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New Treatment Options for
Metastatic Breast Cancer
A Focus on HER2+ & Triple Negative Disease
Maureen Trudeau, MD, FRCP(C)
October 29 th , 2010
Sunnybrook Odette Cancer Center
Toronto, Canada

1.
2.
3.
Objectives
Discuss the treatment options for HER2+
metastatic breast cancer
Discuss the treatment options for triple
negative (TN) metastatic breast cancer
Discuss recent clinical trial results in HER2+ and
TN metastatic breast cancer

•
•
•
•
•
Case 1: AK
45‐year old woman treated for Hodgkin’s disease at
age 17 with chemo and upper mantle radiation
In 2003 developed right infiltrating duct breast
cancer
ER‐, PR‐, HER2+ disease, 6 nodes +, treated with
ACT after bilateral mastectomies
In 2006 relapsed in bone. Treated with Taxol plus
Herceptin then Herceptin alone for 1 year
At progression in skin enrolled in a phase II study of
Pertuzumab +/‐ Trastuzumab in July 2008

•
•
•
•
•
Case #2: MB
35‐year old female at diagnosis (2006), 2.2cm, grade 3 IDC, LVI ‐, node‐, triple
negative
Treated with adjuvant FEC100 at outside hospital and adjuvant radiation
Winter 2008, recurrent chest colds, persistent cough (6 months after
completing adjuvant tx)
CT scan Chest April 2008 ‐ multiple lung mets (no other mets)
Seen in consultation at SB
–
–
Significant shortness of breath and cough
Treated on ATHENA trial with wkly taxol + AVASTIN (switched to Abraxane b/c
of hypersensitivty reaction to taxol)

The London Underground
Where to start?
A human cancer cell,
pathways visualized by
Gene Network Sciences

The oncology roadmap: A mechanism‐driven (rather
than indication‐driven) approach to cancer
I. Bombing the Tumor
Targeting antibody-drug
conjugates to tumor antigens
III. Starving the Tumor
Targeting angiogenesis
Signal
transduction
Proteolysis
Metabolism
DNA repair
Cell cycle
II. Choking the Tumor
Targeting pathways for
growth, life, and death
IV. Undermining the Tumor
Halting the regrowth and
spread of cancer cells
V. Rejecting the Tumor
Cancer immunotherapy

All Breast Cancer
ER+
65-75%
HER2+
15-20%
Basaloid
15%

Gene Expression Patterns of Breast
ER
Gene
expression
Basal-like HER2
Subgroup Subgroup
= E = D
Carcinomas Predict Survival
Normal
breast
like
Adapted from Sorlie et al. PNAS, 2001
Luminal
Subtype
C
Luminal
Subtype
B
ER
Gene
expression
Luminal
Subtype
A
O.S.
E
D
months
B
C
A

Herceptin appears to change the course of
HER2+ Breast Cancer (NEJM 2006)
• Effect of HER2/neu Amplification and Trastuzumab on the Kaplan–Meier Estimates of Survival Free
of a First Distant Recurrence of Breast Cancer. CI denotes confidence interval.
• Joensuu et al. 354 (8): 809, Figure 3 NEJM, February 23, 2006

Patients, n
In MBC, Trastuzumab increases
survival, but does not provide “cure”
20,000
18,000
16,000
14,000
12,000
10,000
8000
6000
4000
2000
Trastuzumab introduced (adjuvant)
No. of patients prevented from developing metastases
Incidence of HER2+ MBC following without Trastuzumab
introduction of Trastuzumab
27,737
0
2000 2005 2010 2015
Year
MBC, metastatic breast cancer
50-60% 1st line objective response
Most eventually progress on therapy
Weisgerber-Kriegl et al 2008

Anti-signaling
-
-
MOA of Trastuzumab
Inhibition of HER2 shedding.
Inactivation of AKT signaling.
Engagement of Fc
Receptor Binding
- Immune Effector Function: ADCC.
-FcR
binding and ADCC are not the same.
- Hypercross-linking of Cell Surface Receptors.
Not necessarily mutually exclusive

