1. A Phase III study (EMBRACE. ) of eribulin mesylate vs
A Phase III study (EMBRACE*) of eribulin mesylate vs. treatment of physician’s choice in patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane
Dr Chris Twelves
Professor of Clinical Cancer Pharmacology and Oncology
University of Leeds & St James’s University Hospital, Leeds, UK
On behalf of the abstract co-authors and EMBRACE investigators
*Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus Eribulin (E7389)

2. Introduction
There is a significant need for therapies that improve overall survival in MBC
Several established cytotoxic therapies for MBC
however, many patients do not respond, or become refractory
No single standard of care for heavily pre-treated MBC
depends upon prior treatment, availability, and patient / oncologist preference
To date, no single agent has demonstrated overall survival benefit in heavily pre-treated MBC
MBC, metastatic breast cancer

3. Eribulin mesylate Halichondrins ― a new class of antineoplastic agents
Eribulin is a synthetic analog of halichondrin B, a natural marine sponge product
Non-taxane microtubule dynamics inhibitor with a novel mode of action
Potent anti-proliferative agent in vitro and in vivo
Active against β-tubulin mutated cell lines
Wide therapeutic window and induces less neuropathy in mice than paclitaxel
Halichondria okadai
Halichondrin B H O Me HO 1 O
MeO
Eribulin Mesylate HO
H3N +
MsO - H O O O H H O O O O Me H O
Towle et al 2001; Jordan et al 2005; Kuznetsov et al 2004; Okouneva et al 2008; Smith et al 2010 3

4. Phase II clinical activity
Study 201 (N=87 per protocol)†
Study 211 (N=269 eligible population)†
Median number of prior therapies (range)
4 (1-11)§
4 (2-5)
ORR, %
11.5*
9.3*
Clinical benefit rate, % (CR + PR + SD ≥6 months)
17.2
17.1
this slide
*No complete responses
†Results are based upon independent radiological review
§Intent-to-treat population (n=103)
ORR, objective response rate; PR, partial response;
SD, stable disease.
Vahdat et al JCO 2009; 27: Cortes et al 2010 (accepted for publication by JCO)

5. Treatment of Physician’s Choice (TPC)
EMBRACE study design
Global, randomized, open-label Phase III trial (Study 305)
Eribulin mesylate
1.4 mg/m2, 2-5 min IV Day 1, 8 q21 days
Patients (N=762)
Primary endpoint
Locally recurrent or MBC
2-5 prior chemotherapies
Progression ≤6 months of last chemotherapy
Neuropathy ≤grade 2
ECOG ≤2
Overall survival
≥2 for advanced disease
Prior anthracycline and taxane
Randomization 2:1
Secondary endpoints
Treatment of Physician’s Choice (TPC)
Any monotherapy (chemotherapy, hormonal, biological)* or supportive care only†
PFS
ORR
Safety
Stratification:
Geographical region, prior capecitabine, HER2/neu status
* Approved for treatment of cancer
†Or palliative treatment or radiotherapy administered according to local practice, if applicable
ECOG, Eastern Cooperative Oncology Group; IV, intravenous; PFS, progression-free survival; HER2/neu, human epidermal growth factor receptor 2

6. Statistical plan Primary pre-defined analysis in the ITT population
Two-sided stratified log-rank test by randomization parameters
Overall survival nominal significance level (adjusted interim analysis); no other adjustments made
Analysis planned at 411 events (actual number 422 events)
Achieved 12 May 2009
Survival follow up analysis ongoing
All subset analyses were pre-planned
ITT, intent-to-treat population

7. Patient characteristics
Eribulin (n=508)
TPC
(n=254)
TOTAL (n=762)
Median age (range)
55 (28-85)
56 (27-81)
55 (27-85)
ECOG, % 1 2
Missing 43 48 8
1.6 41 50 9 42 49
Geographic region, %
I North America, Western Europe, Australia II Eastern Europe, Russia, Turkey
III Latin America, South Africa 64 25 11
Prior capecitabine, %
Yes No 73 27 74 26
Median no. prior chemotherapy regimens (range)
4 (1-7)
4 (2-7)
ITT population

8. Disease characteristics
Eribulin (n=508)
TPC
(n=254)
TOTAL (n=762)
ER positive, % 66 67
PR positive, % 50 48
HER2/neu status, %
Positive 16
Negative 73 76 74
Unknown 10 9
Triple (ER/PR/HER2) negative, % 18 21 20
No. organs involved, % ≤2 51 46 49
>2 54
Sites of disease,* %
Liver 58 63 61
Lung 39 37 38
Bone 60 62
ITT population; *Clinically relevant sites of disease; ER, estrogen receptor; PR, progesterone receptor

