Diapositiva 1

RECEPTOR DE FOLATO Y SU APLICACION EN LA
TERAPEUTICA DEL CANCER
CANCER DE OVARIO
La Expresión del Receptor de Folato
como Criterio para la Selección de Pacientes
Josep Mª del Campo
Unidad de Oncología Ginecológica
y Tumores de Cabeza y Cuello
Departamento de Oncología Médica
Hospital Universitari Vall d’Hebron. Barcelona
1
Cáncer Avanzado de Ovario
• El cáncer de ovario es la primera causa de muerte entre las
neoplasia ginecológicas.
• El 75% se diagnostican en fases avanzadas.
• Aunque el 80% de estas pacientes reponden al tratamiento
inicial, la mayor parte recidivan.
• A lo largo del tiempo la supervivencia ha aumentado
ligeramente:
– Cirugía más agresiva
– Nuevos fármacos
• A pesar de ello, la supervivencia a 5 años es solo del 30%.
2
4th Ovarian Cancer Consensus Conference
June 25 – 27, 2010
UBC Life Sciences Institute, Vancouver, BC
B-2 What are the promising targets for future
therapeutic approaches?
Caelyx
A good partner for Clinical Trials
• The most promising targets in clinical trials are
 Angiogenesis
 Homologous recombination deficiency.
 Folate Receptor
 PI3K/mTOR
Stuart, et al. Int J Gynecol Cancer 2011;21:750–5
3
Receptor Folato y Cáncer
•
•
•
•
•
•
•
Papel del Receptor de Folato
Diana potencial en Cáncer
Expresión en Cáncer de Ovario
Diana en Cáncer de Ovario
Uso como Marcador predictivo de eficacia
Aplicación clínica
Selección de pacientes
4
Papel de los Folatos y sus Receptores
• Las células tumorales dependen del metabolismo de los
folatos: Replicación del DNA.
• Uso de antifolatos en cáncer:
– Inhibidores de la Timidilato Sintetasa
• Metotrexate , 5-FU, Raltitrexed, Pemetrexed
• Los folatos utilizan dos vias:
– RFC: via regular
– FR (α,β,): pobremente expresados en cel. normales
• Las células tumorales pueden desarrollar sobreexpresión RF.
– FRα: sobreexpresado en diversos tipos de cáncer
• C. Epiteliales 80%
• Relacionado con Estadío.
5
1. Muller. Current Pharmaceutical Design, 2012, 18(8):1058-1082
Mecanismo de acción del RF
6
Receptor Folato α y Expresión
7
1. Low. Current Opin Chem Biol. 2009; 13:256-262
RFα: Expresión en C. Ovario
8
RFα: Expresión en C. Ovario
Est III: 93%
9
RFα en C. Ovario:
Estadío, Tipo H. Y Grado
10
Bloqueo de RFα en líneas celulares
SKOV·3
Siu MK et al. Paradoxical impact of two folate receptors, FRa and RFC, in ovarian cancer:
11
effect on proliferation, invasion and clinical outcome. PLoS One 2012; 7(11): 47201
RFα como diana en CAO
• Anticuerpos monoclonales
– Alta especificidad
– Bajos autoanticuerpos
– Farletuzumab
• Conjugados
– Folato-Fármaco activo: Vintafolide
– Folato-Compuestos para imagen: Etarfolatide
• Células T
– Marcar las cel. Diana para ser reconocidas por cel, T (CAR-T cells)
• Nanotecnología
– Liposomas, etc.
• Virus oncolíticos
12
Receptor Folato y Cáncer
•
•
•
•
•
•
•
Papel del Receptor de Folato
Diana potencial en Cáncer
Expresión en Cáncer de Ovario
Diana específica en Cáncer de Ovario
Uso como Marcador predictivo de eficacia: Imagen
Aplicación clínica
Selección de pacientes
13
Técnicas de imagen mediadas por receptor
Etarfolatide
• Características necesarias
–
–
–
–
–
Alta afinidad por el receptor
Alta selectividad: Sobreexpresado en cel. tumorales
Aclaramiento rápido en tejidos no diana: t1/2= 25 minutos
Biocompatible
Estable
• Utilidad en diagnóstico y cirugía
1. Sega Cancer and Metastasis Reviews 2008 27 (4) 655-664
14
2. Muller. Current Pharmaceutical Design, 2012, 18(8):1058-1082
Etarfolatide: Características
CO2H
H2N
N
HN
O
N
N
H
N
O
O
H
N
O
O
H
N
N O
N
CO2H
Tc
NH2
S
CO2H
•Folate-targeted molecular imaging agent
•Companion diagnostic to vintafolide
•Minimally invasive technique to identify lesions that express folate
receptors
•Injected into subjects chelated with technetium 99m
•Detected by SPECT imaging (single-photon emission computerized
tomography)
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1. Fisher. J Nucl Med 2008;49:899-906