Trastuzumab –
There are four
1. Activation of antibody-dependent
cellular cytotoxicity (ADCC)
2. Prevention of formation of
p95 HER2 , a truncated and very
active form of HER2
3. Inhibition of cell proliferation by
preventing HER2-activated
intracellular signalling
4. Inhibition of HER2-regulate
angiogenesis
Mechanism of Action
distinct mechanisms of action:
Trastuzumab
HER2
p95 HER2
HER2
Cleaved
Signalling cell
proliferation
tumor tumor
NK
cell
Release
substances
Metalloproteinase
HER2
Angiogenesis
Tumor Cell Death
Trastuzumab
HER2
No signalling
tumor
Trastuzumab
Decreased
blood
supply
Nahta et al. Breast Cancer Res 2006; Clynes et al. Nat Med 2000; Gennari et al. Clin Cancer Res 2004; Arnould et al. Br J Cancer 2006; Molina et al. Cancer Res 2001; Fry et al. Breast Cancer
Res 2001; Gershtein et al. Clin Chim Acta 1999; Yakes et al. Cancer Res 2002;Longva et al. Int J Cancer 2005; Izumi et al. Nature 2002; Nahta et al. Breast Cancer Res 2006; Wen et al.
Oncogene 2006

Trastuzumab and Pertuzumab: Distinct
Epitopes on HER2 Extracellular Domain
I I
III
IV
II
• Potent inhibitor of HER2-mediated
signaling pathways
• Activates antibody-dependent
cellular cytotoxicity
• Inhibits shedding and, thus,
formation of p95
II
III
Trastuzumab Pertuzumab
IV
Prevents receptor dimerization
Potent inhibitor of HER-mediated signaling
pathways

Pertuzumab: Phase II Results
•
•
•
Novel HER2‐targeted monoclonal antibody
Phase II study of pertuzumab/trastuzumab
–
–
–
HER2+ MBC; progression on prior trastuzumab
ORR = 24%
No significant cardiac events observed
Pertuzumab +/‐ trastuzumab after progression on
prior HER2‐targeted therapy
Efficacy Endpoint
Pertuzumab
(n = 29)
Pertuzumab/
Trastuzumab
(n = 14)
ORR 1 (3%) 3 (21%)
CBR 3 (10%) 6 (43%)
Combination active in pts with
progression on prior
trastuzumab and pertuzumab
Baselga et al., J Clin Oncol 2010; 28: 1138‐44.
Baselga et al. SABCS 2009; abstract 5114.

Phase III Cleopatra Trial ‐
Eligibility Eligibility criteria:
criteria:
• • HER2+
HER2+
• • Locally Locally recurrent
recurrent
or or MBC
MBC
• • No No prior
prior
chemotherapy chemotherapy or
or
targeted targeted therapy
therapy
for for metastatic
metastatic
disease
disease
• • = = 1 1 prior prior hormonal
hormonal
therapy therapy for
for
metastatic metastatic disease
disease
• • =12 =12 month month diseasediseasefreefree
interval interval since
since
completion completion of
of
systemic systemic therapy
therapy
R
a
n
d
o
m
i
z
e
Accrual goal = 800
Ongoing
Trastuzumab 8mg/kg loading,
then 6mg/kg q3w
+ Docetaxel 75 mg/m2 Trastuzumab 8mg/kg loading,
then 6mg/kg q3w
+ Docetaxel 75 mg/m q3w
+ Placebo
2 q3w
+ Placebo
Trastuzumab 8mg/kg loading,
then 6mg/kg q3w
+ Docetaxel 75 mg/m2 Trastuzumab 8mg/kg loading,
then 6mg/kg q3w
+ Docetaxel 75 mg/m q3w
+ Pertuzumab 840mg (cycle1),
then 420mg q3w
2 q3w
+ Pertuzumab 840mg (cycle1),
then 420mg q3w
1° endpoint: PFS by
independent review