9. TPC treatment received
96% of patients treated with chemotherapy
Total patients = 247
% of patients
n=61
n=46
n=44
n=38
n=24
n=25
n=9
No patient received best supportive care or “biological” therapies only
ITT population; Taxanes: paclitaxel, docetaxel, abraxane, (ixabepilone) Anthracyclines: doxorubicin, liposomal doxorubicin, mitoxantrone 9

10. Eribulin Median 13.12 months Overall survival (months)
TPC (n=254)
Eribulin (n=508)
53.9%
1 year survival
43.7%
1.0
0.8
Eribulin Median months
0.6
Survival probability
HR* 0.81 (95% CI 0.66, 0.99) p-value†=0.041
0.4
TPC Median months
0.2
2.47 months
0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Overall survival (months)
ITT population; *HR Cox model including geographic region, HER2/neu status, and prior capecitabine therapy as strata †p value from stratified log-rank test (pre-defined primary analysis); HR, hazard ratio; CI, confidence intervals 10

11. Progression-free survival
Proportion progression-free
Investigator review (ITT)
Time (months) 10 20
0.0
0.2
0.4
0.6
0.8
1.0 2 4 6 8 12 14 16 18
Median (months)
Eribulin
TPC
HR 0.76 (95% CI 0.64, 0.90)
p-value=0.002
Eribulin (n=508)
TPC (n=254) 20
Eribulin (n=508)
TPC (n=254)
Time (months)
Independent review (ITT)
Proportion progression-free
1.0
0.0
0.2
0.4
0.6
0.8 2 4 6 8 10 12 14 16 18
Eribulin
TPC
HR 0.87 (95% CI 0.71, 1.05)
p-value=0.14
Median (months)
PFS in the per-protocol population was significant with both independent (p=0.02) and investigator review (p<0.001) 11

12. Best overall response Independent review Eribulin (n=468) TPC (n=214)
ORR (CR+PR), %
12.2
4.7
p-value
0.002
SD, %
44.4
44.9
PD, %
40.6
49.1
NE, %
2.6
1.4
Clinical benefit rate (CR + PR + SD ≥6 months),%
22.6
16.8
Response evaluable population CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, non-evaluable

13. Best overall response Independent review Investigator review Eribulin
TPC
(n=214)
ORR (CR+PR), %
12.2
4.7
13.2
7.5
p-value
0.002
0.028
SD, %
44.4
44.9
46.8
PD, %
40.6
49.1
37.6
45.3
NE, %
2.6
1.4
2.4
2.3
Clinical benefit rate (CR + PR + SD ≥6 months),%
22.6
16.8
27.8
20.1
Response evaluable population CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, non-evaluable

14. Overall incidence of AEs
Adverse event (AE), %
Eribulin (n=503)
TPC (n=247)
All AEs
98.8
93.1
Serious AEs
25.0
25.9
AEs leading to
interruption
5.0
10.1
discontinuation
13.3
15.4
dose reduction
16.9
15.8
dose delay
35.2
32.4
Fatal AEs
4.0
7.3
Fatal AEs (treatment-related)
1.0
0.8 14

15. Grade 3 and 4 AEs* Grade 3 Grade 4 Eribulin (n=503) TPC (n=247)
Hematologic events, %
Neutropenia
21.1
14.2
24.1
6.9
Leukopenia
11.7
4.9
2.2
0.8
Anemia
1.8
3.2
0.2
0.4
Febrile neutropenia
3.0
1.2
Non-hematologic events, %
Asthenia / fatigue
8.2
10.1
0.6
Peripheral neuropathy†
7.8
2.0
Nausea
2.4
Dyspnea
3.6
Mucosal inflammation
1.4
Hand-foot syndrome
*>2% incidence; † Neuropathy peripheral, neuropathy, paresthesia, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, peripheral sensorimotor neuropathy, demyelinating polyneuropathy 15

16. EMBRACE: conclusions
EMBRACE is the first Phase III single-agent study in heavily pre-treated MBC to meet its primary endpoint of prolonged overall survival
Eribulin demonstrated a statistically significant improvement in overall survival
Improvement of median overall survival was 2.5 months (23%)
Clinically meaningful in heavily pretreated patients
Overall response rate and progression-free survival also favored eribulin
These benefits were achieved with a manageable safety profile
These results potentially establish eribulin as a new option for women with heavily pre-treated MBC
Acknowledgements
We would like to thank all of the patients, as well as the investigators and their teams, who participated in the EMBRACE study 16