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A Phase III study (EMBRACE*) of eribulin mesylate vs. treatment of physicians 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 Jamess 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)

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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

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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 -tubulin mutated cell lines Wide therapeutic window and induces less neuropathy in mice than paclitaxel Eribulin mesylate Towle et al 2001; Jordan et al 2005; Kuznetsov et al 2004; Okouneva et al 2008; Smith et al 2010 Halichondria okadai O O H H O H H O Me O O O O Halichondrin B H H O O Me O H H H O O O HO Me H H O O H H 1 O MeO Eribulin Mesylate HO H3NH3N + MsO -

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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) 17.217.1 Vahdat et al JCO 2009; 27: 2954-2961 Cortes et al 2010 (accepted for publication by JCO) *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.

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Locally recurrent or MBC 2-5 prior chemotherapies Progression 6 months of last chemotherapy Neuropathy grade 2 ECOG 2 Eribulin mesylate 1.4 mg/m 2, 2-5 min IV Day 1, 8 q21 days Treatment of Physicians Choice (TPC) Any monotherapy (chemotherapy, hormonal, biological)* or supportive care only Randomization 2:1 PFS ORR Safety Overall survival Primary endpoint Secondary endpoints EMBRACE study design Stratification: Geographical region, prior capecitabine, HER2/neu status Global, randomized, open-label Phase III trial (Study 305) Patients (N=762) 2 for advanced disease Prior anthracycline and taxane * 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

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Statistical plan Primary pre-defined analysis in the ITT population Two-sided stratified log-rank test by randomization parameters Overall survival nominal significance level 0.049 (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

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Patient characteristics Eribulin (n=508) TPC (n=254) TOTAL (n=762) Median age (range) 55 (28-85) 56 (27-81) 55 (27-85) ECOG, % 0 1 2 Missing 43 48 8 1.6 41 50 9 1 42 49 8 1 Geographic region, % I North America, Western Europe, Australia II Eastern Europe, Russia, Turkey III Latin America, South Africa 64 25 11 64 25 11 64 25 11 Prior capecitabine, % Yes No 73 27 74 26 73 27 Median no. prior chemotherapy regimens (range)4 (1-7)4 (2-7)4 (1-7) ITT population

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Disease characteristics Eribulin (n=508) TPC (n=254) TOTAL (n=762) ER positive, %6667 PR positive, %504850 HER2/neu status, % Positive16 Negative737674 Unknown109 Triple (ER/PR/HER2) negative, %182120 No. organs involved, % 2514649 >2495451 Sites of disease,* % Liver586361 Lung393738 Bone606261 ITT population; *Clinically relevant sites of disease; ER, estrogen receptor; PR, progesterone receptor

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

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Overall survival (months) 0.0 0.2 0.4 0.6 0.8 1.0 0282624222018161412108642 Survival probability Overall survival Eribulin Median 13.12 months TPC Median 10.65 months HR* 0.81 (95% CI 0.66, 0.99) p-value =0.041 2.47 months TPC (n=254) Eribulin (n=508)53.9% 1 year survival 43.7% 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

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Progression-free survival 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 02468 10 12141618 Eribulin TPC HR 0.87 (95% CI 0.71, 1.05) p-value=0.14 Median (months) 3.7 2.2 PFS in the per-protocol population was significant with both independent (p=0.02) and investigator review (p

Grade 3Grade 4 Eribulin (n=503) TPC (n=247) Eribulin (n=503) TPC (n=247) Hematologic events, % Neutropenia21.114.224.16.9 Leukopenia11.74.92.20.8 Anemia1.83.20.20.4 Febrile neutropenia3.00.81.20.4 Non-hematologic events, % Asthenia / fatigue8.210.10.60 Peripheral neuropathy 7.82.00.40 Nausea1.22.400 Dyspnea3.62.400.4 Mucosal inflammation1.42.000 Hand-foot syndrome0.43.600 Grade 3 and 4 AEs* *>2% incidence; Neuropathy peripheral, neuropathy, paresthesia, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, peripheral sensorimotor neuropathy, demyelinating polyneuropathy

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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 Acknowledgements We would like to thank all of the patients, as well as the investigators and their teams, who participated in the EMBRACE study These results potentially establish eribulin as a new option for women with heavily pre-treated MBC