ERIBULINA: COMO OPTIMIZAR UN

FÁRMACO QUE PROLONGA LA VIDA

DE LAS PACIENTES CON CÁNCER

DE MAMA METASTÁSICO

Dra. Martínez Jáñez. Hospital Ramón y Cajal 3 de abril de 2014

Cáncer de mama: incidencia y mortalidad.

Incidencia al diagnóstico

ESTADIO

PRECOZ

AVANZADO

Enfermedad localizada

1ª L

R.I.P.

2ª L

3ª L

4ª L

5ª L

6ª L

7ª L ………nª L

Enfermedad avanzada

Enfermedad avanzada

Enfermedad avanzada

Enfermedad avanzada

Enfermedad avanzada

Enfermedad avanzada

Enfermedad avanzada

Adyuvancia

Neoadyuvancia

CURACIÓN

3-4 años

20-50%

Evolución de la enfermedad

MAYOR SUPERVIVENCIA

Aumento de la

eficacia del Tto.

Detección precoz

CMM: dificultad terapéutica.

CMM: dificultad terapéutica.

Eribulin was named as a standard treatment option for patients who

had progressed following anthracyclines and taxanes.

¿Que es la Eribulina?

MW = 1110

32 stereocenters

0.2 nM (MDA-MB-435)

MW = 730

19 stereocenters

0.1 nM (MDA-MB-435)

Paclitaxel (Taxol)

MW = 854

11 stereocenters

2.5 nM (MDA-MB-435)

>200 analogs, 6 years

¿Cuál es su mecanismo de acción?

1. Alteración irreversible del microtúbulo.

2. Alteración del TEM- TME.

3. Alteración de la vascularización.

4. Inhibición de la síntesis de proteínas

14

MECANISMO DE ACCIÓN

Growing microtubule

Shortening microtubule

Microtubule Polymerization

MTOC

Eribulin has no effect on microtubule shortening

2

Eribulin Eribulin inhibits microtubule growth 1

3 Eribulin causes globular tubulin

aggregates

Eribulin

Globular tubulin aggregates

Microtubule Depolymerization

Microtubule Dynamics

MT drawing created by M. Asada, TRL, Eisai; later adapted by B. Littlefield, ERI Jordan et al., 2005)

MECANISMO DE ACCION DIFERENTE

16 Modified from Jordan M and Wilson L. Nat Rev Cancer. 2004;4:253–265; Smith J, Wilson L et al. Biochemistry. 2010;49:1331–1337

Binds to (+) ends of microtubules

Binds to (+) ends and along sides of microtubules

Bind to subunits inside of microtubules

Paclitaxel, docetaxel

and epothilone B

Inhibits growth only Inhibit microtubule growth and shortening

Vinblastine Eribulin

Desarrollo clínico de Eribulina

BREAST CANCER

GENITOURINARY CANCER (bladder)

PROSTATE CANCER

LUNG CANCER (NSCLC)

SARCOMAS (soft tissue)

GYNAECOLOGIC CANCER (ovary)

Phase II - III

Phase II

Phase II

Phase II - III

Phase II

Phase II

H&N CANCER Phase II

Estudios FASE II y III ERIBULINA CMM

1Vahdat LT, et al. J Clin Oncol. 2009;27:2954-2961. 2 Cortes J, et al. J Clin Oncol. 2010:28(25):3922-8. 3Twelves C, et al. J Clin Oncol. 2010;28:18s, 2010 (suppl; abstr CRA1004^).

4www.clinicaltrials.gov. NCT00337103; Accessed 28 August 2010.

Study 211: Single-arm

Primary endpoint ORR2

Study 305: Eribulin vs TPC

Primary endpoint OS3

TPC, Treatment of Physician’s Choice.

