Download New Treatment Paradigms in the Management of Metastatic Breast

10/30/2013
New Treatment Paradigms in the
Management of Metastatic Breast
Cancer
Sara A. Hurvitz, MD, FACP
Assistant Professor of Medicine
Director, Breast Oncology Program, UCLA
Co-Director, Outpatient Oncology Clinics SM-UCLA
Medical Director, Clinical Research Unit,
Jonsson Comprehensive Cancer Center/UCLA
Objectives
• Review efficacy and safety of current & emerging
therapies for MBC
• Implement strategies to improve survival in patients
whose MBC has progressed after previous treatment
courses
• Implement ASCO and NCCN guidelines for management
of patients with MBC
• Differentiate among the different taxanes used in MBC
• Analyze strategies for reducing disease and treatmentrelated AEs associated with new and emerging therapies
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FIGURE 1 Ten Leading Cancer Types for Estimated New
Cancer Cases by Sex, US, 2013
Siegel et al. CA: A Cancer Journal for Clinicians
2013 Volume 63
FIGURE 1 Ten Leading Cancer Types for Estimated Cancer
Deaths by Sex, US, 2013
Siegel et al. CA: A Cancer Journal for Clinicians
2013 Volume 63
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How many in US have MBC?
Incidence and prevalence of stage IV breast
cancer are not formally collected but
estimated that >160,000 are living with MBC
in the US
Molecular heterogeneity of
breast cancer
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An Enduring Paradigm
Rudolf Ludwig Karl Virchow (1821-1902)
Die Krankhaften Geschwülste 1863
Types of Invasive Breast Cancer:
Distinguishing Subtypes Based on Microscopic
Appearance
Type of Cancer
Frequency
Associated features
Infiltrating Ductal
70-80%
When DCIS is associated, goal is to obtain surgical margins clear of
both invasive tumor and DCIS to reduce risk of recurrence
Invasive Lobular
5-10%
Mucinous/Colloid
2.4%
Well circumscribed, tumor cells dispersed in large pools of
extracellular mucus; uniform, low grade nuclei, prognostically
favorable variant of invasive breast carcinoma.
Metaplastic
<5%
Poorly differentiated ductal carcinoma combined with squamous
cell carcinoma and/or various forms of sarcomatous differentiation;
tends to be resistant to chemotherapy
Tubular
<5%
Well differentiated, low-grade, unusual pre-mmg era, now more
common, indolent and rarely metastasizes
Medullary
<5%
Poorly differentiated, lymphoplasmacytic infiltrate, prognosis more
favorable despite aggressive histologic features, associated with
BRCA1, usually ER-PR-
Micropapillary
<5%
Aggressive with lymph node metastases even when small
Adenoid cystic
<5%
Rare, morphologically identical to that of salivary glands, tends to
be favorable prognosis,
LCIS or DCIS; higher freq bilateral & multicentric, spread to
unusual locations (meninges, peritoneum, GI)
Li, et al. Br J Cancer. 2005 Oct 31;93(9):1046-52; UpToDate 2006
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Revolutionary
Realization:
Breast Cancer is Not
All One Disease
Sorlie et al PNAS 2001
HER2+ MBC
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Identifying and Exploiting the Molecular
Underpinnings of Breast Cancer: HER2
Normal (1X)
~20,000-50,000
HER2 receptors
Overexpressed HER2 (10-100X)
Up to ~2,000,000 HER2 receptors
HER2 is overexpressed in
~25% of breast cancers
Pegram et al. Cancer Treat Res. 2000;103:57.
Ross and Fletcher. Am J Clin Pathol. 1999;112(suppl 1):S53.
Slamon et al. Science. 1987;235:177.
Excessive cellular division
Trastuzumab Has Changed the Natural
History of HER2+ Breast Cancer
Burstein H. N Engl J Med. 2005;353(16):1652-1654.
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Trastuzumab Has Changed the Natural
History of HER2+ Metastatic Breast Cancer
• Patients with HER2-positive metastatic breast cancer (MBC)
now have comparable outcomes with HER2-negative MBC
Probability of Survival, %
100
HER2 positive, trastuzumab (n = 191)
HER2 negative (n = 1782)
HER2 positive, no trastuzumab (n = 118)
80
60
40
20
0
0
12
24
36
48
60
Dawood S, et al. J Clin Oncol. 2010;28(1):92-98.
HER2+ Advanced Breast Cancer:
Major Clinical Advances
Phase 3
of pertuzumab
TRAS
approved
(advanced)
Lapatinib
approved
(advanced)
Phase 2
randomized
trial of T-DM1
Phase 3
of everolimus
Pertuzumab
approved
(advanced)
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Initial trials
of T-DM1,
pertuzumab,
neratinib,
afatinib
White = clinical study results prior to 2013.
Orange = regulatory approvals prior to 2013.
Yellow = clinical study results reported and regulatory approval in 2013.
Adapted from Krop I. SABCS 2011, Abst ES1-3.
T-DM1
phase 3
reported
T-DM1
2nd
phase 3
report
T-DM1
approved
(advanced)
14
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Prognosis of HER2+ MBC
Population-Level Influence of Trastuzumab
• Trastuzumab approved in 1998 for HER2+ MBC
• Model of effect of trastuzumab on life expectancy over 15 years (19992013)
Danese M. ASCO 2013. Abstract 625.
HER2+ MBC
First-line setting
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Latest Developments in HER2-Targeted
First-line (Metastatic) Treatment
 Trastuzumab plus chemotherapy
 HER2-targeted agent plus endocrine
therapy (post-menopausal, ER+)
 Pertuzumab plus trastuzumab plus
taxane
 Under investigation:
 T-DM1
 Everolimus
Chemotherapy Plus Trastuzumab
in Metastatic Disease
Slamon et al
n = 469
Marty et al
n = 186
AC or T*
vs
AC or T→H†
Docetaxel
vs
Docetaxel →H†
Treatment arms
P value
P value
Time to Disease
Progression (mos)
4.6
7.4
< 0.001
6.1
11.7
0.0001
Response Rate
32%
50%
< 0.001
34%
61%
0.0002
Median Overall
Survival (mos)
20
25
0.046
23
31
0.0325
*T = paclitaxel; †H = trastuzumab.
Hudis CA. N Engl J Med. 2007;357:36-51;
Slamon DJ, et al. N Engl J Med. 2001;344:783-792 ; Marty M, et al. J Clin Oncol. 2005;23:4265-4267.
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Recommended First-line
Combinations With Trastuzumab
• HER2+ disease without previous trastuzumab: trastuzumab
plus
–
–
–
–
–
–
Paclitaxel ± carboplatin
Vinorelbine
Capecitabine
Docetaxel
Docetaxel/pertuzumab (approved June 2012)
Paclitaxel/pertuzumab
• HER2+ disease with previous trastuzumab
– Ado-trastuzumab emtansine (T-DM1)
– Lapatinib + capecitabine
– Trastuzumab plus:
- Other first-line agents
- Capecitabine
- Lapatinib (without cytotoxic therapy)
NCCN. Clinical practice guidelines in oncology: breast cancer. v.2.2013.
Hormonal Therapy in HER2Positive Metastatic Breast Cancer
Regimen
ORR, %
Median PFS, Mos
Trastuzumab (N = 114; HER2 positive
n = 79)[1]
26
3.5-3.8
Anastrozole/trastuzumab (n = 103)[2]
20
4.8
Anastrozole (n =
104)[2]
7
2.4
28
8.2
Letrozole (n =
644)[3]
15
3.0
Lapatinib (N =
138)[4]
24
NA
Lapatinib/letrozole (n = 642)[3]
1. Vogel C, et al. J Clin Oncol. 2002;20:719-726. 2. Kaufman B, et al. J Clin Oncol. 2009;27:5529-5537.
3. Johnston S, et al. J Clin Oncol. 2009;27:5538-5546. 4. Gomez HL, et al. J Clin Oncol. 2008;26:2999-3005.
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HER dimerization (receptor pairing) is
essential for HER activity
HER1/EGFR
HER2
HER3
HER2 has no known ligand
and constitutively exists in an
“open” state, ready to pair with
other HER proteins
HER4
HER3 although able to bind
several ligands, lacks intrinsic
tyrosine kinase activity
HER3 receptor has the
strongest phosphorylation
potential
Effects of ligand binding to the
HER3 receptor
HER3
Ligand binds
Conformational change
from “closed” to “open” state
Exposes the dimerization
domain and allows the
formation of dimers
Triggers intracellular
signaling pathways
through transphosphorylation
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Effects of ligand binding to the
HER3 receptor
HER3
Ligand binds
Conformational change
from “closed” to “open” state
Exposes the dimerization
domain and allows the
formation of dimers
Triggers intracellular
signaling pathways
through transphosphorylation
Effects of ligand binding to the
HER3 receptor
HER3
Ligand binds
Conformational change
from “closed” to “open” state
Exposes the dimerization
domain and allows the
formation of dimers
Triggers intracellular
signaling pathways
through transphosphorylation
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Effects of ligand binding to the
HER3 receptor
HER3
Ligand binds
Conformational change
from “closed” to “open” state
Exposes the dimerization
domain and allows the
formation of dimers
Triggers intracellular
signaling pathways
through transphosphorylation
Effects of ligand binding to the
HER3 receptor
HER3
Ligand binds
Conformational change
from “closed” to “open” state
Exposes the dimerization
domain and allows the
formation of dimers
Triggers intracellular
signaling pathways
through transphosphorylation
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Effects of ligand binding to the
HER3 receptor
HER3
Ligand binds
Conformational change
from “closed” to “open” state
Exposes the dimerization
domain and allows the
formation of dimers
Triggers intracellular
signaling pathways
through transphosphorylation
Effects of ligand binding to the
HER3 receptor
HER2
HER3
Ligand binds
Conformational change
from “closed” to “open” state
Exposes the dimerization
domain and allows the
formation of dimers
Triggers intracellular
signaling pathways
through transphosphorylation
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Effects of ligand binding to the
HER3 receptor
Ligand binds
HER3
HER2
Conformational change
from “closed” to “open” state
Exposes the dimerization
domain and allows the
formation of dimers
Triggers intracellular
signaling pathways
through transphosphorylation
P
P
P
P
P
P
P
P P P P P
AKT
P13K
PDK1
mTOR
P
BAD
Cyclin D1
P
GSK3
NFB
survival
p27
P
P
angiogenesis
proliferation cell cycle
control
↓ apoptosis
Pertuzumab: a HER
dimerization inhibitor
HER3
HER2
Pertuzumab
A mechanism of action designed to
bind to the HER dimerization
domain
•
By targeting HER2, the preferred
pairing partner for HER1, HER3 and
HER4, pertuzumab may inhibit
multiple HER signaling pathways
P P P P P
AKT
P13K
•
PDK1
GSK3
NFB
mTOR
BAD
Cyclin D1
p27
angiogenesis
proliferation cell cycle
control
survival
↓ apoptosis
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CLEOPATRA: Study Design
Women with
previously untreated,
HER2-positive locally
recurrent/metastatic
breast cancer
(N = 808)