•
•
•
•
Case again…
Response in skin nodule on Pertuzumab
Developed brain mets in March 2009 and
Trastuzumab added back plus brain radiation
After 6 months presented with confusion, slowed
motor and mental functions. CT changes called
central pontine myelinolysis (CMP). Treatment
stopped
At progression in liver in June 2010 enrolled in
clinical trial of TDM‐1 vs. Capecitabine + Lapatinib

Phase III Randomized Trial of Capecitabine/Lapatinib
vs. Trastuzumab MCC‐DM1 in HER2‐Postive MBC
Previously Treated with Trastuzumab
Randomize
T-DM1 3.6mg/kg IV Day 1
Capecitabine 1000mg/m 2 PO bid, Days 1-14
Lapatinib 1250mg PO daily
Both regimens repeated q 21 days

Novel Cytotoxics: Antibody Drug Conjugates
Trastuzumab‐MCC‐DM1 (T‐DM1)
• Binds to HER2 with affinity similar to
trastuzumab
• Provides intracellular delivery of mertansine
• Derivative of maytansine, a natural-product microtubule
polymerization inhibitor
• 20-100 more potent than vincristine

T-DM1 Selectively Delivers a Highly Toxic
Payload to HER2-Positive Tumor Cells
UNIQUE
DUAL MoAb
•
•
Receptor-T-DM1 complex is
internalized into HER2-
positive cancer cell
Baselga J, et al. Nat Rev Cancer. 2009;9:463-475.
Trastuzumab-like activity by binding to HER2
Targeted intracellular delivery T-DM1 binds of to a the potent HER2
protein on cancer cells
antimicrotubule agent, DM1
Potent antimicrotubule
agent is released once
inside the HER2-positive
tumor cell

Phase II Study: TDM4374g
• Single-agent T-DM1, a novel HER2 directed ADC, demonstrated
robust antitumor activity in a predefined population that had a
median time from metastatic diagnosis of >3 years and received
>2 years of prior HER2-directed therapy:
– ORR: 32.7% IRF, 30% INV
–CBR: 44.5% IRF, 40% INV
• This robust level of activity was seen in an advanced patient
population not previously studied:
– Required prior treatment included an anthracycline, a taxane,
capecitabine, trastuzumab, and lapatinib
– Received 2 HER2-directed regimens in the metastatic setting
– Progressive disease on last regimen received

T‐DM1 Clinical Trials for HER2+ MBC Patients
• Phase I
– N=52, with 2 schedules of single agent T-DM1
• Ph II (pivotal)
– T-DM1 in patients who progressed on HER2 therapy
• Randomized Ph II study in the front-line setting*
– N=120, T-DM1 vs trastuzumab + docetaxel
• Randomized Phase III
– N=580, T-DM1 vs lapatinib + capecitabine
• Exploratory combination trials
– T-DM1 + pertuzumab, T-DM1 + taxanes
Stuart Lutzker, Scott Holden, Barb Klencke

•
•
•
Case again…
Response in liver, skin, nodes on TDM‐1 on
study
Response ongoing
Hemorrhage into eyes secondary to diabetic
retinopathy treated with intraocular
Bevacizumab