Study 301: Eribulin vs Capecitabine

Primary endpoint OS/PFS4

Study 201 (proof of concept) Single-arm

Primary endpoint ORR1

Late-stage Second-line

Ph

ase

III

Tria

ls

Ph

ase

II T

rial

s

http://www.google.es/url?sa=i&rct=j&q=revista+lancet&source=images&cd=&cad=rja&docid=vstgcB3VExrRdM&tbnid=H2Hx3_JaAWMchM:&ved=0CAUQjRw&url=http://www.elmundo.es/elmundosalud/2006/08/04/hepatitissida/1154676809.html&ei=MPcjUf62J8Gn0AXA0YFA&bvm=bv.42553238,d.d2k&psig=AFQjCNHQBUg94q1l8xpJC4iQXKC3nOv9Ag&ust=1361397852993095

DISEÑO DEL ESTUDIO

• Locally recurrent or MBC

• 2-5 prior chemotherapies

• Progression ≤6 months of last chemotherapy

• Neuropathy ≤grade 2

• ECOG ≤2

Eribulin mesylate

1.4 mg/m2, 2-5 min IV Day 1, 8 q21 days

Treatment of Physician’s Choice (TPC)

Any monotherapy (chemotherapy, hormonal, biological)* or supportive

care only†

Randomization 2:1

• PFS

• ORR

• Safety

• Overall survival

Primary endpoint

Secondary endpoints

Stratification:

– Geographical region, prior capecitabine, HER2/neu status

Global, randomized, open-label Phase III trial (Study 305)

Patients (N=762)

− ≥2 for advanced disease

− Prior anthracycline and taxane

* Approved for treatment of cancer

†Or palliative treatment or radiotherapy administered according to local practice, if applicable

ECOG, Eastern Cooperative Oncology Group; IV, intravenous; PFS, progression-free survival;

HER2/neu, human epidermal growth factor receptor 2

PATIENTS IN THE TPC GROUP

96% of patients in the TPC group received chemotherapy No patient received best supportive care or biological therapies

*Taxanes: paclitaxel, docetaxel, abraxane (ixabepilone) † Anthracyclines: doxorubicin, liposomal doxorubicin, mitoxantrone

TPC = treatment of physician’s choice Cortes J, O’Shaughnessy J et al. Lancet. 2011;377:914–923

Total patients N=247

Study 305 EMBRACE Prior Chemotherapies

Eribulin, %

n=508

TPC, %

n=254

Total, %

N=762

Number of prior chemotherapy

regimens INCLUDING NEO &

ADJUVANT

1 0.2 0 0.1

2 13 12 13

3 35 33 34

4 (median) 33 31 32

5 17 20 18

>6 3 4 3

TPC, treatment of physician’s choice.

*intent-to-treat population.

The “correct” position for Eribulin

TRATAMIENTO ERIBULINA

TERCERA LÍNEA: 43%

CUARTA LÍNEA : 32%

UPDATED OS ANALYSIS : 75% PATIENTS

Analysis occurred at 589 events (deaths), representing 77% of the ITT population *Nominal P value from stratified log-rank test

CI = confidence interval; HR = hazard ratio; ITT = intent-to-treat; OS = overall survival; TPC = treatment of physician’s choice Cortes J, O’Shaughnessy J et al. Lancet. 2011;377:914–923; Twelves C, Loesch D et al. San Antonio Breast Cancer Symposium. 2010;Poster P6-14-18

Median OS, months

Eribulin (n=508) 13.2

TPC (n=254) 10.5

HR 0.81

95% CI 0.67, 0.96

P value* 0.014

A Phase III, Open-label, Randomized, Multicenter Study Of Eribulin Mesylate Versus

Capecitabine In Patients With Locally Advanced Or Metastatic Breast Cancer

Previously Treated With Anthracyclines And Taxanes

Peter A. Kaufman,1 Ahmad Awada,2 Christopher Twelves,3 Louise Yelle,4 Edith A. Perez,5 Jantien Wanders,6

Martin S. Olivo,7 Yi He,7 Corina E. Dutcus,7 Javier Cortes8

2012

Capecitabina

1250 mg/m2 c/12

hs

Days 1-14, q21

days

2º Fase III. ESTUDIO 301

29

29 29

Pacientes

(planeados N=1100)

