Locally advanced and metastatic disease Eribulin mesylate (E7389): review of efficacy and tolerability Jennifer Foglietta Ospedale Santa Maria della Misericordia Perugia

Eribulin mesylate (E7389) - Indications - Structure of molecule - Mechanism of action - Clinical trials (phase II and III) - efficacy outcomes - safety

Indications of eribulin Eribulin is a microtubule inhibitor indicated for the treatment of patients with metastatic breast cancer who have previously received at least 2 chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. 3 3

Eribulin: structure of molecule - Synthetic analogue of halichondrin B; natural product from marine sponge Halichondria okadai - Tubulin-targeting agent - Eribulin could be effective in patients with disease that is resistant to other tubulin-targeting-agents Halichondria okadai Jordan MA, et al. Mol Cancer Ther. 2005;4:1086-1095.

Mechanism of action 1 Eribulin 3 2 Blocks microtubule polymerization Polimerizzazione tubulina 3 Growth of microtubules Sequesters tubulin into non functional aggregates Spindle Pole Eribulin Eribulin Eribulin 2 No effect on depolymerization Shortening of microtubules Eribulin Jordan MA, et al. Mol Cancer Ther. 2005;4:1086-1095. Jordan MA et al. Current Cancer Drug Targets. 2007; 7:730-742. 5 5

Different sites of action Paclitaxel, docetaxel e epothilone B Eribulina Vinblastina Eribulina lega solo all’estremità in crescita, (+) ends Si lega lungo il lato esterno e lega le (+) ends Legano le subunità β all’interno dei microtubuli Inibisce solo l’allungamento Inibiscono l’allungamento e l’accorciamento dei microtubuli Modified from Jordan MA and Wilson L. Nat Rev Cancer. 2004; 4:253-265. and Smith J. Biochemistry. 2010; 49:1331-1337.

Phase II trials Eribulin-EU2035d, December 2010 7

Eribulin mesylate 1.4 mg/m2 administered by IV for up to 5 min Study 201: trial design Alternative schedule Initial schedule Eribulin mesylate 1.4 mg/m2 administered by IV for up to 5 min Patients (N=103) Advanced breast cancer Prior anthracycline and taxane Progression <6 months of last chemotherapy ECOG PS: 0-1 Pre-existing neuropathy Grade ≤2 28-day cohort (n=70) 21-day cohort (n=33) Dosing days 1, 8, and 15 q28 days Days 1, 8 q21 days Neutropenia day 15 Vahdat LT, et al. J Clin Oncol. 2009;27:2954-2961. 8

Eribulin mesylate 1.4 mg/m2 Study 211: trial design Patients (N=299) Advanced breast cancer Prior anthracycline, taxane, capecitabine Progression on or within 6 months of last chemotherapy ECOG PS: 0-2 Pre-existing neuropathy Grade <2 Primary endpoint ORR by IRR Other endpoints Duration of response ORR by investigator PFS, OS EORTC QoL Safety Eribulin mesylate 1.4 mg/m2 2-5 minute IV Days 1,8 q21 days Cortes J, et al. J Clin Oncol 2010;28:3922–3928. 9

Phase II trials: 201 and 211 study Prior taxane & anthracycline* ORR: 11.5% Median DOR: 5.6 months Median PFS: 2.6 months 6-month PFS 25.9% [95% CI, 15.5, 36.3] Median OS: 9 months (range 15–826 days) 6-month survival 67.8% [95% CI, 58.0, 77.6) 1-year survival 45.7% [95% CI, 35.2, 56.2] Primary Endpoint: ORR with independent review Secondary Endpoints: DOR, PFS, OS, Adverse events 211 Study2 (n = 299): Prior taxane, anthracycline, & capecitabine* ORR: 9.3% Median DOR: 4.1 months Median PFS: 2.6 months 6-month PFS 15.6% (95% CI, 10.7, 20.5) Median OS: 10.4 months 6-month survival 72.3% (95% CI, 66.9, 77.6) 1-year survival 45.7% [95% CI, 35.2, 56.2] ORR, overall response rate; DOR, duration of response; PFS, progression-free survival; OS, overall survival *MBC patients with progression of disease ≤6 months of last chemotherapy and, if present, preexisting neuropathy ≤ grade 2 1. Vahdat L, et al. J Clin Oncol. 2009;27:2954-2961. 2. Cortes J, et al. J Clin Oncol. 2010;28:3922-3928.