Phase III Trials of Continued HER2‐Targeted Therapy in
MBC Previously Treated with Trastuzumab
TBPTriala TBPTrial EGF100151 Trial
a EGF100151 Trial
Capecitabine/
Trastuzumab
(n = 75)
Capecitabine
(n = 68)
Capecitabine/
Lapatinib
(n = 198)
Capecitabine
(n = 201)
Overall Response Rate
37 (48%) 20 (27%)
OR 2.50; P = .0115
24% 14%
OR 1.9; P = .017
Clinical Benefit Rate b Capecitabine/
Trastuzumab
(n = 75)
Capecitabine
(n = 68)
Capecitabine/
Lapatinib
(n = 198)
Capecitabine
(n = 201)
Overall Response Rate
37 (48%) 20 (27%)
OR 2.50; P = .0115
24% 14%
OR 1.9; P = .017
Clinical Benefit Rate
58 (75%) 40 (54%)
OR 2.59; P = .0068
29% 17%
OR 2.0; P = .008
b 58 (75%) 40 (54%)
OR 2.59; P = .0068
29% 17%
OR 2.0; P = .008
Median Time to
Progression
Median Overall Survival
8.2 months 5.6 months 6.2 months 4.3 months
HR 0.69; P = .0338 HR 0.57; P < .001
25.5 months 20.4 months 15.6 months 15.3 months
HR 0.76; P = .2570 HR 0.78; P = .177
a German Breast Group 26/Breast International Group 03-05 trial
b CR + PR + SD > 24 weeks for TBP trial; CR + PR + SD ≥ 6 months for EGF100151 trial.
von Minckwitz et al. J Clin Oncol 2009; 27:1999‐2006.
Cameron et al. Oncologist Aug 2010 (epub ahead of print).

Lapatinib + Capecitabine vs. Capecitabine
Cameron, Casey, Olivia, et al., The Oncologist 2010

Lapatinib + Capecitabine vs. Capecitabine
Cameron, Casey, Olivia, et al., The Oncologist 2010

Lapatinib Studies in Patients with CNS Metastases
•
•
•
Phase III trial of lapatinib/capecitabine (n = 198) vs.
capecitabine alone (n = 201) in MBC:
– Exploratory analysis of the brain as site of first
progression: 2% vs. 6%; P = .045
Small phase II trial of recurrent CNS metastases (n = 39):
– 2.6% PR; 18% progression free at 16 weeks
Phase II trial of recurrent CNS metastases:
Geyer et al. J Clin Oncol 2007 26(suppl):40s (abstract 1035).
Lin et al. J Clin Oncol 2008; 26:1993‐9.
Lin et al. Cancer Therapy Res 2009; 15:1452‐9.

Clinical Trials of Neratinib in Patients Previously
Treated with HER2‐Targeted Agents
a
b
Intent-to-treat population
ORR for patients who have received prior lapatinib or trastuzumab
Burstein et al. J Clin Oncol; February 8, 2010 [e‐pub ahead of print].
Swaby et al. J Clin Oncol 2009; 27(suppl):42s (abstract 1004).
Chow et al. Cancer Res 2009; 69(suppl):792s (abstract 5081).

Trastuzumab disrupts ligand‐independent
HER2‐HER3‐PI3K complex
The oncogenic unit in HER2+ve breast cancer is a
complex between HER2-HER3
Junttila et al. Cancer Cell, 2009.

O
PI3 Kinase Inhibitor: GDC‐0941
S O S O
N
N
Class 1A PI3K
Pan inhibitor
S
O
N
N
N
N
NH
Inhibition of PI3K by GDC-0941
Enzyme IC 50
Class 1A:
p110 alpha 3 nM
p110 alpha E545K 3 nM
p110 alpha H1047R 3 nM
p110 beta 33 nM
p110 delta 3 nM
Class 1B:
p110 gamma 75 nM
PIK Family, (>200 fold selectivity)
Class II: CIIbeta 0.670 uM
Class III: VPS34 >10 uM
Class IV: DNA-PK 1.230 uM
Class IV: mTOR (Ki) 0.580 uM
Protein Kinase panel
>300 fold selectivity against 228 kinase panel
Folkes et al. 2008 J Med Chem.

GDC‐0941 Overcomes Trastuzumab Resistance
Junttila et al. Cancer Cell, 2009.

