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

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

3. 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

4. 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:

5. 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:
Jordan MA et al. Current Cancer Drug Targets. 2007; 7: 5 5

6. 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: and Smith J. Biochemistry. 2010; 49:

7. Phase II trials
Eribulin-EU2035d, December 2010 7

8. 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: 8

9. 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

10. 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:
2. Cortes J, et al. J Clin Oncol. 2010;28:

11. Safety: Hematologic adverse events
Cortes J, et al. J Clin Oncol. 2010;28:
Vahdat L, et al. J Clin Oncol. 2009;27:

12. Safety: Not hematologic adverse events
Cortes J, et al. J Clin Oncol. 2010;28:
Vahdat L, et al. J Clin Oncol. 2009;27:

13. Eribulin+trastuzumab as first line MBC: trial design
Vahdat L et al. SABCS2012 poster P

14. Eribulin+trastuzumab: characteristics of patients
Vahdat L et al. SABCS2012 poster P

15. Eribulin+trastuzumab: primary outcome
Vahdat L et al. SABCS2012 poster P

16. Eribulin+trastuzumab: Secondary efficacy outcomes
Final results are expected by December 2013
Vahdat L et al. SABCS2012 poster P

17. Eribulin+trastuzumab: safety
Vahdat L et al. SABCS2012 poster P

18. Phase III trials
Eribulin-EU2035d, December 2010 18

19. 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: 19

20. 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:

21. 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:

22. 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:

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

24. 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

25. 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: 25

26. EMBRACE: secondary endpoint PFS
Cortes J, et al. Lancet 2011;377:

27. 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: 27

28. 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: 28

29. 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: 29

30. 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: 30

31. 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

32. 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

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

34. 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

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

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

37. 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…)?