Safety: Hematologic adverse events Cortes J, et al. J Clin Oncol. 2010;28:3922-3928 Vahdat L, et al. J Clin Oncol. 2009;27:2954-2961

Safety: Not hematologic adverse events Cortes J, et al. J Clin Oncol. 2010;28:3922-3928 Vahdat L, et al. J Clin Oncol. 2009;27:2954-2961

Eribulin+trastuzumab as first line MBC: trial design Vahdat L et al. SABCS2012 poster P5-20-04

Eribulin+trastuzumab: characteristics of patients Vahdat L et al. SABCS2012 poster P5-20-04

Eribulin+trastuzumab: primary outcome Vahdat L et al. SABCS2012 poster P5-20-04

Eribulin+trastuzumab: Secondary efficacy outcomes Final results are expected by December 2013 Vahdat L et al. SABCS2012 poster P5-20-04

Eribulin+trastuzumab: safety Vahdat L et al. SABCS2012 poster P5-20-04

Phase III trials Eribulin-EU2035d, December 2010 18

EMBRACE: Physician’s Choice (TPC) vs Eribulin Patients (n=762) Locally recurrent or MBC 2–5 prior chemotherapies ≥ 2 for advanced disease Prior anthracycline and taxane Progression ≤ 6 months of last chemotherapy Neuropathy ≤ grade 2 ECOG ≤ 2 Eribulin mesylate (n=508) 1.4 mg/m2* IV over 2-5 minutes on Day 1,8 q21 days Primary Endpoint: OS Secondary Endpoints: PFS ORR Safety RANDOMISATION 2:1 TPC (n=254): Any monotherapy (cytotoxic, hormonal, biological); or Palliative treatment; or Radiotherapy Stratification: Geographical region Prior capecitabine HER2 status *Equivalent to 1.23 mg/m2 eribulin Exploratory subgroups: Hormone receptor expression status (ER, PgR, HER2, triple-negative); number of organs involved; sites of disease Cortes J, et al. Lancet 2011;377:914-923. 19

EMBRACE: main characteristics of patients Eribulin (n=508) TPC (n=254) TOTAL (n=762) Median age (range) 55 (28-85) 56 (27-81) 55 (27-85) OR and PgR status OR+ and/or PgR+, % 64 OR and PgR -, % 24 25 Unknown 11 HER2/neu status, % Positive 16 Negative 73 76 74 10 9 Triple (ER/PgR/HER2) negative, % 18 20 19 No. organs involved, % ≤2 51 46 49 >2 54 Visceral disease Yes 391 181 572 No 77 33 110 Cortes J, et al. Lancet 2011;377:914-923.

EMBRACE: Prior antitumour therapies   ERIBULINA n=508 TPC n=254 Totale N=762 Prior chemotherapy regimens, n (%) 1 1 (<1) 0 (0,0) 2 65 (13) 31 (12) 96 (13) 3 176 (35) 83 (33) 259 (34) 4 (median) 166 (33) 79 (31) 245 (32) 5 85 (17) 51 (20) 136 (18) ≥ 6 13 (3) 9 (4) 22 (3) Refractory to, n (%) Taxanes 503 (99) 251 (99) 754 (99) Anthra 502 (99) 250 (98) 752 (99) Capecitabine 370 (73) 189 (74) 559 (73) Cortes J, et al. Lancet 2011;377:914-923.

96% pts treated with chemotherapy EMBRACE: TPC 96% pts treated with chemotherapy Total patients = 247 N= 61 % of Patients N= 46 N= 44 N= 38 N= 25 N= 24 N= 9 None of patients received only supportive care or immunotherapy **Include: paclitaxel, docetaxel, abraxane, (ixabepilone) Cortes J, et al. Lancet 2011;377:914-923.

EMBRACE: Overall Survival p-value= 0.041 HR (95CI) = 0.81 Eribulin TPC Cortes J, et al. Lancet 2011;377:914-923.