The “Triple Negative”
Cancer
“Basal-Like”
Breast
Estrogen Receptor (ER) negative
Progesterone receptor (PR) negative
Her2neu (HER2) negative
ER/PR/HER2 -

•
•
•
“Triple Negative”
Breast Cancers
Comprise approximately 15% of all invasive
cancers
More common in:
–
–
–
Younger patients
African Americans (up to 60% premenopausal women in Africa)
BRCA1 mutation carriers ( up to 80%)
Unique Morphologic Attributes
– Pushing border
– high grade
– central scarring/acellular zone
– Stromal/peritumoral lymphocytic infiltrate

•
•
•
•
•
•
•
•
•
Triple-Negative Tumors are
IDC NOS, high grade
ILC high grade, pleomorphic
Metaplastic, high grade
Myoepithelial carcinoma
Heterogeneous
High grade (oat-cell) neuroendocrine
Apocrine
Medullary
Adenoid-cystic
Metaplastic, low grade
–
–
low grade adenosquamous
fibromatosis-like
Poor
prognosis
Good prognosis

Hazard Rate
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
Hazard Rate of Distant Recurrence
Other (290 of 1421) “Triple-negative”
0 1 2 3 4 5 6 7 8 9 10
Years after first surgery
(61 of 180)
Median Time to Distant Recurrence
TN Breast Ca = 2.6 yrs
Dent R, Trudeau M, Pritchard K, Hana W, Narod S. et al. Clinical Cancer Res 2007
Other Breast Ca = 5 yrs p < 0.0001

Median Time from Distant Relapse to
“Triple Negative”
Breast CA
Other Breast CA
9 months
Death
22 months
0 5 10 15 20 25
Dent R, Trudeau M, Pritchard K, Hana W, Narod S. et al. Clinical Cancer Res 2007

Poor Outcome of Metastatic TNBC (N = 112)
Initial
therapy
F. Kassam, #1121
F. Heitz, #1010
Median D.F.I.
First distant
relapse
First
Line
CT
12 weeks
Second
Line
CT
9 weeks
Is RECIST adequate ?
Third
Line
CT
4 wks
Higher risk for developing brain mets OR : 4.16
(95% CI 2.26 – 7.64)
Median O.S. = 3.0 months

Patterns of Metastatic Spread
Non-productive
dry cough
But...Bone Marrow
infiltration

•
•
•
What is “Standard Therapy”
Negative Breast Cancer?
for Triple
No specific systemic regimen guidelines exist
Little data in which to base decisions
Few historical controls making it challenging
to design clinical trials for this subgroup

Chemosensitive early TNBC
has a favourable Outcome

Taxanes for Metastatic TNBC?
Trial Phase N Setting Taxane Outcome in TNBC
Harris et
al.
CALGB
9342
ECOG
2100
III 44 1 st / 2 nd
line
Metastatic
III 10
9
1 st line
Metastatic
AVADO III 52 1 st line
Metastatic
Paclitaxel
Weekly and
q3wk
Paclitaxel
Weekly
Docetaxel
q3wk
ORR = 26%
TTF= 2.8 months
OS = 8.6 months
ORR = 11.7%
PFS = 5.3 months
ORR = 23.1%
PFS = 8.2 months

Angiogenic Switch and VEGF
Small tumour (1–2mm)
• Avascular
• Dormant
Angiogenic
switch
Adapted from Bergers G, et al. Nature 2002;3:401–10
dependency
Larger tumour
• Vascular
• Metastatic potential
Over-expression of pro-angiogenic signals, such as VEGF

Trial / Arm
E2100
Bevacizumab for TNBC
Median PFS (mo) in TNBC
Subset
Paclitaxel (n=110) 5.3
Paclitaxel + bevacizumab (n=122) 10.6
AVADO
Docetaxel + placebo (n=52) 5.4
Docetaxel + bevacizumab 15 mg/kg (n=58) 8.2
RIBBON-1
Taxane/anthracycline + placebo (n=46) 6.2
Taxane/anthracycline + bevacizumab (n=96) 6.5
Capecitabine + placebo (n=50) 4.2
Capecitabine + bevacizumab (n=87) 6.1
ATHENA
Taxane-based regimen + bevacizumab (n=577) 7.2*
*Median PFS vs non-TNBC subgroup.
No survival data in TNBC