Primary endpoint: PFS (independently
assessed)

Secondary endpoints: PFS (investigator
assessment), ORR, OS, Safety
Trastuzumab 6 mg/kg q3w* +
Docetaxel 75-100 mg/m2 q3w† +
Pertuzumab 420 mg q3w‡
(n = 402)
Trastuzumab 6 mg/kg q3w* +
Docetaxel 75-100 mg/m2 q3w† +
Placebo q3w
(n = 406)
Treatment until
disease progression
or unacceptable
toxicity
*Trastuzumab 8 mg/kg loading dose given.
†Minimum of 6 docetaxel cycles recommended; < 6 cycles permitted for unacceptable toxicity or PD.
‡Pertuzumab 840 mg loading dose given.
Baselga J, et al. SABCS 2011. Abstract S5-5.
CLEOPATRA: PFS
Independent Assessment
Baselga J, et al. N Engl J Med. 2012;366(2):109-119,
Swain S, et al. 2013; Lancet Oncol. Epub ahead of print.
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CLEOPATRA: PFS by Previous
Trastuzumab Therapy
Patient Subgroup
Median PFS, Mos
HR
(95% CI)
Placebo +
Trastuzumab +
Docetaxel
Pertuzumab +
Trastuzumab +
Docetaxel
Previous (neo)adjuvant
trastuzumab treatment
(n = 88)
10.4
16.9
0.62
(0.35-1.07)
No previous (neo)adjuvant
trastuzumab treatment
(n = 288)
12.6
21.6
0.60
(0.43-0.83)
Baselga J, et al. N Engl J Med. 2012;366:109-119.
CLEOPATRA: OS
1 year
100
94%
Overall Survival (%)
90
2 years
89%
80
81%
3 years
70
66%
69%
60
HR = 0.66
95% CI 0.52 - 0.84
P = 0.0008
50
50%
40
30
20
Ptz + T + D: 113 events; median not reached
Pta + T + D: 154 events; median 37.6 months
10
0
No. at Risk
Time (months)
0
Ptz + T + D 402
Pta + T + D 406
5
10
15
20
25
30
35
40
45
50
55
387
383
371
350
342
324
317
285
230
198
143
128
84
67
33
22
9
4
0
0
0
0
Baselga J, et al. N Engl J Med. 2012;366(2):109-119,
Swain S, et al. 2013; Lancet Oncol. Epub ahead of print.
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HER2+ MBC
First-Line
Under Investigation:
T-DM1
Everolimus + trastuzumab/taxane
T-DM1: Mechanism of Action
HER2
T-DM1
Emtansine
release
P
Inhibition of
microtubule
polymerization
P
P
Lysosome
Internalization
Nucleus
Adapted from LoRusso PM, et al. Clin Cancer Res 2011.
36
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TDM4450 Study Design
Trastuzumab
8 mg/kg loading dose;
6 mg/kg q3w IV
HER2-positive,
recurrent locally
advanced breast
cancer or MBC
(N=137)
1:1
+ Docetaxel
75 or 100 mg/m2 q3w
PDa
Crossover to
T-DM1
(optional)
(n=70)
T-DM1
3.6 mg/kg q3w IV
PDa
(n=67)
• Randomized, phase II, international, open-label studyb
• Stratification factors: World region, prior adjuvant trastuzumab therapy, disease-free interval
• Primary end points: PFS by investigator assessment, and safety
• Data analyses were based on clinical data cut of Nov 15, 2010 prior to T-DM1 crossover
• Key secondary end points: OS, ORR, DOR, CBR, and QOL
aPatients
bThis
were treated until PD or unacceptable toxicity.
was a hypothesis generating study; the final PFS analysis was to take place after 72 events had occurred.
Kaplan-Meier estimates of progression-free survival (PFS) in the overall study population.
Hurvitz S A et al. JCO 2013;31:1157-1163
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TDM4450: Kaplan-Meier estimates of duration of response (DOR) by investigator.
Hurvitz S A et al. JCO 2013;31:1157-1163
TDM4450: Summary of Adverse Events
Safety Evaluable Patients
a,b
Trastuzumab +
a
T-DM1 (n=69) ,
docetaxel (n=66) ,
n (%)
n (%)
Any grade ≥3 AE
59 (89.4)
32 (46.4)
AE leading to discontinuation of
any study treatment component
(any grade)
19 (28.8)
5 (7.2)
1 (1.5)c
1 (1.4)d
17 (25.8)
13 (18.8)
AE leading to death
Serious AEs (any grade)
aTwo
patients mistakenly received a dose of T-DM1 and were thus included in the T-DM1 arm for safety analyses.
3 patients who received at least 1 dose of trastuzumab alone or trastuzumab plus docetaxel.
to cardiopulmonary failure.
dDue to sudden death.
bIncludes
cDue
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1st Line mBC Phase III MARIANNE
Study: BO22589/TDM4788g
FPI July 6 2010
n=1092
Arm A
Patients stratified by:
Trastuzumab + taxane (until PD)
n=364
World region
Arm B
Neo/Adjuvant therapy
(Y/N)
T-DM1 + pertuzumab (until PD)
n=364
Trastuzumab and/or
lapatinib based therapy
(Y/N)
Arm C
T-DM1 + pertuzumab placebo (until PD)
n=364
Visceral disease (Y/N)
Patients with HER2 positive progressive or recurrent locally advanced
breast cancer or previously untreated metastatic breast cancer
Primary endpoints:
PFS as assessed by IRF; Safety
Secondary endpoints: OS; PFS by investigator; PRO analyses; Biomarkers
Non-inferiority followed by Superiority analysis between each of the experimental
arms and the control arm
Interim futility analysis: Option to drop experimental arm
BOLERO-1: EVE Phase III Trial Design
(HER2+ ABC First Line)
Key endpoints
• Primary: PFS
• Secondary: OS, ORR, CBR, safety, pharmacokinetics, biomarker/laboratory
assessments; patient reported outcomes
EVE + Paclitaxel + TRAS
BOLERO-1
N = 719
• HER2+ ABC
• No prior therapy
for ABC
• Stratified by prior
neo/adjuvant TRAS
R
2:1
(E: 10 mg/d)
(P: 80 mg/m2 weekly, days 1, 8, 15)
(T: 2 mg/kg, days 1, 8, 15)
28 day cycle
Paclitaxel + TRAS
(P: 80 mg/m2 weekly, days 1, 8, 15)
(T: 2 mg/kg, days 1, 8, 15)
28-day cycle
US National Institutes of Health. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00876395. Accessed
April 1, 2013.
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HER2+ MBC
After Progression
Therapies Available for
Trastuzumab-Resistant Disease
• Lapatinib plus capecitabine
• Lapatinib plus trastuzumab
• Trastuzumab plus capecitabine
• T-DM1
• Emerging data: Pertuzumab/trastuzumab,
everolimus
Continuing HER2-blockade in trastuzumabresistant disease improves outcomes
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HER2 Beyond Progression
Author
Agents
N
TTP
PFS
OS
Von Minckwitz
et al
Capecitabine
+ trastuzumab
vs
capecitabine
156
8.2 months vs
5.6 months,
P = 0.03
NR
25.5 months vs
20.4 months
P = 0.257
Geyer et al
Capecitabine
+ lapatinib
vs
capecitabine
324
8.4 months vs
4.4 months,
P < 0.001
8.4 months vs
4.1 months,
P < 0.001
19 months vs
16 months
P = 0.206
Blackwell et al
Lapatinib +
trastuzumab
vs lapatinib
296
NR
12 weeks vs
8.1 weeks,
P = 0.008
14 months vs
9.5 months,
P = 0.026
Blackwell K, et al. J Clin Oncol. 2010;28(7):1124-1130; Blackwell K, et al. J Clin Oncol. Epub June 11, 2012;
Geyer CE, et al. N Engl J Med. 2006;355:2733-2743; Cameron D, et al. Oncologist. 2010:15(9):924-934;
Von Minckwitz G, et al. J Clin Oncol. 2009;27(12):1999-2006..
Combination of Lapatinib and Trastuzumab has
Superior Anti-tumor Activity