Tissue Distribution of Etarfolatide and Vintafolide in
M109 Tumor-bearing Mice
1. Leamon. Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; AACR 2012. Abstract nr163622.
Etarfolatide distribution
Marrow
Liver
Kidney
Marro
w
Spleen
Bladder
FR positive lesions
Planar 99mTc-etarfolitide scan
Anterior
Posterior
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Inguinal lymph node (1.5 cm- short axis)
18
19
20
FR-negative Lesion
21
Pre-injections of Folic Acid Improves Image Quality
Ovarian Cancer
Patient 1
Ovarian Cancer
Patient 1
Target
Lesion
No FA pre-injection
0.5 mg IV FA pre-injection
22
Receptor Folato y Cáncer
•
•
•
•
•
•
•
Papel del Receptor de Folato
Diana potencial en Cáncer
Expresión en Cáncer de Ovario
Diana en Cáncer de Ovario
Uso como Marcador predictivo de eficacia: Imagen
Aplicación clínica de los conjugados
Selección de pacientes
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Aplicación clínica: Conjugados
Vintafolide (MK-8109, EC-145)
24
Vintafolide
• A small drug conjugate of folate coupled chemically to
desacetylvinblastine hydrazide (DAVLBH) that specifically
targets the folate receptor (FR).
Vlahov, Bioconjugate Chem. 2012; 23(7)1357-1369
25
Leamon. Int J Cancer 2007; 121:1585-1592
Vintafolide and PLD in M109 Tumor model1
Gross Toxicity
M109 Tumor Growth
25
1400
Control
15
1000
Vintafolide
(3/5 cures)
800
PLD
(3/5 cures)
600
400
Vintafolide and PLD
(5/5 cures)
200
%Weight Loss
Tumor Size (mm3)
1200
5
-5
-15
Vintafolide:
2 µmol/kg TIW, x 2
®
PLD (Doxil ): 4 mg/kg/wk x 2
-25
0
5
15
25
35
45
55
65
75
Days Post Tumor Implant
85
95
5 drugs
15
25
35
45
55
65
Other
Docetaxel
Days Post Tumor Implantation
Carboplatin
Cisplatin
Topotecan
75
1. Reddy: Proceedings of the 102nd Annual Meeting of the American Association
for
26
Cancer Research; AACR; 2011. Abstract nr 2570.
Correlación entre Etarfolatide y Vintafolide:
Datos preclínicos
Species
Tumor
cell line
Tissue
FR Protein
Expression
(functional)
Human
A549
Lung
Negligible
1.6%
Unresponsive
SKOV3
Ovarian
Negligible
1.6%
Unresponsive
Ov90
Ovarian
Low Positive
4.7%
Durable PR, CR
KB/HeLa
Cervical*
High Positive
10.7%
Curative
4T1
Breast
Negligible
2.5%
Unresponsive
M109
Lung
High Positive
15.5%
Curative
Mouse
Etarfolatide uptake
% injected dose in
tissue , n ≥3
Response to Vintafolide
*nasopharyngeal/cervical. Negligible <2.5 pmol/mg membrane protein, low positive ≥2.5 to < 6
pmol/mg, high positive ≥ 6 pmol/mg; PR = partial response, CR = Complete response
1. Leamon. Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research;
27
AACR 2012. Abstract nr 3622
Phase I Study of Folate Conjugate Vintafolide in
Patients with Refractory Solid Tumors
• MTD = 2.5 mg days 1, 3, and 5 and days 15, 17, and 19 of each
28-day cycle.
• One patient with metastatic ovarian cancer maintained a
REICST-defined partial response (PR) for a period of 111 days.
• Another patient with metastatic ovarian cancer maintained SD
for 172 days during treatment with vintafolide.
• The most commonly reported adverse events were
constipation, nausea, fatigue, and vomiting. Constipation was
the dose-limiting toxicity.
• On the basis of these findings, Phase II studies with vintafolide
were initiated in patients with advanced epithelial ovarian
cancer and non-small cell cancer.
