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

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locally advanced and metastatic disease

Locally advanced and metastatic disease

Eribulin mesylate (E7389):

review of efficacy and tolerability

Jennifer Foglietta

Ospedale Santa Maria della Misericordia

Perugia

slide2

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

Eribulin mesylate (E7389)

indications of eribulin
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.

eribulin structure of molecule
Eribulin: structure of molecule

- Synthetic analogue of halichondrin B; natural product from marine sponge Halichondriaokadai

- 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
Mechanism of action

Polimerizzazione tubulina

1

Eribulin

Blocks microtubule polymerization

3

Growth of

microtubules

  • Sequesters tubulin into non functional aggregates

Spindle

Pole

Eribulin

Eribulin

Eribulin

No effect on depolymerization

2

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.

different sites of action
Different sites of action

Paclitaxel, docetaxel e epothilone B

Eribulina

Vinblastina

  • Eribulina lega solo all’estremità in crescita, (+) ends
  • Legano le subunitàβall’internodeimicrotubuli
  • Si lega lungo il lato esterno e lega le (+) ends
  • Inibiscono l’allungamento e l’accorciamento dei microtubuli
  • Inibisce solo l’allungamento

Modified from Jordan MA and Wilson L. Nat Rev Cancer. 2004; 4:253-265. and Smith J. Biochemistry. 2010; 49:1331-1337.

study 201 trial design
Study 201: trial design

Vahdat LT, et al. J Clin Oncol. 2009;27:2954-2961.

  • Patients (N=103)
  • Advanced breast cancer
  • Prior anthracyclineand taxane
  • Progression <6 months of last chemotherapy
  • ECOG PS: 0-1
  • Pre-existing neuropathy Grade ≤2

Eribulin mesylate 1.4 mg/m2 administered by IV for up to 5 min

28-day cohort

(n=70)

Initial schedule

Dosing days1, 8, and 15q28 days

Alternative schedule

21-day cohort(n=33)

Days 1, 8 q21 days

Neutropenia day 15

study 211 trial design
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

Eribulinmesylate 1.4 mg/m2

2-5 minute IV

Days 1,8 q21 days

Cortes J, et al. J ClinOncol 2010;28:3922–3928.

phase ii trials 201 and 211 study
Phase II trials: 201 and 211 study
  • 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]

201 Study1

(n = 103):

Prior taxane & anthracycline*

  • Primary Endpoint:
    • ORR with independent review

Secondary Endpoints:

    • DOR, PFS, OS, Adverse events
  • 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]

211 Study2

(n = 299):

Prior taxane, anthracycline,

& capecitabine*

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 ClinOncol. 2009;27:2954-2961.

2. Cortes J, et al. J ClinOncol. 2010;28:3922-3928.

slide11

Safety: Hematologic adverse events

Cortes J, et al. J ClinOncol. 2010;28:3922-3928

Vahdat L, et al. J ClinOncol. 2009;27:2954-2961

slide12

Safety: Not hematologic adverse events

Cortes J, et al. J ClinOncol. 2010;28:3922-3928

Vahdat L, et al. J ClinOncol. 2009;27:2954-2961

eribulin trastuzumab as first line mbc trial design
Eribulin+trastuzumabas first line MBC:trial design

Vahdat L et al. SABCS2012 poster P5-20-04

eribulin trastuzumab characteristics of patients
Eribulin+trastuzumab: characteristics of patients

Vahdat L et al. SABCS2012 poster P5-20-04

eribulin trastuzumab primary outcome
Eribulin+trastuzumab: primaryoutcome

Vahdat L et al. SABCS2012 poster P5-20-04

eribulin trastuzumab secondary efficacy outcomes
Eribulin+trastuzumab:Secondaryefficacyoutcomes

Final results are expected by December 2013

Vahdat L et al. SABCS2012 poster P5-20-04

eribulin trastuzumab safety
Eribulin+trastuzumab:safety

Vahdat L et al. SABCS2012 poster P5-20-04

embrace physician s choice tpc vs eribulin
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
  • Primary Endpoint:
    • OS

Secondary Endpoints:

    • PFS
    • ORR
    • Safety

Eribulinmesylate (n=508)

1.4 mg/m2* IV over

2-5 minutes on Day 1,8 q21 days

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/m2eribulin
  • 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.

embrace main c haracteristics of patients
EMBRACE: main characteristics of patients

Cortes J, et al. Lancet 2011;377:914-923.

slide21

EMBRACE: Priorantitumourtherapies

Cortes J, et al. Lancet 2011;377:914-923.

embrace tpc
EMBRACE: TPC

96% pts treated with chemotherapy

Total patients = 247

N= 61

N= 46

% of Patients

N= 44

N= 38

N= 25

N= 24

N= 9

None of patientsreceivedonlysupportive care or immunotherapy

**Include: paclitaxel, docetaxel, abraxane, (ixabepilone)

Cortes J, et al. Lancet 2011;377:914-923.

embrace overall survival
EMBRACE: Overall Survival

Eribulin

TPC

p-value= 0.041

HR (95CI) = 0.81

Cortes J, et al. Lancet 2011;377:914-923.

slide24

1-year survival

Eribulin (n=508)

54.5%

TPC (n=254)

42.8%

EMBRACE: OS (ITT Population)

Updated 3 March 2010

1.0

0.8

EribulinMedian 13.2 months

0.6

HR* 0.81 (95% CI 0.68, 0.96)Nominal p value=0.014

Overall survival (%)

TPCMedian 10.6 months

0.4

0.2

0.0

0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

30

32

34

36

Time (months)

embrace overall survival by stratification factor
EMBRACE: Overall Survival by Stratification Factor*

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.

embrace secondary endpoint pfs
EMBRACE: secondary endpoint PFS

Cortes J, et al. Lancet 2011;377:914-923.

embrace s econdary endpoint orr
EMBRACE: secondary endpoint ORR

Cortes J, et al. Lancet 2011;377:914-923.

slide28

EMBRACE: safety

Cortes J, et al. Lancet 2011;377:914-923.

embrace hematologic adverse events
Embrace: hematologic adverse events

Cortes J, et al. Lancet 2011;377:914-923.

embrace not hematologic adverse events
Embrace: not hematologic adverse events

Cortes J, et al. Lancet 2011;377:914-923.

study 301 eribulin vs capecitabine trial design
Study 301: eribulin vs capecitabinetrialdesign

*

Stratification: - geographicregion

- HER2 status

Co-primary end-points: OS and PFS

Secondaryendpoints: ORR, QoL, DOR, 1-, 2-, 3-year survival and safety

* ≤ 2 for advanceddisease

Kaufman PA et al. SABCS 2012 S6-6

study 301 eribulin vs capecitabine characteristics of patients
Study 301: eribulin vs capecitabinecharacteristics of patients

Kaufman PA et al. SABCS 2012 S6-6

slide33

Study 301: eribulin vs capecitabine

Co-primaryendpoints

Kaufman PA et al. SABCS 2012 S6-6

slide34

Study 301: eribulin vs capecitabine

OS Pre-specifiedSubgroup 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

slide35

Study 301: eribulin vs capecitabine

Response Rate

Kaufman PA et al. SABCS 2012 S6-6

slide36

Study 301: eribulin vs capecitabine

Toxicity

Kaufman PA et al. SABCS 2012 S6-6

slide37

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…)?
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