● Localmente

avanzada o CMM

● ≤3 QT previas

(≤2 si enfermedad

avanzada)

● Antraciclina o

taxano previo en

neoady o en

enfermedad

avanzada/metastási

ca

Eribulina

1.23 mg/m2,* 2-5 min IV

Dia 1 & 8 c 21 dias Randomización 1:1

Stratification

● Región

Geográfica

● HER2

Objetivos primarios

● OS and PFS Objetivos secundarios ● Calidad de vida ● ORR ● Duración de

respuesta ● Supervivencia al 1,2

y 3 años ● T ● Safety parameters ● Population PK

(eribulin arm only)

*Equivalent to 1.4 mg/m2 eribulin mesilate. BID=twice daily; HER2=human epidermal growth factor receptor type 2; IV=intravenous; MBC=metastatic breast cancer.

ESTUDIO DE SUPERIORIDAD

Capecitabina

1250 mg/m2 c/12

hs

Days 1-14, q21

days

2º Fase III. ESTUDIO 301

30

30 30

Pacientes

(planeados N=1100)

● Localmente

avanzada o CMM

● ≤3 QT previas

(≤2 si enfermedad

avanzada)

● Antraciclina o

taxano previo en

neoady o en

enfermedad

avanzada/metastási

ca

Eribulina

1.23 mg/m2,* 2-5 min IV

Dia 1 & 8 c 21 dias Randomización 1:1

Stratification

● Región

Geográfica

● HER2

Objetivos primarios

● OS and PFS Objetivos secundarios ● Calidad de vida ● ORR ● Duración de

respuesta ● Supervivencia al 1,2

y 3 años ● T ● Safety parameters ● Population PK

(eribulin arm only)

*Equivalent to 1.4 mg/m2 eribulin mesilate. BID=twice daily; HER2=human epidermal growth factor receptor type 2; IV=intravenous; MBC=metastatic breast cancer.

ESTUDIO DE SUPERIORIDAD

STATISTICAL PLAN: ANALYSIS OF

CO-PRIMARY ENDPOINTS

• Primary pre-defined analyses in the ITT population

• Two-sided, stratified log-rank test stratified for HER2 and geographic region; HR based on Cox regression model

• 1,100 patients planned enrolment. OS determination, 905 events (final analysis, 82% events) sufficient for 90% probability if the HR <= 0.8 (Type I error = 0.04)

• Two planned interim analyses of OS: 453 and 603 deaths

• Final analysis would be declared positive if either

• OS with eribulin is significantly better vs capecitabine (p≤0.0372)

• PFS (independent review) with eribulin is significantly better vs capecitabine (p≤0.01) and HR for OS (eribulin/capecitabine) is <1

San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 4-8, 2012

This presentation is the intellectual property of the author.

Eribulin (N=554)

Capecitabine (N=548)

n (%) n (%)

HER2/neu status + 86 (15.5) 83 (15.1)

– 375 (67.7) 380 (69.3)

Not Done 93 (16.8) 85 (15.5)

Estrogen receptor

(ER) status

+ 259 (46.8) 278 (50.7)

– 233 (42.1) 216 (39.4)

Not Done 62 (11.2) 54 (9.9)

Progesterone receptor (PR)

status

+ 227 (41.0) 234 (42.7)

– 262 (47.3) 248 (45.3)

Not Done 65 (11.7) 66 (12.0)

Triple negative 150 (27.1) 134 (24.5)

Patient Tumor Characteristics at

Study Entry: Receptor Status

ITT Population. Both HER2/neu and hormone receptor status were obtained from the local clinical records and not confirmed centrally.

Study 301: Overall Survival

*Stratified log-rank test based on Geographical regions Her2 status by the Clinical Database.

Trt 1 554 512 450 381 332 264 217 184 150 122 87 49 36 25 15 10 5 2 Trt 2 548 484 413 353 288 236 194 165 132 111 72 41 29 21 13 10 2 1

0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Time (days)

No. of subjects at risk:

Median OS (months)

Eribulin (N=554) 15.9

Capecitabine (N=548) 14.5

HR 0.879

95% CI 0.770, 1.003

p-value* 0.0560

ITT Population

Su

rviv

al D

istr

ibu

tio

n F

un

cti

on

CI = confidence interval; IVRS=interactive voice response system.