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Vintafolide in Subjects with Advanced Ovarian
and Endometrial Cancers: a Phase II study. Protocol
EC-FV-02
Inclusion criteria
• Folate receptor (FR) positive platinum resistant or platinum refractory
epithelial ovarian, fallopian tube, or primary peritoneal carcinoma
• Measurable disease with ≥ 1 target lesion by RECIST 1.0
• ≥ 4 prior chemotherapy regimen
• ECOG performance status 0-2
Exclusion criteria
• Pregnancy or lactating
• Symptomatic central nervous system metastasis
• Prior therapy with vinorelbine or other vinca-containing compounds
29
30
Baseline Patient Demographics
Population
Age, years, mean ± SD (range)
Race, n
White/all others
ECOG Performance Status, n
0/1/2
Histologic Classification, n (%)
Papillary Serous
Serous
Endometrioid
Other
Cancer Type, n
Ovarian/Peritoneal/Endometrial
•
•
•
•
Vintafolide
(N=49)
61.2 ± 8.94 (43-75)
45/3
17/28/4
21 (42.9)
7 (14.3)
5 10.2)
15 (30.6)
The majority of women had Stage IIIC disease (n=29, 59.2%)
The majority of patients had a histologic grade of 2 or 3 (n=37)
34% of women had 3 or fewer previous therapies
Months Since Diagnosis (Mean ± SD) 51.68 ±27.00
37/7/5
31
Progression-Free Survival
Probability of Progression – Free Survival
1.0
Vintafolide ITT
(n=43)
Vintafolide ITT≤3
(n=15)
0.9
Progression, n
31
11
0.8
Censored, n
12
4
Median PFS
7.4
15.6
0.7
0.6
0.5
0.4
0.3
Vintafolide ITT
Vintafolide ITT≤3
0.2
0.1
0.0
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
Weeks From First Administration of Vintafolide
32
Vintafolide ITT ≤ 3 analysis set = patients in the trial who received three or fewer previous chemotherapy regimen
FR status
EC20 status was determined from Etarfolatide imaging:
– EC20 (100%)
• all target lesions EC20 positive (subject score, 100%).
– EC20 (10-90%)
• at least one EC20-positive lesion but not all target lesions EC20
positive (subject score, 1%-9%).
– EC20(0%)
• no EC20-positive target lesions with at least one evaluable target
lesion (subject score, 0%)
– EC20 (?)
• no evaluable target lesions (subject score, nonevaluable).
33
Results: Patients with ≤3 prior therapies
FR 100%
(N=7)
n (%)
FR 10-90%
(N=6)
n (%)
FR 0%
(N=1)
n (%)
FR NE
(N=1)
n (%)
Clinical Benefit
1 (14.3)
1 (16.7)
0 (0.0)
0 (0.0)
Response
Complete Response (CR)
Partial Response (PR)
Stable Disease (SD)
Progressive Disease (PD)
0 (0)
1 (14.3)
5 (71.4)
1 (14.3)
0 (0)
1 (16.7)
2 (33.3)
3 (50)
0 (0)
0 (0)
0 (0)
1 (100)
0 (0)
0 (0)
0 (0)
1 (100)
Overall Response (CR+PR)
1 (7.1)
1 (16.6)
0 (0)
0 (0)
Disease Control Rate
(CR+PR+SD)
6 (85.7)
3 (50)
0 (0)
0 (0)
34
PRECEDENT
35
Key Inclusion/Exclusion Criteria
Inclusion
• Pathology-confirmed platinum-resistant ovarian cancer
• ≥ 1 RECIST-defined measurable lesion (RECIST 1.0—up to 10 lesions)
• Prior platinum-based chemotherapy but ≤ 2 prior systemic cytotoxic
regimens (allowed 1 prior line of non-cytotoxic therapy)
• ECOG performance status of 0 to 2 with adequate organ function
Exclusion
• Borderline tumors
• Prior exposure to PLD, folate receptor-targeted therapy, mouse
antibodies, vinorelbine or other vinca-containing compounds
• Prior abdominal or pelvic radiation therapy, radiation therapy to >10%
of the bone marrow, or radiation therapy within the past 3 years to
the breast/sternum, dermal lesions, head or neck
• Other concurrent chemotherapy, immunotherapy, radiotherapy, or
any other investigational therapy.