RIBBON-1 2
E2100 1 AVADO 2 Capecitabine Taxane/anthracycline
Median, months Median, months Median, months Median, months
Pac Bev
+ pac
Pla
+ doc
Bev
+ doc
Pla
+ cap
Bev
+ cap
Pla
+ t/a
Overall* n=722 n=488 n=615 n=622
Triple-
negative ‡
Bevacizumab Delivers a Consistent PFS
*Stratified analyses
‡ Unstratified analyses
Benefit in Patients With
Triple‐Negative Disease
Bev
+ t/a
5.8 11.3 8.1 10.0 5.7 8.6 8.0 9.2
HR=0.48 HR=0.67 HR=0.69 HR=0.64
n=232 n=111 n=137 n=142
5.3 10.6 6.1 8.1 4.2 6.1 6.2 6.5
HR=0.49 HR=0.68 HR=0.72 HR=0.78
1. O’Shaughnessy, et al. SABCS 2009; 2. Glaspy, et al. EBCC 2010

•
•
•
Case #2: MB
Treated from April 2008 to September 2008 with excellent clinical
and radiological response
October 2008 presented with new headaches, MRI shows diffuse
brain and leptomeningeal disease
– Treated with WBR with good response
Treated with Cisplatin and Gemcitabine x 8 months with good
clinical and radiologic response

TNBC Shares Clinical and Pathologic Features with
BRCA‐1‐Related Breast Cancers
Characteristics Hereditary BRCA1 Triple Negative/Basal-Like 1,2,3
ER/PR/HER2 status Negative Negative
TP53 status Mutant Mutant
BRCA1 status Mutational inactivation* Diminished expression*
Gene-expression pattern Basal-like Basal-like
Tumor histology
Chemosensitivity to DNA-
damaging agents
Poorly differentiated
(high grade)
Poorly differentiated
(high grade)
Highly sensitive Highly sensitive
*BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID4 4
1 Perou et al. Nature. 2000; 406:747-752
3Sorlie et al. Proc Natl Acad Sci U S A 2001;98:10869-74
4 Miyoshi et al. Int J Clin Oncol 2008;13:395-400
2 Cleator et al.Lancet Oncol 2007;8:235-44 4

Platinum for Neoadjuvant Therapy in
BRCA1 Mutation Carriers in Poland
Gronwald et al. ASCO 2009
BRCA1
Mutation
Carriers with
Tumors >2cm
•N = 25
•median age: 46
.
CISPLATIN
75mg/m2
q 3wks IV x 12 wks
•28% with clinically positive lymph nodes
•22 pts completed 4 cycles of Cisplatin,
3 patients completed 2 cycles
Results
Clinical and
Pathological
Response
Complete PR = 72%

Trial Phase /
No. of
TNBC
pts
Platinum Agents for TNBC
Setting Regimen Outcome in TNBC
Gronwald II (N =25) Neoadjuvant Cisplatin pCR = 72%
Sikov
(2009)
Torrisi
(2008)
Silver
(2010)
Uhm
(2009)
II (n=12) Neoadjuvant Carbo-P vs
carbo-P-H
II (n=30) Neoadjuvant
TNBC
II (n=28) Neoadjuvant
TNBC
II (n=36) Metastatic Carbo-P or
Cis-P
pCR=67%
E-Cis-FP pCR=40%; ORR=86%
Cis pCR=22%
ORR 37.5%