Treatment with lapatinib plus
trastuzumab resulted in complete
tumor remission


Lapatinib induced accumulation of
inactive HER2 at plasma membrane


Effect was durable: no tumor
relapse observed after 8 mo
post treatment
Trastuzumab-mediated
cytotoxicity was higher with
the addition of lapatinib in
MCF7/HER2 cells
In vivo activity was consistent with
in vitro data demonstrating the
combination as synergistic
Reprinted by permission. Scaltriti, et al. Oncogene 2009;28(6):803-814
Konecny, et al. Cancer Res 2006;66:1630-1639; Xia, et al. Oncogene 2004;23: 646–653
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Phase III Trial: Lapatinib ± Trastuzumab
in Heavily Pretreated MBC Following
Progression on Trastuzumab
N = 296
• HER2+ (FISH+/IHC 3+)
• Progressed on most
recent trastuzumab
regimen
• Prior anthracycline- and
taxane-based regimens
Lapatinib (1500 mg/day PO)
(n = 148)
R
A
N
D
O
M
I
Z
E
Crossover if PD after 4 wk therapy (N = 73)
Lapatinib (1000 mg/day PO) +
Trastuzumab (4 mg/kg load →
2 mg/kg weekly)
(n = 148)
Primary endpoint:
Progression-free survival: Investigator
Secondary endpoints include:
•Overall survival
•Overall response rate
•Clinical benefit rate
•Quality of life
•Safety
FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; PD, progressive disease
Blackwell KL, et al. J Clin Oncol. 2010;28(7):1124-1130.
Progression-Free Survival in ITT
Alive Without Progression,
Cumulative %
100
L
N = 145
80
60
Progressed or died, n
128
127
Median, weeks
8.1
12.0
Hazard ratio (95% CI)
0.73 (0.57, 0.93)
Log-rank P
40
L+T
N = 146
.008
28%
6-month PFS
20
13%
0
0
L
10
53
20
30
40
Time From Randomization, weeks
21
13
5
50
60
0
ITT, intent-to-treat population; L, lapatinib; PFS, progression-free survival; T, trastuzumab
Blackwell KL, et al. J Clin Oncol. 2010;28(7):1124-1130.
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Updated Overall Survival in ITT
L
N =145
Died, N (%)
113 (78) 105 (72)
Median, months
80%
L+T
N =146
Hazard ratio (95% CI)
9.5
14
0.74 (0.57, 0.97)
Log-rank P value
.026
56%
70%
6 Month OS
41%
12 Month OS
Blackwell KL, et al. J Clin Oncol. 2012;30(21):2585-2592.
Lapatinib ± Trastuzumab in Heavily
Pretreated MBC: Selected Adverse
Events
Adverse Event (All Grades), %
Lapatinib + Trastuzumab
(n = 149)
Lapatinib
(n = 146)
P Value
Nausea
28
28
NS
Fatigue
21
19
NS
Diarrhea*
60
48
.03
Rash
22
29
NS
*7% grade 3/4 events on each treatment arm.
Cardiac Events*
Lapatinib + Trastuzumab
(n = 149)
Patients with events, N
Lapatinib
(n = 146)
8
3
Symptomatic, n
3
2
Therapy related, n
8
3
Deaths, n
1
0
*Defined by ≥ 20% LVEF drop compared with baseline and below institution’s lower limits of normal.
Blackwell KL, et al. J Clin Oncol. 2010;28:1124-1130.
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Conclusions
• Continuing HER2-blockade in face of
trastuzumab-resistance is beneficial
• Clinical evidence confirming preclinical
data that dual blockade of HER2 is
synergistic
EMILIA: T-DM1 Phase III Trial Design
Key endpoints
• Primary: Progression-free survival (PFS, central assessment), safety, OS
• Secondary: Objective response, duration of objective response, PFS
(investigator review)
• Stratification factors: World region, number of prior chemo regimens for
ABC or unresectable LABC, presence of visceral disease
EMILIA
N = 978
•Postmenopausal
•ABC
•Prior taxane and
progression on TRAS
•Cardiac ejection fraction
≥50%
•ECOG PS ≤1
T-DM1
R
1:1
(3.6 mg/kg IV q3w)
Lapatinib + capecitabine
(L: 1250 mg/d PO)
(C: 1000 mg/m2 PO BID, days 1-14q3w)
Estimated Study Completion Date: April 2014
1. Blackwell KL, et al. J Clin Oncol. 2012;20(suppl): Abstract LBA1. 2. Verma S, et al. N Engl J Med.
2012;367(12):183-1791.
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EMILIA: PFS by Independent Review
Progression-Free Survival, %
100
80
Median, months
No. Events
CAP + LAP
6.4
304
T-DM1
9.6
265
Stratified HR = 0.65 (95% CI, 0.55, 0.77)
P<.001
60
40
20
0
0
2
4
6
No. at risk by independent review:
CAP+ LAP 496 404 310 176
T-DM1
495 419 341 236
8
10
12
129
183
73
130
53
101
14
16
18
TIme, months
35
72
25
54
14
44
20
22
24
26
28
30
9
30
8
18
5
9
1
3
0
1
0
0
CAP, capecitabine; LAP, lapatinib
Verma S, et al. N Engl J Med. 2012;367(12):183-1791.
EMILIA: OS
Median No.
of Months
85.2% (95% CI, 82.0-88.5)
1.0
LAP + CAP 25.1
182
T-DM1 30.9
149
64.7% (95% CI, 59.3-70.2)
0.8
Overall Survival, %
No. of
Events
78.4% (95% CI, 74.6-82.3)
0.6
0.4
51.8% (95% CI, 45.9-57.7)
0.2
Stratified HR: 0.68; (95% CI, 0.55-0.85); P<.001
Efficacy stopping boundary, P = .0037 HR: 0.73
0.0
8
10
12
14
No. at risk:
LAP + CAP 496 471 453 435
0
2
4
6
16 18 20
Time, months
403
368
297
240
204 159
133
T-DM1 495 485 474 457
439
418
349
293
242 197
164
22
24
26
28
30
32
34
36
110
86
63
45
27
136
111
86
62
38
17
7
4
28
13
5
CAP, capecitabine; LAP, lapatinib
Verma S, et al. N Engl J Med. 2012;367(12):183-1791.
27
10/30/2013
EMILIA: T-DM1 vs
Capecitabine/Lapatinib ORR and
DOR
ORR
DOR
Median, Mos (95% CI)
Difference: 12.7% (95% CI: 6.0-19.4;
P = .0002)
Cap + Lap
Responding Patients (%)
40
30.8%
30
20
10
0
120/389
173/397
Cap + Lap
T-DM1
Blackwell KL, et al. ASCO 2012.
Abstract LBA1.
1.0
Proportion Progression Free
43.6%
50
T-DM1
6.5 (5.5-7.2)
12.6 (8.4-20.8)
0.8
0.6
0.4
0.2
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Pts at Risk, n
Cap + lap 120105 77 48 32 14 9 8 3 3 1 1
T-DM1
173159126 84 65 47 42 33 27 19 12 8
0
2
0
0
0
0
0
0
EMILIA: T-DM1 vs
Lapatinib/Capecitabine
Adverse
T-DM1
vs Lapatinib/Capecitabine
in HER2+
Events
MBC (EMILIA): Adverse
Events Overview
Adverse Event, n (%)
Cap + Lap
(n = 488)
T-DM1
(n = 490)
All-grade adverse events
477 (97.7)
470 (95.9)
Grade ≥ 3 adverse events
278 (57.0)
200 (40.8)
52 (10.7)
29 (5.9)
Adverse events leading to death on treatment
5 (1.0)
1 (0.2)
LVEF < 50% and ≥ 15-point decrease from
baseline
7 (1.6)
8 (1.7)
Adverse events leading to treatment
discontinuation (for any study drug)
Blackwell KL, et al. ASCO 2012. Abstract LBA1.
28
10/30/2013
TH3RESA Study Schema
HER2-positive (central)
advanced BCa
(N=600)
≥2 prior HER2-directed
therapies for advanced BC
T-DM1
3.6 mg/kg q3w IV
2
(n=400)
1
Treatment of
physician’s choice
(TPC)b
Prior treatment with
trastuzumab, lapatinib,
and a taxane
PD
PD
(n=200)
T-DM1c
(optional
crossover)
• 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
TPC Treatment Category
TPC treatment category
Combination with HER2-directed agent, %
Chemotherapyb
+ trastuzumab
Lapatinib + trastuzumab
TPC
(n=184a)
83.2
68.5
10.3 T-containing
Hormonal therapy + trastuzumab
1.6
Chemotherapyb + lapatinib
2.7
Single-agent chemotherapy,b %
80.4
16.8
a
Includes patients who received study treatment.
b The most common chemotherapy agents used were vinorelbine, gemcitabine, eribulin, paclitaxel, and docetaxel.
Wildiers, et al. ESMO 2013
29
10/30/2013
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
2013
Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months.
Unstratified HR=0.521 (P<0.0001).
59
PFS for Patients Treated With Trastuzumab-Containing Regimens
TPC (T-containing)
(n=149)
Median (months)
3.2
Proportion progression-free
1.0
T-DM1
(n=404)
6.2
No. of events
101
219
Stratified HR=0.558 (95% CI, 0.437, 0.711)
P<0.0001
0.8
0.6
0.4
0.2
0.0
0
2
4
6
8
10
12
14
Time (months)
No. at risk:
TPC
149
99
50
20
12
5
1
0
T-DM1
334
241
114
66
27
12
0
404
2013
Unstratified HR=0.54 (P<0.0001).
60
30
10/30/2013
First Interim OS Analysis
1.0
Proportion surviving
Observed 21% of targeted events
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
T-DM1
381
316
207
127
65
30
7
0
404
2013
44 patients in the TPC arm received crossover T-DM1 treatment after documented progression.
Unstratified HR=0.57 (P=0.004).
61
ORR in Patients With Measurable Disease
By Investigator Assessment
Difference: 22.7% (95% CI, 16.2, 29.2)
P<0.0001
Patients, %
31.3%
8.6%
14/163
108/345
TPC
T-DM1
2013
62
31
10/30/2013
Overview of AEs
TPC
(n=184a)
T-DM1
(n=403a)
88.6
93.5
Grade ≥3 AEs, %
43.5
32.3
AEs leading to treatment
c
discontinuation, %
10.9
6.7
AEs leading to dose reduction, %
19.6
9.4
1.1
1.5
All-grade AEs, %
b
LVEF <50% and ≥15% decrease from
baseline,d %
a
One patient randomized to the TPC arm received 2 cycles of T-DM1 by mistake; this patient was included in the T-DM1 group for safety analyses.
Grade 5 AEs: TPC, 1.6% (n=3); T-DM1, 1.2% (n=5). Three were considered related to T-DM1: hepatic encephalopathy, subarachnoid hemorrhage, and
pneumonitis. One was considered related to TPC: noncardiogenic pulmonary edema.
c For any study drug.
d No patient experienced an LVEF <40%.
LVEF, left ventricular ejection fraction.
b
Wildiers, et al. ESMO 2013
Grade ≥3 AEs With Incidence ≥2%
in Either Arm
TPC (n=184)
Nonhematologic AEs, %
Diarrhea
