Locally advanced and metastatic disease
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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


Locally advanced and metastatic disease

- 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.


Phase ii trials

Phase II trials


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.


Locally advanced and metastatic disease

Safety: Hematologic adverse events

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

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


Locally advanced and metastatic disease

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


Phase iii trials

Phase III trials


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.


Locally advanced and metastatic disease

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.


Locally advanced and metastatic disease

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.


Locally advanced and metastatic disease

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


Locally advanced and metastatic disease

Study 301: eribulin vs capecitabine

Co-primaryendpoints

Kaufman PA et al. SABCS 2012 S6-6


Locally advanced and metastatic disease

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


Locally advanced and metastatic disease

Study 301: eribulin vs capecitabine

Response Rate

Kaufman PA et al. SABCS 2012 S6-6


Locally advanced and metastatic disease

Study 301: eribulin vs capecitabine

Toxicity

Kaufman PA et al. SABCS 2012 S6-6


Locally advanced and metastatic disease

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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