EMBRACE: OS (ITT Population) Updated 3 March 2010 TPC (n=254) Eribulin (n=508) 54.5% 1-year survival 42.8% 0.0 0.2 0.4 0.6 0.8 1.0 36 26 24 22 20 18 16 14 12 10 8 6 4 2 Overall survival (%) Eribulin Median 13.2 months TPC Median 10.6 months HR* 0.81 (95% CI 0.68, 0.96) Nominal p value=0.014 28 30 32 34 Un aggiornamento non pianificato della sopravvivenza globale è stato richiesto sia dall’FDA che dall’EMA dopo che il 75% dei pazienti era deceduto Time (months) 24

EMBRACE: Overall Survival by Stratification Factor* Eribulin-EU2035f HER2, human epidermal growth factor receptor type 2. *Intent-to-treat population; Based upon a stratified Cox analysis including geographic region, HER-2/neu status, and prior capecitabine therapy as strata. Cortes J, et al. Lancet 2011;377:914-923. 25

EMBRACE: secondary endpoint PFS Cortes J, et al. Lancet 2011;377:914-923.

EMBRACE: secondary endpoint ORR Independent review Investigator review Eribulin (n=468) TPC (n=214) ORR (CR+PR), % 12 5 13 7 p value 0,002 0,028 SD, % 44 45 47 PD, % 41 49 38 Not evaluable, % 3 1 2 CBR, % 23 17 28 20 Cortes J, et al. Lancet 2011;377:914-923. 27

EMBRACE: safety Adverse Event, % Eribulin (n=503) TPC (n=247) All adverse events 99 93 Serious adverse events 25 26 Adverse events leading to interruption 5 10 discontinuation 13 15 dose reduction 17 16 dose delay 35 32 Fatal adverse events 4 7 Fatal adverse events (treatment-related) 1 Cortes J, et al. Lancet 2011;377:914-923. 28

Embrace: hematologic adverse events Eribulin (n=503) TPC (n=247) All Grades Grade 3 Grade 4 Grade 3 Neutropenia 52 21 24 30 14 7 Leukopenia 23 12 2 11 5 1 Febrile neutropenia 3 1.2 0.8 0.4 Thrombocytopenia 2.6 0.6 0.2 4.9 1.6 Cortes J, et al. Lancet 2011;377:914-923. 29

Embrace: not hematologic adverse events Eribulin (n=503) TPC (n=247) All Grades Grade 3 Grade 4 Grade 3 Gastrointestinal Nausea 35 1 28 2 Constipation 25 21 Diarrhoea 18 Vomiting <1 General disorders Asthenia/fatigue 54 8 40 10 Pyrexia 13 Nervous system disorders Peripheral neuropathy 16 Headache 19 12 Skin and subcutaneous tissue Alopecia 45 N/A Hand-foot syndrome 14 4 Cortes J, et al. Lancet 2011;377:914-923. 30

Study 301: eribulin vs capecitabine trial design * Stratificazione per area geografica e HER2 Stratification: - geographic region - HER2 status Co-primary end-points: OS and PFS Secondary endpoints: ORR, QoL, DOR, 1-, 2-, 3-year survival and safety * ≤ 2 for advanced disease Kaufman PA et al. SABCS 2012 S6-6

Study 301: eribulin vs capecitabine characteristics of patients Patients N=1102 Median age 54 y (range 24-80) HER2 negative 68.5% First line therapy 27.2% Second line therapy 57.4% Third line therapy 14.7% Kaufman PA et al. SABCS 2012 S6-6

Study 301: eribulin vs capecitabine Co-primary endpoints Kaufman PA et al. SABCS 2012 S6-6

OS Pre-specified Subgroup Analysis Study 301: eribulin vs capecitabine OS Pre-specified Subgroup Analysis Author conclusions: “particular patient subgroups may have greater therapeutic benefit with eribulin and this may warrant further study” Kaufman PA et al. SABCS 2012 S6-6

Study 301: eribulin vs capecitabine Response Rate Kaufman PA et al. SABCS 2012 S6-6

Study 301: eribulin vs capecitabine Toxicity Kaufman PA et al. SABCS 2012 S6-6

Conclusions Efficacy of eribulin in MBC pts Combination with other agents? Manageable toxicity Common EAs: neutropenia, fatigue, neuropathy Low incidence of neuropathy grade 3/4 Trials ongoing in early breast cancer (adjuvant and neoadjuvant setting) Trials in other solid tumours (sarcoma, NSCLC, pancreatic cancer…)?