Abdominal pain
AST increased
Fatigue
Asthenia
Cellulitis
Pulmonary embolism
Dyspnea
Hematologic AEs, %
Neutropenia
Febrile neutropenia
Anemia
Leukopenia
Thrombocytopenia
T-DM1 (n=403)
Any grade
Grade ≥3
Any grade
Grade ≥3
21.7
12.5
5.4
25.0
15.8
3.3
2.2
9.2
4.3
2.7
2.2
2.2
2.2
2.2
2.2
1.6
9.9
6.5
8.4
27.0
15.6
1.2
0.5
9.9
0.7
1.2
2.2
2.0
1.0
0.5
0.5
2.0
21.7
3.8
10.3
6.0
3.3
15.8
3.8
2.7
2.7
1.6
5.5
0.2
8.9
0.7
15.1
2.5
0.2
2.7
0.2
4.7b
Wildiers, et al. ESMO 2013
32
10/30/2013
HER2+ MBC
After Progression
Under Investigation
Trastuzumab Resistance
Mechanisms
IGF-1R
Nutrients
EGFR/HER2
Truncated HER2
PI3K
PTEN
LKB1
AMPK
Increased signaling through
IGF-1R
Constitutive PI3K/AKT activation
AKT
Absent or low PTEN
TSC1 TSC2
Elevated AKT or pAKT
RHEB
Cell growth and
proliferation
Angiogenesis
mTOR
Cell metabolism
Receptor
signaling
Constitutive activation of
downstream pathways
AKT, protein kinase B; EGFR, epidermal growth factor receptor; IGF-1R, insulin-like growth factor-1 receptor; mTOR, mammalian target of
rapamycin; PI3K, phosphatidylinositol-3-kinase; PTEN, phosphatase and tensin; TSC, tuberosis sclerosis complex.
1. Widakowich C, et al. Anticancer Agents Med Chem. 2008,8(5):488-496. 2. Johnston SR. Clin Cancer Res.
2005;11(2 suppl):889s-899s.
33
10/30/2013
Phase I / II Everolimus Experience
Everolimus 10 mg qday
and
Trastuzumab 6 mg/kg q3wk
Everolimus 10 mg qday,
Paclitaxel 80 mg/m2 days 1, 8, and 15 q4wk
+ Trastuzumab 2 mg/kg qwk
N (%)
N = 47
Best Response
Complete response
(CR)
-
Complete response
(CR)
-
Partial response (PR)
7 (15%)
Partial response (PR)
9 (19%)
Stable disease ≥ 24
weeks (SD)
9 (19%)
Stable disease (SD)
30 (62%)
Overall response rate
7 (15%)
Overall response rate
9 (19%)
Clinical benefit rate
16 (34%)
Clinical benefit rate
19 (40%)
Median PFS
4.1 months
Progressive disease
9 (19%)
Most frequent grade
3 / 4 adverse events
(> 10%)
Lymphopenia,
hyperglycemia,
mucositis
Most frequent grade
3 / 4 adverse events
(> 10%)
Neutropenia,
lymphopenia,
stomatitis
Best Response
Morrow PK, et al. J Clin Oncol. 2011;29(23):3126-3123.
N (%)
N = 48
Dalenc F, et al. J Clin Oncol. 2010;28(7S). Abstract 1013.
BOLERO-3: EVE Phase III Trial Design
(HER2+ ABC Pretreated)
Key endpoints
• Primary: PFS
• Secondary: OS, ORR, CBR, safety, PK, biomarker/
laboratory assessments; patient reported outcomes
EVE + Vinorelbine + TRAS
BOLERO-3
N = 572
•HER2+ ABC
•Prior taxane and
progression on
TRAS
•ECOG PS ≤2
• Stratified by prior
lapatinib use
R
1:1
(E: 5 mg/d)
(V: 25 mg/m2 weekly, days 1, 8, 15)
(T: 2 mg/kg, days 1, 8, 15)
21 day cycle
Vinorelbine + TRAS
(V: 25 mg/m2 weekly, days 1, 8, 15)
(T: 2 mg/kg, days 1, 8, 15)
21 day cycle
US National Institutes of Health. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01007942. Accessed
April 1, 2013.
34
10/30/2013
BOLERO-3: Previous Therapy
Characteristic, %
Previous lines of chemotherapy
in metastatic setting
0
1 line
2 lines
3 lines
Prior therapy
Trastuzumab
Taxane
Lapatinib
Hormonal therapy
Everolimus +
Trastuzumab +
Vinorelbine
N = 284
Placebo +
Trastuzumab +
Vinorelbine
N = 285
16
41
34
9
16
43
29
12
100
100
27
43
100
100
27
40
2013 ASCO Annual Meeting. Oral Abstract 505. Presented by: Ruth M.
O’Regan, MD.
69
BOLERO-3: Primary Endpoint
Progression-Free Survival by Local
Assessment
100
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
Probability (%)
80
60
Censoring times
40
Everolimus (n/N = 196/284)
Placebo (n/N = 219/285)
20
0
0
6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 126 132 138 144 150 156 162 168 174
No. of Patients Still at Risk
Everolimus 284 259 233 200 161 126 98 78
Placebo
285 253 202 177 138 109 85 64
Time (weeks)
54
49
40 35
38 26
26
23
18 14
19 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
CI = confidence interval.
2013 ASCO Annual Meeting. Oral Abstract 505. Presented by: Ruth M. O’Regan, MD.
35
10/30/2013
Summary: HER2+ MBC
• 1st Line: Pertuzumab/trastuzumab/taxane
• 2nd/3rd line: T-DM1
• Other options after progression:
– Trastuzumab/lapatinib
– Lapatinib/capecitabine
– Trastuzumab/other chemo
– Trastuzumab or Lapatinib + AI
– ??everolimus-based therapy
Management of HER2 normal MBC
 Hormone receptor positive metastatic breast
cancer
 1st line therapy: Endocrine therapy almost always
 Treatment beyond 1st line
Mechanisms of resistance
MTOR inhibition (BOLERO-2)
 CDK4/6 inhibition
 Triple negative MBC: Area of unmet need
 Chemotherapy
 PARP inhibition?
36
10/30/2013
Hormone Receptor‐Positive (HR+) Breast Cancer
Approximately 60% to 75% of invasive breast
cancers are classified as HR+1,2
About 20% are HER2+
 About 50% of HER2+ tumors are also ER+
ER signaling leads to
 Cell proliferation
 Time available for DNA repair
 Risk of mutation
Abbreviations: ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hormone receptor.
1. Cleator SJ, et al. Clin Breast Cancer. 2009;suppl 1:S6‐S17; 2. Milani M, et al. Clin Med Ther. 2009;1:141‐156.
73
Hormone Receptor‐Positive (HR+) Breast Cancer
HR+ breast cancers are generally slower growing and have a better prognosis than HR– cancers1
Staining of ER+ breast cancer nuclei
by immunohistochemistry (IHC)3
Mostly true for Luminal A cancers
Also may be associated with increased proliferation (Luminal B cancers)
 ER expression correlates with improved response to endocrine therapy1
Multiple mechanisms within the ER pathway allow development of resistance to endocrine therapy2
A. Strong nuclear staining indicating widespread
expression of ER (Allred score = 8)
B. Weak nuclear staining indicating low to
moderate expression of ER (Allred score = 4)
Abbreviations: ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hormone receptor.
1. Cleator SJ, et al. Clin Breast Cancer. 2009;suppl 1:S6‐S17; 2. Arpino G, et al. Endocr Rev. 2008;29(2):217‐233; 3. www.breastpathology.info. Accessed September 14, 2011. Images reprinted from NHS Trust, Edinburgh, UK. (www.breastpathology.info)
74
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Historical Timeline of Therapies for HR+ Advanced Breast Cancer
Others1
Chemo‐
therapy
Endocrine Therapy
Anthracyclines1
Taxanes1
• Doxorubicin
• Epirubicin
• Paclitaxel
• Docetaxel
1980s
1990s
1977
1896
Oopho‐
rectomy2,3
1990s
• Capecitabine
• Gemcitabine
• Ixabepilone • Eribulin
• Nab‐paclitaxel
2000s
2010
2002
SERMs4
AIs4
ERDs5
ERDs5
• Tamoxifen
• Toremifene • Anastrozole
• Letrozole
• Exemestane
• Fulvestrant
• High‐dose
Fulvestrant*
2012 
Targeting mechanisms of endocrine resistance
Abbreviations: AI, aromatase inhibitor; ERDs, estrogen receptor downregulator; HR+; hormone receptor positive; SERMs, selective estrogen receptor modulators. * Marginal improvement over lower dose fulvestrant.
1. http://www.advancedbreastcancercommunity.org/treatment/drugs.htm; 2. Beatson CT. Lancet. 1896;2:104‐107; 3. Beatson CT. Lancet. 1896;2:162‐165; 4. Cohen MH, et al. Oncologist. 2001;6:4‐11; 5. Faslodex [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2011.
75
EGFR
HER2
Endocrine Therapy for HR+
Advanced Breast Cancer
Estrogen
Growth
factor
receptor
Aromatase inhibitors
(AIs)
• Nonsteroidal AIs
− Anastrozole
− Letrozole
• Steroidal AIs
− Exemestane
GRB2
SOS Shc
RAS
Cytoplasm
RAF
PI3K
MEK
Estrogen
receptor
Akt/
m-TOR
MAPK
Estrogen receptor
downregulator
(ERD)
• Fulvestrant
P
Nucleus
Cofactor complex
LBD
LBD
P
P
AF1
AF1
Oophorecto
my
DBD
DBD
Cell
growth
Selective estrogen
receptor modulators
(SERMs)
• Tamoxifen
• Toremifene
Adapted from Yardley DA, et al. J Clin Oncol. 2011;29(suppl 27). Abstract 268.
38
10/30/2013
Endocrine Therapy: Treatment Guidelines for HR+ Advanced Breast Cancer
ABC1 treatment guidelines for advanced breast cancer1,2: Endocrine therapy (ET) is the preferred option for hormone receptor positive disease, even in the presence of visceral disease, unless there is concern or proof of endocrine resistance or rapidly progressive disease needing a fast response
NCCN treatment guidelines for advanced breast cancer3:
Prior ET within 1 year
Systemic disease
No prior ET within 1 year
Premenopausal
Ovarian ablation + ET
Postmenopausal
Up to 3 consecutive ET regimens
Visceral crisisa
Consider initial chemotherapy
Premenopausal
Ovarian ablation + ET or anti‐estrogen Postmenopausal
Aromatase inhibitor (AI) or anti‐estrogen
Visceral crisisa
Consider initial chemotherapy
Abbreviations: AI, aromatase inhibitor; ET, endocrine therapy.
a Visceral crisis includes symptomatic visceral disease and/or a high burden of visceral disease. 1. Cardoso F, et al. Breast. 2012;21(3):242‐252; 2. Wilcken N, et al. Cochrane Database Syst Rev. 2003;2:CD002747; 3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V.3.2012.
77
Initial Endocrine Therapy for Postmenopausal Women With HR+ Advanced Breast Cancer