• Symptomatic central nervous system metastasis
36
Flow Chart of Etarfolatide Imaging Procedure
37
Etarfolatide: Subgroup assignment for PRECEDENT
Subgroup
FR(100%)
FR
expression
% PRECEDENT
Population
All target
lesions
40.4%
At least one target lesion 78.7%
FR (10-90%)
FR(-)
At least one,
but not all
target lesions
38.3%
No target
lesions
21.3%
38
Primary Endpoint: Progression Free Survival (PFS)
39
Response Rates
Best Response
Complete Response (CR)
Partial Response (PR)
Stable Disease (SD)
Progressive Disease (PD)
Not Evaluable
ORR (CR + PR)
DCR (CR + PR + SD)
Vintafolide + PLD
(N=100)
n (%)
1 (1.0)
17 (17.0)
55 (55.0)
23 (23.0)
4 (4.0)
18 (18.0)
73 (73.0)*
PLD Alone
(N=49)
n (%)
1 ( 2.0)
5 (10.2)
20 (40.8)
15 (30.6)
8 (16.3)
6 (12.2)
26 (53.1)
*p=0.018
40
Stratification
41
Progression-Free Survival: Subgroup Analysis
Vintafolide +
PLD
PLD Alone
HR
p-value
n
PFS
(mos)
n
PFS
(mos)
(95% CI)
Logrank
ITT
100
5.0
49
2.7
0.626
(0.409, 0.959)
0.031
FR (10 -100%)
48
5.7
26
1.7
0.547
(0.304, 0.983)
0.041
FR (100%)
23
5.5
15
1.5
0.381
(0.172, 0.845)
0.013
FR (10-90)
25
5.7
11
7.0
0.873
(0.334, 2.277)
0.791
13
3.8
7
5.4
1.806
(0.369, 8.833)
0.468
Population
FR (0%)
42
Progression-Free Survival
Subgroup Analyses – FR(100%)
Variable
Median PFS (wk)
Hazard Ratio
p-value (2-sided Test)
Vintafolide +
PLD Alone
PLD
24.0
6.6
0.387
0.013
43
Progression-Free Survival
Subgroup Analyses FR (0%)
Variable
Median PFS (wk)
Hazard Ratio
p-value (2-sided Test)
Vintafolide
+ PLD
PLD
Alone
16.6
23.3
1.806
0.468
44
Drug-Related Adverse Reaction Occurring in
≥10% of Patients in Either Treatment
45
Treatment-Emergent Drug-Related AEs
Etarfolatide
Adverse Reaction
N=115
n (%)
At Least 1 Treatment-Emergent Drug-Related AE
Gastrointestinal disorders
Vomiting
General disorders and administration site conditions
Edema peripheral
Skin and subcutaneous tissue disorders
Dry skin
Pruritus
Skin exfoliation
4 (3.5)
1 (0.9)
1 (0.9)
1 (0.9)
1 (0.9)
2 (1.7)
1 (0.9)
1 (0.9)
1 (0.9)
46
Conclusions
• Platinum resistant ovarian cancer (PROC) is an orphan indication with high
unmet medical need.
• The results of PRECEDENT demonstrate statistically significant and clinically
meaningful improvement in progression-free survival (PFS) for patients with
PROC, with the greatest efficacy in patients where all target lesions where FR
positive (FR 100%)
• Overall, the safety data suggest that, with appropriate monitoring, vintafolide +
PLD is well tolerated by subjects regardless of their FR status
• Vintafolide + PLD demonstrated an overall positive risk-benefit assessment
• Improved risk-benefit profile for the FR(100%) subject population
• FR(0%) subjects should not be treated with the combination regimen
• These results support the use of etarfolatide to identify PROC patients with FR
positive disease.
47
PROCEED: Phase 3 Study EC-FV-06:
PLD +/- Vintafolide in PROC Patients
N= 640 patients
Platinum resistant ovarian cancer
patients (failed first or second
platinum therapy < 6 months)
Vintafolide + PLD
Receptor Scan
2:1
Vintafolide= 2.5mg TIW wks 1, 3
PLD=50 mg/m2 (IBW) every 28 days
PLD + placebo
50 mg/m2 (IBW) every 28 days
Randomized, double-blind, placebo controlled trial (n=640)
– Initiate April/May 2011, last patient enrolled 4Q2013
All patients will undergo SPECT imaging following administration of
etarfolatide
Primary endpoint: PFS
Co-primary analysis
– Etarfolatide (100%/10-90%)
– Etarfolatide (100%)
– Secondary endpoints: OS (no cross-over), ORR, Duration of Response,
Quality of Life Assessment
48
Conclusiones
• El C. de Ovario en recaida platino-resistente no tiene un
tratamiento definido
• El beneficio de nuevas estrategias terapéuticas es limitado.
• La vía de folatos y sus receptores abren nuevas opciones en
estas pacientes, tanto a nivel diagnóstico como terapéutico.
• Etarfolatide, surge como “marcador biológico” con valor
predictivo de eficacia del tratamiento.
• Vintafolide, ha demostrado incremento de PFS en esta
población resistente (PRECEDENT).
• El estudio PROCEED debe confirmar estos resultados.
49