.1%
89.9%
90.5%
88.6%
0 6 12 18 24 30 36 42
Disease-Free
Survival
(%)
Mos After Randomization

Chan A, et al. SABCS 2015. Abstract S5-02. Reproduced with permission.
ExteNET: 3-Yr iDFS by Hormone Receptor
Status
Slide credit: clinicaloptions.com
100
90
80
70
60
50
0
100
90
80
70
60
50
0
0 6 12 18 24 30 36 42 48
0 6 12 18 24 30 36 42 48
Neratinib
(n = 816)
Placebo
(n = 815)
2-sided P = .003
HR: 0.57 (95% CI: 0.39-0.82)
Disease-Free
Survival
(%)
Disease-Free
Survival
(%)
98.0%
96.1%
95.4%
91.5%
93.6%
89.3%
Neratinib
(n = 604)
Placebo
(n = 605)
2-sided P = .938
HR: 0.98 (95% CI: 0.67-1.45)
97.5%
94.9%
92.5%
91.8%
90.6%
89.9%
Hormone Receptor Positive Hormone Receptor Negative

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