Aromatase inhibitors have become the standard of care for initial treatment of postmenopausal women with HR+ advanced breast cancer
Aromatase inhibitors have demonstrated improved efficacy compared with tamoxifen




Fulvestrant has demonstrated similar efficacy compared with tamoxifen


TTP (mo): anastrozole (10.7) vs tamoxifen (6.4)1
TTP (mo): letrozole (9.4) vs tamoxifen (6.0)2
PFS (mo): exemestane (9.9) vs tamoxifen (5.8)3
TTP (mo): fulvestrant (8.2) vs tamoxifen (8.3)4
Results from combination endocrine therapy trials for the initial treatment of treatment‐naive postmenopausal women with HR+
advanced breast cancer are inconclusive

Results demonstrate marginal clinical benefit
1. Bonneterre J, et al. Cancer. 2001;92(9):2247-2258; 2. Mouridsen H, et al. J Clin Oncol. 2001;19(10):2596‐2606; 3. Paridaens RJ, et al. J Clin 78
Oncol. 2008;26(30):4883‐4890; 4. Howell A, et al. J Clin Oncol. 2004;22(9):1605‐1613.
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10/30/2013
1st Line Hormone Receptor Positive
MBC
UNDER INVESTIGATION
79
Abstract 292
Results of a Randomized Phase 2 Study of
PD
0332991, a Cyclin-Dependent Kinase (CDK) 4/6
Inhibitor, in Combination with Letrozole vs Letrozole
Alone for First-Line Treatment of
+
ER , HER2– Advanced Breast Cancer (TRIO-18)
RS Finn,1 JP Crown,2 K Boer,3 I Lang,4 RJ Parikh,5 A Breazna,6
SN Ho,7 ST Kim,7 S Randolph,7 DJ Slamon1
1University
of California Los Angeles, Los Angeles, CA, USA; 2Irish Cooperative Oncology Research
Group, Dublin, Ireland; 3Szent Margit Korhaz, Onkologia, Budapest, Hungary; 4Orszagos
Onkologiai Intezet, Budapest, Hungary; 5Comprehensive Cancer Centers of Nevada, Henderson,
NV, USA; 6Pfizer Oncology, New York, NY, USA; 7Pfizer Oncology, La Jolla, CA, USA
Presented at: IMPAKT Breast Cancer Conference; 3-5 May 2012; Brussels, Belgium.
40
10/30/2013
Rb as Master-Regulator of the R-point
Target of PD 0332991
p16INK4a
Inactivates Rb and
allows progression
Reprinted from Weinberg RA. The Biology of Cancer. New York, NY: Garland Science; 2006. © 2006 Garland Science.
81
PD 0332991 Preferentially Inhibits Proliferation of
Luminal Estrogen Receptor-Positive Human Breast
Cancer Cell Lines In Vitro
1000
900
800
IC 50 (nM)
700
600
500
400
300
200
100
M
BZR 17 5
75
C A -3 0
M
A
M -1
B
H C 13 4
C
UA 2
C C 02
-8
EF 9 3
SU M 1
M 9
EF 19
M 0
1
M 9 2A
B
H C -36
C1 1
H C 50
C1 0
4
H C 19
C
M 38
BM 41
C 5
U A F -1
C C 0A
H C -81
C2 2
2
Z 1
M R7 8
D A 5M 1
B4
1 8 53
4A
1
T4
7D
M
CF
M BT 7
D A -2
M 0
B4
B T 35
4
SK 74
BR
K 3
H C P LM C1 1
D A 14
M 3
H C B 23
C 1
SU 1 39
M 5
H S 22 5
57
8
18 T
U A 4B
CC 5
7
CA 32
LB 51
C O T5 4
LO 9
D U 82 4
H C 4 47
C 5
H C 1 18
C 7
H C 1 56
C 9
H C 1 80
C 6
H C 1 93
C1 7
9
H C 54
C
M 70
B43
M 6
M
B
D A 15
M 7
B4
68
0
Subtype
Luminal
HER2 Amplified
Immortalized
Non-luminal/post EMT
Non-luminal
Reprinted from Finn RS, et al. Breast Cancer Res. 2009;11(5):R77.
82
41
10/30/2013
Study Design: Phase 2 Part 1
Exploratory study evaluating safety and efficacy of the combination in patients
selected based on hormone receptor status only
R
A
N
D
O
M
I
Z
A
T
I
O
N
Study population
• Postmenopausal
women with ER+
HER2– breast
cancer
N = 60
(actual 66)
PD 0332991 125 mg QD x 3 weeks,
1 week off; plus
letrozole 2.5 mg QD x 4 weeks
1:1
Letrozole 2.5 mg QD x 4 weeks
4-week treatment cycle
Stratification Factors
• Disease site (visceral vs bone only vs other)
• Disease-free interval (>12 vs ≤12 mo from end of adjuvant to recurrence or de novo advanced disease)
Best Overall Response (ITT)
PD 991 + LET
(n = 84)
LET
(n = 81)
84
81
Objective Response Rate, % (95% CI)
Complete Response, n (%)
Partial Response, n (%)
34 (24, 46)
0
29 (34)
26 (17, 37)
1 (1)
20 (25)
Patients with measurable disease, n (%)
64 (76)
65 (80)
Objective Response Rate, % (95% CI)
Complete Response, n (%)
Partial Response, n (%)
45 (33, 58)
0
29 (45)
31 (20, 43)
0
20 (31)
Stable Disease ≥24 weeks, n (%)
30 (36)
15 (18)
Clinical Benefit Rate, % (n)*
70 (59)
44(36 )
Stable Disease <24 weeks, n (%)
14 (17)
22 (27)
Progressive Disease, n (%)
3 (4)
17 (21)
Indeterminate, n (%)
8 (10)
6 (7)
All randomized patients, n
* Complete response + partial response + stable disease ≥24 weeks.
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10/30/2013
Progression-Free Survival Probability
Progression-Free Survival
1.0
Number of Events
(%)
0.9
Median PFS, months
(95% CI)
0.8
0.7
PD 991 +
LET
(n = 84)
LET
(n = 81)
21 (25)
40 (49)
26.1
(12.7, 26.1)
7.5
(5.6,
12.6)
Hazard Ratio
(95% CI)
0.6
0.37
(0.21, 0.63)
P value
<0.001
0.5
0.4
0.3
0.2
0.1
0
0
2
4
6
8
10
60
38
53
29
43
22
35
17
Number of patients at risk
PD991+LET
LET
84
81
75
57
12
14
16
18
20
22
24
26
25
11
18
6
15
5
14
4
9
3
5
3
3
1
1
1
Time (Month)
28
Most Common Treatment-Related
AEs ≥10% (AT)
PD 991 + LET
(n = 83)
LET
(n = 77)
Grade 1/2
Grade 3
Grade 4
Grade 1/2
Grade 3
Grade 4
Neutropenia
19
46
5
1
1
0
Leukopenia
24
14
0
0
0
0
Anemia
19
4
1
0
0
0
Fatigue
17
2
0
13
0
0
Alopecia
18
0
0
3
0
0
Hot flush
17
0
0
10
0
0
Arthralgia
16
0
0
10
0
0
Nausea
12
2
0
1
0
0
Thrombocytopenia
11
1
0
0
0
0
43
10/30/2013
Phase 3 trial of PD-0332991 (Palbociclib)
Next Steps for CDK 4/6 Inhibition


