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

Locally advanced and metastatic disease

Eribulin mesylate (E7389):

review of efficacy and tolerability

Jennifer Foglietta

Ospedale Santa Maria della Misericordia

Perugia

- Indications

- Structure of molecule

- Mechanism of action

- Clinical trials (phase II and III)- efficacy outcomes- safety

Eribulin mesylate (E7389)

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

Halichondria okadai

- 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

Jordan MA, et al. Mol Cancer Ther. 2005;4:1086-1095.

Mechanism of action

Jordan MA, et al. Mol Cancer Ther. 2005;4:1086-1095. Jordan MA et al. Current Cancer Drug Targets. 2007; 7:730-742.

Growth of microtubules

Shortening of microtubules

SpindlePole

Polimerizzazione tubulina

No effect on depolymerization

2

Eribulin Blocks microtubule polymerization

1

Sequesters tubulin into non functional aggregates

Eribulin

EribulinEribulin

3

Eribulin

Different sites of action

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

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

Paclitaxel, docetaxel e epothilone B

Inibisce solo l’allungamento Inibiscono l’allungamento e l’accorciamento dei microtubuli

VinblastinaEribulina

Phase II trials

Study 201: trial design

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

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 days1, 8, and 15

q28 days

Days 1, 8 q21 days

Neutropenia day 15

Study 211: trial design

Eribulin mesylate 1.4 mg/m2

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

2-5 minute IVDays 1,8 q21 days

Primary endpoint• ORR by IRR

Other endpoints • Duration of response• ORR by investigator• PFS, OS• EORTC QoL• Safety

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

Phase II trials: 201 and 211 study

1. Vahdat L, et al. J Clin Oncol. 2009;27:2954-2961.2. Cortes J, et al. J Clin Oncol. 2010;28:3922-3928.

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

201 Study1

(n = 103): Prior taxane & anthracycline*

211 Study2

(n = 299):Prior taxane,

anthracycline, & capecitabine*

Primary Endpoint:

● ORR with independent review

Secondary Endpoints:

● DOR, PFS, OS, Adverse events

• 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]

• 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]

Safety: Hematologic adverse events

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

Safety: Not hematologic adverse events

Cortes J, et al. J Clin Oncol. 2010;28:3922-3928Vahdat 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


Eribulin+trastuzumab: primary outcome


Eribulin+trastuzumab:Secondary efficacy outcomes


Final results are expected by December 2013

Eribulin+trastuzumab:safety


Phase III trials

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

TPC (n=254): ●Any monotherapy (cytotoxic, hormonal, biological); or●Palliative treatment; or●Radiotherapy

RANDOMISATION 2:1

*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

Primary Endpoint:

● OS

Secondary Endpoints:● PFS● ORR● Safety

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

Stratification: Geographical region Prior capecitabine HER2 status

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 64 64OR and PgR -, % 24 25 25Unknown 11 11 11

HER2/neu status, %

Positive 16 16 16Negative 73 76 74Unknown 10 9 10

Triple (ER/PgR/HER2) negative, % 18 20 19

No. organs involved, %

≤2 51 46 49>2 49 54 51

Visceral disease

Yes 391 181 572No 77 33 110


EMBRACE: Prior antitumour therapies

ERIBULINA n=508

TPC n=254

TotaleN=762

Prior chemotherapy regimens, n (%)1 1 (<1) 0 (0,0) 1 (<1)

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)


EMBRACE: TPC

0%5%10%15%20%25%30%

Total patients = 247Total patients = 247

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

96% pts treated with chemotherapy

% o

f P

ati

en

ts

None of patients received only supportive care or immunotherapy

N= 44N= 46

N= 38

N= 61

N= 24 N= 25

N= 9


EMBRACE: Overall Survival

Eribulin TPC


p-value= 0.041HR (95CI) = 0.81

Time (months)

TPC (n=254)

Eribulin (n=508) 54.5%

1-year survival

42.8%

EMBRACE: OS (ITT Population)Updated 3 March 2010

0.0

0.2

0.4

0.6

0.8

1.0

0 362624222018161412108642

Ove

rall

surv

ival

(%

)

EribulinMedian 13.2 months

TPCMedian 10.6 months

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

28 30 32 34

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.


EMBRACE: secondary endpoint PFS


EMBRACE: secondary endpoint ORR


Independent review Investigator review

Eribulin(n=468)

TPC(n=214)

Eribulin(n=468)

TPC(n=214)

ORR (CR+PR), % 12 5 13 7

p value 0,002 0,028

SD, % 44 45 47 45

PD, % 41 49 38 45

Not evaluable, % 3 1 2 2

CBR, % 23 17 28 20

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 1

EMBRACE: safety


Adverse event, %

Eribulin (n=503) TPC (n=247)

All Grades

Grade 3 Grade 4All

GradesGrade 3 Grade 4

Neutropenia 52 21 24 30 14 7

Leukopenia 23 12 2 11 5 1

Febrile neutropenia 5 3 1.2 2 0.8 0.4

Thrombocytopenia 2.6 0.6 0.2 4.9 0.8 1.6

Embrace: hematologic adverse events


Embrace: not hematologic adverse events

Adverse event, %

Eribulin (n=503) TPC (n=247)

All Grades

Grade 3 Grade 4All

GradesGrade 3 Grade 4

Gastrointestinal

Nausea 35 1 0 28 2 0

Constipation 25 1 0 21 1 0

Diarrhoea 18 0 0 18 0 0

Vomiting 18 1 <1 18 1 0

General disorders

Asthenia/fatigue 54 8 1 40 10 0

Pyrexia 21 <1 0 13 <1 0

Nervous system disorders

Peripheral neuropathy 35 8 <1 16 2 0

Headache 19 <1 0 12 0 <1

Skin and subcutaneous tissue

Alopecia 45 N/A N/A 10 N/A N/A

Hand-foot syndrome 1 <1 0 14 4 0Cortes J, et al. Lancet 2011;377:914-923.

Study 301: eribulin vs capecitabinetrial design

*

* ≤ 2 for advanced disease Kaufman PA et al. SABCS 2012 S6-6

Stratification: - geographic region - HER2 status

Co-primary end-points: OS and PFS

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

Study 301: eribulin vs capecitabinecharacteristics 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 capecitabineCo-primary endpoints


Study 301: eribulin vs capecitabineOS Pre-specified Subgroup Analysis


Author conclusions: “particular patient subgroups may have greater therapeutic benefit with eribulin and this may warrant further study”

Study 301: eribulin vs capecitabineResponse Rate



Study 301: eribulin vs capecitabineToxicity

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…)?

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

Documents

j clin oncol

months median pfs

median dor

median os

overall survival

months6month pfs

months6month survival

year survival