Reference Regimen n Prior Rx RR TTP OS
Nagourney JCO
2000
Burch Am J
Oncol 2005
Fuentes
Anticancer
Drugs 2006
Heinemann
Cancer Chemo
Pharmacol 2006
Seo Cancer
Chemo
Pharmacol 2007
Tas Invest New
Drugs 2008
Kim Cancer Res
Treat 2008
Gem 1 g/m2 D1,8,15
Cis 30 mg/m2 D1,8,15
Gem 1g/m2 D1,8,15
Cis 25 mg/m2 D1,8,15
Gem 1.2g/m2 D1,8
Cis 75 mg/m2 D1
Gem 750 mg/m2 D1,8,
Cis 30 mg/m2 D1,8
Gem 1250 mg/m2 D1,
8
Cis 75 mg/m2 D1
Gem 2 g/m2 D1,8
Cis 50 mg/m2 D1,8
Gem 1 g/m2 D1,8
Cis 60 mg/m2
Chew JCO 2009 Gem 1 g/m2 D2,8
Cis 25 mg/m2 D1‐4
Somali
Chemotherapy
2009
Gem 1 g/m2 D1, 8
Cis 30 mg/m2
30 ++ 50% 14 weeks
58 Anthra and
taxane
29%,
then
32%;
31 and 26
weeks
68 and 54
weeks
42 No 81% 15 months 28
months
38 Prior anthra,
taxane
40% 6 months 14
months
30 Prior taxane 30% 7 months 15
months
27 Prior anthra,
taxane
38 Prior anthra
or taxane
26% 7 months
29% 5 months 20
months
136 74 ++ treated 26% 11 and 13
months
31 Prior anthra
and taxane
26% 4 months 10
months

•
•
PARP inhibitors (PARPi)
Single‐stranded breaks are usually repaired by the
base excision repair pathway, of which PARP1 is one
of the central components
In the absence of this pathway, single stranded
breaks degenerate to double stranded breaks, which
are not repaired by BRCA null cells
–
In vitro data has shown that inhibition of PARP1 leads to
highly selective apoptosis of BRCA1 null cells

•
•
•
•
•
Poly(ADP‐ribose) polymerase (PARP)
A key regulator of DNA damage repair processes
Involved in DNA base‐excision repair (BER)
Binds directly to DNA damage
Produces large branched chains of poly (ADP‐ribose)
Attracts and assists BER repair effectors
XRCC1
PNK
Polß
Lig3

ITT cohort
Phase II Trial of Olaparib: Efficacy
400 mg BID
N = 27
100 mg BID
N = 27
ORR 11 (41%) 6 (22%)
CR 1 (4%) 0
PR 10 (37%) 6 (22%)
Median
PFS
5.7 mo
(4.6‐7.4)
3.8 mo
(1.9 –5.6)
Best percent change from baseline
in target lesions by genotype
Tutt A et al. J Clin Oncol 2009; 27(18S):803s (abstr CRA501)

Phase II Trial of Iniparib in TNBC:
• Multicenter
• Open‐label
Gemcitabine (1000 mg/m 2 , IV, d 1, 8)
Carboplatin (AUC 2, IV, d 1, 8)
Study Design
Metastatic TNBC
N = 120
RANDOMIZE
1:1
RESTAGING
Every 2 Cycles
* Patients randomized to gem/carbo alone could crossover to
receive gem/carbo + iniparib at disease progression
Iniparib (5.6 mg/kg, IV, d 1, 4, 8, 11)
Gemcitabine (1000 mg/m 2 , IV, d 1, 8)
Carboplatin (AUC 2, IV, d 1, 8)

Phase II Trial of Iniparib: PFS
(Data through March 09
Iniparib + Gem/Carbo (n = 57)
Median PFS = 6.9 months
Gem/Carbo (n = 59)
Median PFS = 3.3 months
P < 0.0001
HR = 0.342 (95% CI, 0.200-0.584)

OS, %
Phase II Trial of Iniparib:
Overall Survival, ITT
(Data through November 2009
Months
Iniparib/Gem/Carbo: median = 12.2 months
Gem/Carbo: median = 7.7 months
O'Shaughnessy J et al. SABCS 2009. Abstract 3122.

Phase II Study of Olaparib in Advanced Serous Ovarian
Cancer and Triple‐Negative Breast Cancer
Efficacy
ORR in Planned Cohorts
Ovarian
(n = 64)
Breast
(n = 26)
BRCA 4/10 (40%) 0/9 (0)
Unknown BRCA 14/53 (26%) 0/14 (0)
ORR by Actual BRCA Status
Mutant BRCA 7/17 (41%) 0/8 (0)
Non-BRCA 11/46 (24%) 0/15 (0)
Median PFS 219 days 54 days
Gelmon et al., J Clin Oncol 2010; 28(suppl):233s (abstract 3002).