Primary endpoint
 PFS
Secondary endpoints
 OS
 Response
 Response
duration
 Disease control
 Safety
 PK/PD
 Biomarkers
 QoL
Finn RS. ASCO 2013. Abstract 652.
Patients with Disease Progression on One
Hormone Therapy May Respond to Another
Hormone Therapy
40%
30%
25%
15%
1st
Line
2nd
Line
3rd
Line
4th
Line
R
E
S
I
S
T
A
N
C
E
Bavior C, et al. Ann Oncol 2012. Epub Feb 8; Osborne Ck, Schiff R. Ann Res Med 2011;62:233-247
44
10/30/2013
Endocrine Resistance in HR+ Advanced Breast Cancer
 Definition of endocrine resistance in advanced breast cancer is evolving
 Primary resistance: PD within 6 months of starting treatment1
 Secondary resistance: Initial response with relapse 6 months or later1
 Approximately 50% of patients with HR+ advanced breast cancer do not respond to initial endocrine therapy2
 The majority of patients with HR+ advanced breast cancer will ultimately progress despite endocrine therapy
Abbreviations: HR, hormone receptor; PD, progressive disease.
1. Bachelot T, et al. J Clin Oncol. 2012;30(22):2718-2724; 2. Bedard PL, et al. Breast Cancer Res Treat. 2008;108(3):307-317.
Treatment Guidelines for HR+ Advanced Breast Cancer Following Progression on Initial Endocrine Therapy
NCCN treatment guidelines1:
• Hormone receptor positive advanced breast cancer may benefit from sequential use
of ET at time of progression and should receive additional ET for second-line and
subsequent therapy2
Continue
endocrine
therapy until
progression or
unacceptable
toxicity
Progression
No clinical benefit after
3 consecutive endocrine
therapy regimens
Or
Symptomatic visceral
disease
Yes
Chemotherapy
No
Trial of new
endocrine
therapy
• Approaches to switching endocrine therapy3
 Tamoxifen or AI  ERD
 Tamoxifen  AI
 Other endocrine approaches
 Nonsteroidal AI  steroidal AI
Abbreviations: AI, aromatase inhibitor; ET, endocrine therapy; ERD, estrogen receptor downregulator.
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V.3.2012; 2. Wilcken N, et al. Cochrane Database Syst Rev. 2003;2:CD002747; 3. Hurvitz SA, et al. Cancer. 2008;113(9):2385‐2397.
90
45
10/30/2013
Fulvestrant Is Similar to Anastrozole in Postmenopausal Women With HR+ Advanced Breast Cancer Following Prior Endocrine Therapy
2 phase 3 studies; N = 851
Postmenopausal women with HR+ advanced breast cancer
Progressed after endocrine therapy in adjuvant or first‐line metastatic setting (~45% endocrine therapy‐naive in advanced setting)
Primary endpoint
TTP
Fulvestrant 250 mg/mo
Secondary endpoints
ORR, DOR, TTF, TTD, CBR, DoCB
Anastrozole 1 mg/d
Fulvestrant (n = 428)
Median follow‐up, all (mo)
Anastrozole (n = 423)
P value
15.1
TTP (mo)
5.5
4.1
ORR (%)
19.2
16.5
.31
CBR (%)
43.5
40.9
.51
Median follow‐up for DOR (mo)
.48
22.1
DOR, responders (mo)
16.7
Ratio of average DORs (fulvestrant:anastrozole)
13.7
1.30
—
< .01
Abbreviations: CBR, clinical benefit rate; DoCB, duration of clinical benefit; DOR, duration of response; HR, hormone receptor; ORR, objective response rate; PgR, progesterone receptor; TTD, time to death; TTF, time to failure; TTP, time to progression.
Robertson JFR, et al. Cancer. 2003;98(2):229-238.
91
EFECT: Fulvestrant Is Similar to Exemestane in Postmenopausal Women With HR+ Advanced Breast Cancer Following Prior Nonsteroidal Aromatase Inhibitor Therapy
Phase 3 study; N = 693
Postmenopausal women with HR+ advanced breast cancer
Progressed after nonsteroidal AI in adjuvant or first‐line metastatic setting (~15% endocrine therapy‐naive in advanced setting)
Fulvestrant 500 mg d 1
250 mg day 14, 28, mo
Secondary endpoints
ORR, CBR, DOR, DoCB, OS
Exemestane 25 mg/d
Fulvestrant (n = 351)
Median follow‐up, all (mo)
TTP (mo)
ORR (%)
CBR (%)
DoCB (mo)
DOR (mo)
Primary endpoint
TTP
Exemestane (n = 342)
P value
3.7
6.7
31.5
8.3
5.5
.653
.736
.853
—
—
13.0
3.7
7.4
32.2
9.3
7.5
Abbreviations: AI, aromatase inhibitor; CBR, clinical benefit rate; DoCB, duration of clinical benefit; DOR, duration of response; HR, hormone receptor; ORR, objective response rate; OS, overall survival; TTP, time to progression.
Chia S, et al. J Clin Oncol. 2008;26(10):1664-1670.
92
46
10/30/2013
CONFIRM: Fulvestrant 500 mg Is Slightly Better Than 250 mg in Postmenopausal Women With ER+ Advanced Breast Cancer Following Prior Endocrine Therapy
Phase 3 study; N = 736
Postmenopausal women with ER+ advanced breast cancer
Fulvestrant 500 mg/mo
Progressed after endocrine therapy in adjuvant or first‐
line metastatic setting (~45% were endocrine therapy‐
naive in advanced setting)
Fulvestrant 250 mg/mo Fulvestrant 500 (n = 362)
6.5
9.1
45.6
16.6
25.1
PFS (mo)
ORR (%)
CBR (%)
DoCB (mo)
TTD (mo)
Primary endpoint
PFS
Secondary endpoints
ORR, CBR, DoCR, OS, TTD, QoL
Fulvestrant 250 (n = 374)
5.5
10.2
39.6
13.9
22.8
P value
.006
.795
.100
—
.091
Abbreviations: CBR, clinical benefit rate; DoCB, duration of clinical benefit; ER, estrogen receptor; ORR, objective response rate; OS, overall survival; PFS, progression‐free survival; TTD, time to death; QoL, quality of life.
Di Leo A, et al. J Clin Oncol. 2010;28(30):4594-4600.
93
SoFEA: Fulvestrant + Anastrozole Is Similar to Fulvestrant or Exemestane Alone in Postmenopausal Women With HR+
Advanced Breast Cancer Following Prior Nonsteroidal Aromatase Inhibitor Therapy
Phase 3 study; N = 750
Postmenopausal women with HR+ advanced breast cancer
