Post on 22-Oct-2018
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.
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
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.…
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
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