Study 301: Progression Free Survival

Independent Review

Trt 1 554 356 229 133 88 61 44 29 26 23 17 16 12 12 8 8 8 6 5 1 1 1 0 Trt 2 548 329 220 121 89 66 47 33 28 21 19 15 14 9 8 5 3 2 2 2 1 0 0

0 2 4 6 8 10 12 16 18 20 22 24 26 28 30

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.0

PF

S D

istr

ibu

tio

n F

un

cti

on

Time (months)

0.1

No. of subjects at risk:

Stratified log-rank test: P=0.3045

ITT population – Independent Review

CI = confidence interval; HR = hazard ratio.

Median PFS (months)

Eribulin (N=554) 4.1

Capecitabine (N=548) 4.2

HR 1.079

95% CI 0.932, 1.250

P value* 0.3045

14 32 36 34 38 40 42 44

Events/N Median (months)

Subgroup Eribulin Cape HR (95% CI) Eribulin Cape

Overall 446/554 459/548 0.879

(0.770, 1.003) 15.9 14.5

HER2 status

Positive 73/86 73/83 0.965

(0.688, 1.355) 14.3 17.1

Negative 296/375 316/380 0.838

(0.715, 0.983) 15.9 13.5

Unknown 77/93 70/85 0.988

(0.710, 1.375) 18.7 17.2

Study 301: Overall Survival by HER2 Status

36

0.2 0.5 1 2 5

ITT Population.

19/83 (23%) of HER2+ capecitabine patients did not receive anti-HER2 therapy prior to study, but did receive it afterwards.

The corresponding figure for eribulin is 7/86 (8%).

Events/N Median (months)

Subgroup Eribulin Cape HR (95% CI) Eribulin Cape

Overall 446/554 459/548 0.879 (0.770, 1.003) 15.9 14.5

ER Status

Positive 198/259 219/278 0.897 (0.737, 1.093) 18.2 16.8

Negative 196/233 199/216 0.779 (0.635, 0.955) 14.4 10.5

Not Done 52/62 41/54 1.135 (0.738, 1.747) 17.6 20.4

PR Status

Positive 173/227 185/234 0.850 (0.684, 1.055) 18.1 16.2

Negative 219/262 223/248 0.849 (0.701, 1.029) 14.5 12.0

Not Done 54/65 51/66 1.111 (0.738, 1.670) 17.9 19.1

Triple-negative patients

Yes 124/150 121/134 0.702 (0.545, 0.906) 14.4 9.4

No 322/404 338/414 0.927 (0.795, 1.081) 17.5 16.6

Overall Survival by Receptor Status

ITT Population.

0.2 0.5 1.0 2 5

¿En que línea de QT debemos optimizar la eribulina?

1. Segunda línea.

2. Tercera línea.

3. Cuarta línea.

4. Quinta línea.

El Oncólogo.…

http://www.grupogallegocancerdepulmon.org/pdf/seor-2013-programa.pdf

EVENTOS ADVERSOS HEMATOLÓGICOS

• Febrile neutropenia occurred with eribulin (5%) and TPC (2%)