Progressed after nonsteroidal AI therapy in adjuvant or first‐line metastatic setting
PFS (mo)
OS (mo)
ORR (%)
Fulvestrant +
Anastrozole
(n = 250)
4.4
20.2
7.4
Fulvestrant 250 mg/mo
+ Anastrozole 1 mg/d
Fulvestrant 250 mg/mo
Primary endpoint
PFS
Secondary endpoints
OS, ORR, safety
Exemestane 25 mg/d
Fulvestrant
(n = 250)
4.8
19.4
6.9
Exemestane
(n = 250)
3.4
21.6
3.6
P valuea
.98
.61
.82
P valueb
.56
.68
.10
Abbreviations: AI, aromatase inhibitor; HR, hormone receptor; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.
a Fulvestrant + anastrozole versus fulvestrant alone. b Fulvestrant alone versus exemestane alone.
Johnston S, et al. EBCC 2012. Abstract LBA2.
94
47
10/30/2013
Mechanisms of Endocrine Resistance
IGF1R
MoAb
P
AB P
P
P
MoAb
P
TKI
PI3-K
P SOS
TKI
RAS
RAF
MEK
Akt
CCI RAD
p90RSK
MAPK
SERD
AI
ER
T
Increased upstream
signaling through
EGFR and/or IGF-IR
and or VEGFR
EGFR/HER2
TKI
VEGFR
Increased signaling
through PI3-K pathway
E2
Cytoplasm
PP P P
ERER p160 CBP
ERE
Basal
Transcription
Machinery
ER Target Gene Transcription
Nucleus
Plasma
Membrane
Cell
Growth
Mechanisms of intrinsic and acquired resistance likely similar
From Johnston CCR 2005
BOLERO-2: Everolimus in Postmenopausal,
Hormone Receptor Positive ABC
N = 724
Postmenopausal
ER+ HER2breast cancer pts
refractory to
letrozole or
anastrozole
Everolimus 10 mg/day +
Exemestane 25 mg/day
(N = 485)
Placebo +
Exemestane 25 mg/day
(N = 239)
Primary
PFS
Secondary
OS
ORR
Bone Markers
Safety
PK
 Stratification:
1. Sensitivity to prior hormonal therapy
2. Presence of visceral disease
 No cross-over
Baselga J, et al. N Engl J Med 2012;366(6):520-9.
48
10/30/2013
BOLERO-2: Baseline Characteristics
Everolimus +
Exemestane
Placebo +
Exemestane
(N = 485), %
(N = 239), %
62 (34, 93)
61 (28, 90)
Caucasian
74
78
Asian
20
19
Performance status 0
60
59
Liver involvement
33
30
Lung involvement
29
33
Measurable disease*
70
68
Characteristic
Median age (range), years
Race
*All
other patients had ≥ 1 bone lesion.
Baselga J, et al. N Engl J Med 2012;366(6):520-9.
BOLERO-2: Prior Therapy
Everolimus +
Exemestane
Placebo +
Exemestane
(N = 485), %
(N = 239), %
Sensitivity to prior hormonal therapy
84
84
Last treatment: LET/ ANA
74
75
Adjuvant
21
16
Metastatic
79
84
Prior tamoxifen
47
49
Prior fulvestrant
17
16
Prior chemotherapy for metastatic BC
26
24
Number of prior therapies: ≥ 3
54
53
Therapy
Last treatment
Baselga J, et al. N Engl J Med 2012;366(6):520-9.
49
10/30/2013
BOLERO-2 Primary Endpoint: PFS
Central Assessment
Probability of Event (%)
100
HR = 0.36 (95% CI: 0.27-0.47)
Log rank P value = 3.3 x 10 -15
80
EVE + EXE: 10.6 Months
PBO + EXE: 4.1 Months
60
40
20
Everolimus + Exemestane (E/N=114 / 485)
Placebo + Exemestane (E/N=104 / 239)
0
0
6
12
18
24
30
36
42
48
54
60
66
72
78
Time (weeks)
Everolimus plus exemestane increased
progression-free survival by 64%
Baselga J, et al. N Engl J Med 2012;366(6):520-9.
BOLERO 2: PFS Subgroup Analyses
Favors EVE + EXE
Subgroups (N)
Favors PBO + EXE
All (724)
Age
<65 (449)
≥65 (275)
Region
Asia (137)
Europe (275)
North America (274)
Other (38)
Sensitivity to prior hormonal therapy
Yes (610)
No (114)
Visceral metastasis
Yes (406)
No (318)
Last therapy
Aromatase inhibitor (532)
Antiestrogen (122)
Other (70)
Last therapy setting
Metastatic (586)
Adjuvant (138)
Prior chemotherapy
Adjuvant only (306)
Metastatic (186)
None (232)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
1.3
1.4
1.5
Hazard Ratio
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
50
10/30/2013
BOLERO-2: Overall Response Rate and
Clinical Benefit Rate by Local
Assessment
40
35
Everolimus + Exemestane
33.4%
Placebo + Exemestane
30
P < 0.0001
25
18.0%
20
P < 0.0001
15
10
9.5%
5
0.4%
0
Response
Clinical Benefit
Baselga J, et al. N Engl J Med 2012;366(6):520-9.
BOLERO-2: Most Common G3/4 AEs
Everolimus + Exemestane
(N = 482), %
Placebo + Exemestane
(N = 238), %
All
Grades
Grade
3
Grade
4
All
Grades
Grade
3
Grade
4
Stomatitis
56
8
0
11
1
0
Fatigue
33
3
<1
26
1
0
Dyspnea
18
4
0
9
1
<1
Anemia
16
5
<1
4
<1
<1
Hyperglycemia
13
4
<1
2
<1
0
AST
13
3
<1
6
1
0
Pneumonitis
12
3
0
0
0
0
AE: Adverse Event; AST: Aspartate aminotransferase
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
102
51
10/30/2013
Summary: HR+/HER2- MBC
● Endocrine therapy should be used until options
exhausted
– Exceptions: Rare case of symptomatic, severe,
visceral metastases
● In post-menopausal women whose disease has
progressed on non-steroidal AI, exemestane/everolimus
is excellent option but toxicity needs to be anticipated
and closely managed
● Exciting data re: CDK4/6i
103
Triple Negative Breast Cancer
Area of Unmet Need
104
52
10/30/2013
Triple Negative vs. Basal-like
Breast Cancer
Triple negative
–
–
–
–
Defined by IHC
Lacks expression of ER, PR and Her2/neu
10-18% of all breast cancer
Not synonymous with basal-like breast cancer
(10-30% not basal-like)
 Basal-like Breast Cancer
– Defined by gene expression profile
– 14-26% of breast cancer
– 15-40% ER+PR+ or Her2+
Parker et al. JCO 2009
Using IHC to define Basal type?
 Problem with using 3 IHC markers
– How do you define ER and PR
 No positive cells?
 <1%? <10%? <20%
– How reproducible/accurate is IHC testing?
 20% false negative ER
 12% false positive PR
 Up to 20% false positive Her2
53
10/30/2013
Features of TN breast cancer
 More aggressive