Phase I/II Study of Olaparib Plus Paclitaxel for
Triple‐Negative Metastatic Breast Cancer
• Dose modifications:
Cohort 1 (No G-CSF)
(n = 9)
- Cohort 1: paclitaxel modified in 89%; olaparib modified in 44%
- Cohort 2: paclitaxel modified in 60%; olaparib modified in 30%
• Conclusions:
- Olaparib/paclitaxel is active in triple-negative MBC.
- Associated neutropenia reduced paclitaxel dose intensity
Cohort 2 (G-CSF )
(n = 10)
Overall Response Rate 33% 40%
Stable Disease = 7 Weeks 33% 40%
Median Progression-Free
Survival (95% CI)
6.3 (3.5-8.9) months 5.2 (3.5-NC) months
Eligibility: = 1 prior cytotoxic regimen
Regimen: olaparib 200 mg p.o., b.i.d.
paclitaxel 90 mg/m 2 /week 3 of 4 weeks

Phase II Study of Veliparib Plus Temozolomide in
Metastatic Breast Cancer: Efficacy
Overall Response
Rate
Total
(n = 41)
(23 TNBC)
BRCA1/2 Mutant
(n = 8)
BRCA1/2
Normal/Unknown
(n = 33)
7% 37.5% 0
Clinical Benefit Ratea Clinical Benefit Rate 17% 62.5% 6%
a 17% 62.5% 6%
Median Progression-
Free Survival
a ORR + stable disease
1.9 months
5.5 months 1.8 months
P = .0042
• Efficacy appears to be restricted to BRCA1/2 mutation carriers.
• Further evaluation of this combination is ongoing in BRCA1/2mutated
cancers.
Isakoff et al. J Clin Oncol 2010; 28(suppl):118s (abstract 1019).

Development of PARP inhibitors in
Triple-negative breast cancer
Defining triple-negative breast
cancers
Identifying subset with homologous
recombination deficiency
What are standards of care for
treatment?
What should comparators be?
TNBC
Challenges
Dosing: iv vs po
PARP inhibitors
Schedule: Intermittent vs
continuous
Timing: Delivery before, during or
after chemotherapy
Are they best combined with DNA
damaging agent?

Capecitabine for Metastatic TNBC?
Trial Phase N Setting Treatment Outcome in TNBC
Rugo et al.
SABCS 2008
III 208 3 rd line or
greater
Metastatic
Pooled
Analysis
RIBBON 1 III 50 1 st line
Metastatic
Capecitabine
vs. Cape +
Ixabepilone
Cape vs. Cape + Ixap
ORR = 15 vs. 31%
PFS = 1.7 vs. 4.2 mo
Capecitabine ORR = 4.2 months

Other Targets for TNBC
Target Agent/Approach
DNA repair pathways
PARP inhibitors (BSI-201, olaparib, AG014699,
ABT-888), trabectedin
VEGFR-VEGF Bevacizumab, Sorafenib, IMC113
EGFR Erlotinib, Gefinitib, Cetuximab, Panitumumab
Angiogenesis Endo TAG-1, metronomic chemotherapy
Src kinase Dasatinib
Checkpoint kinase 1 UCN-01
mTOR RAD001, everolimus, temsirolimus
Androgen receptor Bicalutamide
TRAIL Lexatumumab
TGF-beta GC1008, AP 12009, LY2157299
Androgen receptor Bicalutamide
Adapted from Tan and Swain. Cancer Journal. 2008;14.

•
•
•
Treatment Summary for TNBC
No standard therapy for metastatic TNBC
–
No evidence that one chemotherapy is superior to
another
Most active agents currently licensed for use
appear to be:
–
–
Chemotherapy + Bevacizumab
Cisplatin based chemotherapy
Promising agents likely to be licensed:
– PARP inhibitors