• Neutropenia was managed with dose delays, dose reductions and G-CSF

• Administration of prophylactic G-CSF was not permitted in the study

• <1% of eribulin patients discontinued treatment due to haematological AEs

•

eve

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

All

Grades Grade 3 Grade 4

All

Grades

Grade

3 Grade 4

Haematological, %

Neutropenia 52 21 24 30 14 7

Leucopenia 23 12 2 11 5 1

Anaemia 19 2 <1 23 3 <1

Cortes J, O’Shaughnessy J et al. Lancet. 2011;377:914–923

EVENTOS ADVERSOS NO HEMATOLOGICOS

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

All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4

Non-haematological, %

Asthenia/fatigue 54 8 1 40 10 0

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

Nausea 35 1 0 28 2 0

Peripheral neuropathy† 35 8 <1 16 2 0

Constipation 25 1 0 21 1 0

Arthralgia/myalgia 22 <1 0 12 1 0

Pyrexia 21 <1 0 13 <1 0

Weight decrease 21 1 0 14 <1 N/A

Cortes J, O’Shaughnessy J et al. Lancet. 2011;377:914–923

http://www.google.es/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&docid=TSLfNPDRjFTvkM&tbnid=h7MtAA1JVIHyeM:&ved=0CAYQjRw&url=http://cala.unex.es/cala/epistemowikia/index.php?title=Historia_econ%C3%B3mica_de_Espa%C3%B1a_en_la_Edad_Moderna&ei=u3UnU-78B4am0AXVhoDYCA&bvm=bv.62922401,d.d2k&psig=AFQjCNG9-j6-hBV5B9mHtCdUnJLGi5JmSg&ust=1395181301802236

SEPTIMA LÍNEA

ERIBULINA: COMO OPTIMIZAR UN FÁRMACO QUE PROLONGA LA VIDA DE LAS PACIENTES CON

CÁNCER DE MAMA METASTÁSICO.

TRATAMIENTO ERIBULINA:

EMBRACE

TERCERA LÍNEA: 43%

CUARTA LÍNEA : 32%

SURVIVAL BENEFIT WITH ERIBULIN VS TPC

≤3 chemotherapy

regimens previously

received

>3 chemotherapy

regimens previously

received

OS, months (95% CI)

Eribulin-treated patients

13.3

(12.0, 14.9)

n=362

11.7

(9.3, 12.5)

n=106

TPC-treated patients

10.7

(9.3, 12.5])

n=162

10.0

(6.3, 18.0])

n=51

Median survival difference, months 2.6 1.7

P value 0.039 0.607

Hazard ratio (95% CI) 0.774

(0.606, 0.988)

0.899

(0.600, 1.348)

CI = confidence interval; OS = overall survival; TPC = treatment of physician’s choice Blum J, Twelves C et al. San Antonio Breast Cancer Symposium. 2010;Poster P6-13-01

301: Prior Breast Cancer Treatments

59

Eribulin (N=554)

Capecitabine (N=548)

n (%) n (%)

Number of prior

chemotherapy

regimens for

advanced disease

0 116 (20.9) 104 (19.0)

1 280 (50.5) 293 (53.5)

2 154 (27.8) 146 (26.6)

>2 4 (0.7) 5 (0.9)

Number of subjects refractory to:

Taxane 250 (45.1) 260 (47.4)

Anthracycline 134 (24.2) 139 (25.4)

Taxane and anthracycline

91 (16.4) 103 (18.8)

ITT Population

Refractory is defined as progressed within 60 days after taking the last dose.

Study 301: Overall Survival

*Stratified log-rank test based on Geographical regions Her2 status by the Clinical Database.

Trt 1 554 512 450 381 332 264 217 184 150 122 87 49 36 25 15 10 5 2 Trt 2 548 484 413 353 288 236 194 165 132 111 72 41 29 21 13 10 2 1

0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Time (days)

No. of subjects at risk:

Median OS (months)

Eribulin (N=554) 15.9

Capecitabine (N=548) 14.5

HR 0.879

95% CI 0.770, 1.003

p-value* 0.0560

ITT Population

Su

rviv

al D

istr

ibu

tio

n F

un

cti

on

CI = confidence interval; IVRS=interactive voice response system.

¿Qué fármacos debemos utilizar

previamente?

1. Antraciclinas y taxanos.

2. Capecitabina.

3. Vinorelbina.

4. Todos.

Events/N Median (months)

Subgroup Eribulin Cape HR (95% CI) Eribulin Cape

Overall 446/554 459/548 0.879

(0.770, 1.003) 15.9 14.5

HER2 status

Positive 73/86 73/83 0.965

(0.688, 1.355) 14.3 17.1

Negative 296/375 316/380 0.838

(0.715, 0.983) 15.9 13.5

Unknown 77/93 70/85 0.988

(0.710, 1.375) 18.7 17.2

Study 301: Overall Survival by HER2 Status

65

0.2 0.5 1 2 5

ITT Population.