– High grade
– High relapse pattern (esp in first 5 years, low late risk)
– Sites of relapse different from luminal type
 Tends to metastasize to organs and CNS
– Responsive to chemotherapy
 TNBC pts with PCR to neoadjuvant chemo good outcome
similar to non-TNBC
Younger women
African American
BRCA1 mutations (80% have basal-like)
BRCA pathway dysfunction
P53 mutations common
Liedtke, JCO 2008 and Lin, Cancer 2008
Outcome TNBC
54
10/30/2013
Rates of distant recurrences: TNBC vs Others
Challenge
 Little data regarding molecular
characteristics and associated signaling for
TN/BL breast cancer
 Targeted therapy does not exist
– Her2/neu+ breast cancer: trastuzumab, lapatinib
– ER+ breast cancer: Tamoxifen, AIs, MTORi
55
10/30/2013
Modest Benefit of Single‐Agent Chemotherapy for Advanced Breast Cancer
Treatment Line
First‐line
Second‐line
Third‐line
Subsequent lines
Typical Clinical Outcomes
Response Rate, % Median TTP, mo
25 – 45 5 – 8 15 – 30 2 – 5 0 – 20 1 – 4 Limited or no data
Abbreviation: TTP, time to progression.
Burstein HJ. ASCO 2010. Metastatic Breast Cancer Oral Abstract Session.
Combination Versus Sequential Single‐Agent Chemotherapy
ABC1 treatment guidelines1:  Both combination and sequential single agent chemotherapy are reasonable options
 Based on available data, sequential monotherapy is the preferred choice for advanced breast cancer  Combination chemotherapy should be reserved for patients with rapid clinical progression, life‐threatening visceral metastases, or need for rapid symptom and/or disease control
 Duration of each regimen and number of regimens should be tailored to each individual patient
 Usually each regimen should be given until progression of disease or unacceptable toxicity (unacceptable should be defined together with the patient)
1. Cardoso F, et al. Breast. 2012;21(3):242‐252.
56
10/30/2013
NCCN Guidelines Single Agent
Chemotherapy Regimens for MBC
 Anthracyclines (doxorubicin, liposomal
doxorubicin)
 Taxanes (paclitaxel, docetaxel, alb-bound
paclitaxel)
 Anti-metabolites (capecitabine,
gemcitabine)
 Other microtubule inhibitors (vinorelbine,
eribulin
 Other: cisplatin, cyclophosphamide,
epirubicin, ixabepilone
NCCN Guidelines Combination
Regimens Chemotherapy Regimens
for MBC






CAF, FAC, FEC, AC, EC
CMF
Docetaxel/capecitabine
Gemcitabine/paclitaxel
Gemcitabine/carboplatin
Paclitaxel/bevacizumab (no longer FDA
approved but still in NCCN v3.2013)
57
10/30/2013
Triple-Negative Breast Cancers:
Some Potential Therapeutic Targets
Cetuximab
EGFR
Tyrosine
Kinase
C-KIT
tyrosine
kinase
MAP Kinase Pathway
MAPK inhibitors;
NOTCH inhibitors
AntiAngiogenesis
Dasatinib
Sunitinib
Akt Pathway
Transcriptional Control
Cell
Cycle
Bevacizumab
Cell Death
PARP inhibitors;
Trabectedin
DNA
Repair
pathways
After Cleator S et al. Lancet
Oncol. 2006:8:235-244
PARP inhibitors for Breast Cancer
58
10/30/2013
117
PARP as a Target
• Key regulator of DNA
damage repair
– Involved in DNA baseexcision repair
• Binds directly to DNA
damage and produces
large branched chains of
poly(ADP-ribose)
• It is differentially
upregulated in primary
breast cancers, including
the ER-, PR-, and HER2negative subtype
Amé JC, et al. Bio Essays. 2004;26:882-893.
118
Gemcitabine / Carboplatin +/- Iniparib in
Triple Negative MBC (TNBC)
MBC
ER / PR / HER2 Negative
ECOG of 0 or 1
≤ 2 previous
chemotherapies for MBC
No prior gemcitabine,
carboplatin, or PARP
inhibitor
Co-primary endpoints:
Phase II: CBR, safety,
and tolerability
Phase III: PFS and OS
R
A
N
D
O
M
I
Z
E
Iniparib 5.6 mg/kg IV,
Days 1, 4, 8, 11
+ Gemcitabine 1000 mg/m2
+ Carboplatin AUC = 2
Days 1 & 8
q3wk
Gemcitabine 1000 mg/m2
+ Carboplatin AUC = 2
Days 1 & 8
q3wk
1:1
N=123
O’ Shaughnessy J, et al. N Engl J Med. 2011;364(3):205-214; O’ Shaughnessy J, et al. J Clin Oncol. 2011;29. Abstract 1007.
59
10/30/2013
119
Phase II Trial: Gemcitabine / Carboplatin
+/- Iniparib in TNBC
Efficacy
Toxicity
Efficacy
I+G/C
N = 61
G/C
N = 62
Selected Grade ≥ 3
Adverse Events
I+G/C
N = 57
G/C
N = 59
CBR
P = 0.01
56%
34%
Fatigue or asthenia
7%
19%
Diarrhea
2%
2%
OS
P = 0.01
12.3
months
7.7
months
Leukopenia
12%
10%
Neutropenia
67%
63%
PFS
P = 0.01
5.9 months
3.6
months
Anemia
23%
15%
Thrombocytopenia
37%
27%
O’ Shaughnessy J, et al. N Engl J Med. 2011;364(3):205-214.
120
Phase III Study: Gemcitabine /
Carboplatin +/- Iniparib in TNBC
• Neither of the co-primary endpoints of the phase
III trial were met
1.0
0.9
GC
GCI
(N = 258)
(N = 261)
4.1
5.1
(3.1, 4.6)
(4.2, 5.8)
0.79 (0.65, 0.98)
0.027
OS
0.9
0.8
GC
GCI
(N = 258)
(N = 261)
11.1
11.8
(9.2, 12.1) (10.6, 12.9)
0.88 (0.69, 1.12)
0.28
Pre-specified alpha = 0.04
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Median OS, mos
(95% CI)
HR (95% CI)
P value
1.0
Pre-specified alpha = 0.01
Probability of Survival
Probability of Progression-Free Survival
PFS
Median PFS, mos
(95% CI)
HR (95% CI)
P value
0.1
0
No. at risk
258
GC
261
GCI
2
171
187
4
6
8 10 12 14
Months Since Study Entry
116
138
63
83
38
53
18
11
6
2
1
0
16
0
0
0
0
No. at risk
GC
258
261
GCI
2
4
6
8 10
Months
239
248
214
230
181 151
204 169
99
111
12
14
16
38
52
11
15
0
0
O’ Shaughnessy J, et al. J Clin Oncol. 2011;29. Abstract 1007.
60
10/30/2013
Problems with Iniparib Study
•
•
Drug: Does not work by inhibiting PARP
Patient population: No central-review
mandated to confirm that tumors were
all triple negative
Parp inhibitors still may work
 Being developed primarily in BRCA 1 & 2
mutated patients now
 Some drug companies in phase I/II
development




Abbott
Clovis
Biomarin
Astra Zeneca
 Any role for triple negative?
 How to best define basal-like ca clinically?
61
10/30/2013
Germline BRCA Mutation – Breast
Cancer BMN673 Phase I data
Response
Deleterious
Mutation
N
BRCA 1
PR
CR
SD
> 24
weeks
SD<24
weeks/
PD
7
2
0
1
4
BRCA 2
11
5
1
4
1
Total
18
7
1
5
5
Overall
RECIST response rate: 8/18 (44%); Clinical benefit response rate (CR,PR, SD
> 24 weeks) = 13/18 (72%)
At the 1 mg/day Phase 3 dose, 7/14 (50%) and 12/14 (86%) had objective
and clinical benefit responses, respectively
European Cancer Congress 2013 – Abstract 29LBA
Germline BRCA Mutation – Breast Cancer
RECIST waterfall plot
20
% Change in Target Lesions
0
*
-20
*
*
-40
*
-60
-80
-100
Median duration of response: 27.9 weeks
95% C.I.: 19.9‐40.3 weeks
Median progression‐free survival: 33.1 weeks 95% C.I. 13.1‐40.4 weeks Dose (g/day)
900
1000
1100
BRCA 1
BRCA 2
*
Treatment ongoing
*
*
*
*
*
12
4
62
10/30/2013
Conclusions
 HER2+
 Multiple promising therapies (Pertuzumab,
trastuzumab, lapatinib, T-DM1, everolimus)
 HER2 negative/Hormone receptor positive
breast cancer: Many therapies available,
resistance still remains




Endocrine therapy
MTOR inhibition validated
On the horizon: CDK inhibitors
Chemo after exhausting endocrine options
 Triple negative breast cancer
 Chemo, clinical trials (PARPi?)
Questions & Discussion
63