19/83 (23%) of HER2+ capecitabine patients did not receive anti-HER2 therapy prior to study, but did receive it afterwards.

The corresponding figure for eribulin is 7/86 (8%).

Events/N Median (months)

Subgroup Eribulin Cape HR (95% CI) Eribulin Cape

Overall 446/554 459/548 0.879 (0.770, 1.003) 15.9 14.5

ER Status

Positive 198/259 219/278 0.897 (0.737, 1.093) 18.2 16.8

Negative 196/233 199/216 0.779 (0.635, 0.955) 14.4 10.5

Not Done 52/62 41/54 1.135 (0.738, 1.747) 17.6 20.4

PR Status

Positive 173/227 185/234 0.850 (0.684, 1.055) 18.1 16.2

Negative 219/262 223/248 0.849 (0.701, 1.029) 14.5 12.0

Not Done 54/65 51/66 1.111 (0.738, 1.670) 17.9 19.1

Triple-negative patients

Yes 124/150 121/134 0.702 (0.545, 0.906) 14.4 9.4

No 322/404 338/414 0.927 (0.795, 1.081) 17.5 16.6

Overall Survival by Receptor Status

ITT Population.

0.2 0.5 1.0 2 5

CONCLUSIONES I

• ERIBULINA: Fármaco en imprescindible en pacientes con CMM.

• Único que fármaco que ha demostrado aumento de SG en monoterapia, tras la progresión a una segunda línea.

• Indicación: Pacientes que hayan progresado a dos líneas de quimioterapia, que incluyan antraciclinas y taxanos, en algún momento.

CONCLUSIONES I

• ERIBULINA: Fármaco en imprescindible en pacientes con CMM.

• Único que fármaco que ha demostrado aumento de SG en monoterapia, tras la progresión a una segunda línea.

• Indicación: Pacientes que hayan progresado a dos líneas de quimioterapia, que incluyan antraciclinas y taxanos, en algún momento.

CONCLUSIONES I

• ERIBULINA: Fármaco en imprescindible en pacientes con CMM.

• Único que fármaco que ha demostrado aumento de SG en monoterapia, tras la progresión a una segunda línea.

• Indicación: Pacientes que hayan progresado a dos líneas de quimioterapia, que incluyan antraciclinas y taxanos, en algún momento.

CONCLUSIONES

• QT de elección en CMM TN y HER negativos.

• Manejo “eficaz” en dosis, intervalos y duración de tratamiento.

• Fármaco seguro , poco toxico y fácilmente manejable.

• Pendientes de datos de combinaciones con antiHER2, otros quimioterápicos y CMP: adyuvancia y neoadyuvancia.

CONCLUSIONES

• QT de elección en CMM TN y HER negativos.

• Manejo “eficaz” en dosis, intervalos y duración de tratamiento.

• Fármaco seguro , poco toxico y fácilmente manejable.

• Pendientes de datos de combinaciones con antiHER2, otros quimioterápicos y CMP: adyuvancia y neoadyuvancia.

CONCLUSIONES

• QT de elección en CMM TN y HER negativos.

• Manejo “eficaz” en dosis, intervalos y duración de tratamiento.

• Fármaco seguro , poco tóxico y fácilmente manejable.

• Pendientes de datos de combinaciones con antiHER2, otros quimioterápicos y CMP: adyuvancia y neoadyuvancia.

CONCLUSIONES

• QT de elección en CMM TN y HER negativos.

• Manejo “eficaz” en dosis, intervalos y duración de tratamiento.

• Fármaco seguro , poco toxico y fácilmente manejable.

• Pendientes de datos de combinaciones con antiHER2, otros quimioterápicos y CMP: adyuvancia y neoadyuvancia.

ASTORGA