ES2586328T3 - Factores predisponentes para el tratamiento del cáncer - Google Patents

Factores predisponentes para el tratamiento del cáncer Download PDF

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ES2586328T3
ES2586328T3 ES12754124.1T ES12754124T ES2586328T3 ES 2586328 T3 ES2586328 T3 ES 2586328T3 ES 12754124 T ES12754124 T ES 12754124T ES 2586328 T3 ES2586328 T3 ES 2586328T3
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rituximab
biomarkers
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cancer treatment
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Deborah Ricci
Weimin Li
Erin Devay HENITZ
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Janssen Pharmaceutica NV
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Abstract

Un método de predicción de la respuesta a un tratamiento del cáncer que comprende bortezomib y rituximab en un paciente con cáncer de linfoma no Hodgkin, que comprende: determinar el nivel o la cantidad de un primer factor predisponente en una muestra biológica de dicho paciente, en el que dicho primer factor predisponente es CD68 o el polimorfismo de PSMB1 (P11A); y determinar la presencia o cantidad de un segundo factor predisponente en dicho paciente; en el que CD68 bajo o la presencia del polimorfismo de PSMB1 (P11A) se correlaciona con al menos un resultado positivo, y la presencia, ausencia o cantidad de dicho segundo factor predisponente se correlaciona con al menos un resultado positivo.

Description

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Ciento dos pares de biomarcadores tuvieron una p<0,05 de rangos logarítmicos. De estos, 97 pares tenían una frecuencia de >1 % en la población. Catorce pares mostraron, además, una mejora de PFS de ≥6 meses. En este análisis, se hicieron 1.140 comparaciones por pares (las covariables se aparearon con cada marcador individual para complementar los análisis). Después de la corrección de FDR, 1 par fue significativo (FDR = 0,051). Este par de biomarcadores identificó el 33 % de la población evaluable de biomarcadores con una ventaja de 7,5 meses de PFS cuando se trataron con Vc-R en comparación con rituximab solo (Tabla 4) y una tendencia a una mejor OS (p = 0,055, HR: 0,426 [0,174,1,046], Este par se compone de PSMB1 P11A (heterocigoto C/G) y baja expresión de CD68 definido como 0-50 células teñidas positivamente. A continuación, este par se mencionará como el subgrupo de biomarcadores positivos. El subgrupo de biomarcadores negativos no tiene este par de biomarcadores y tiene un diferente genotipo de PSMB1 y nivel de expresión de CD68.
Tabla 4: Comparación de la PFS y la OS de la población de biomarcadores positivos con la población de biomarcadores negativos
Biomarcador positivo (N=118)
Biomarcador negaitivo (N=238) Total (N=356)
Vc-R
Rituximab Vc-R Rituximab Vc-R Rituximab
N
57 61 118 120 175 181
Mediana (meses
16.6 9.1 12.5 12.5 13.6 11.3
PFS
95% CI (0.26-0.639) (0.759-1.425) (0.621-1.032)
Valor-p
0.0001 0.8097 0.0855
HR
0.407 1.04 0.801
Vc-R
Rituximab Vc-R Rituximab Vc-R Rituximab
N
57 61 118 120 175 181
Mediana (meses
NA NA NA NA NA NA
OS
95% CI (0.174-1.046) (0.617-1.658) (0.527-1.239)
Valor-p
0.0550 0.9645 0.3270
HR
0.426 1.011 0.808
Biomarcador positivo = PSMB heterocigoto P11a y CD68 "baja" par biomarcador, biomarcador negativo = todos los sujetos sin este par, Vc-R = Bortezomib + Rituximab, PFS = supervivencia libre de progresión, OS = supervivencia global, IC = confianza intervalo, HR = cociente de riesgos instantáneos
De manera importante, el subgrupo de biomarcadores positivos (heterocigoto de PSMB1 P11A y baja expresión de CD68) tuvo, además, una velocidad de respuesta total significativamente mejor del 73,7 % para los tratados con Vc-R en comparación con el 47,5 % con R solo (p=0,0077), y un tiempo más largo hasta el siguiente tratamiento (p = 0,0013) y duración del intervalo sin tratamiento (p=0,0017).
Se observaron perfiles AE similares en las poblaciones de biomarcadores positivos y biomarcadores negativos. Se observó una exposición al tratamiento similar en las poblaciones de biomarcadores positivos y de biomarcadores negativos. Los sujetos tratados con rituximab en la población de biomarcadores positivos tuvieron una mediana de la dosis de 2941 mg/m2 en comparación con 2940 mg/m2 en la población de biomarcadores negativos. Los sujetos tratados con Vc-R en la población de biomarcadores positivos tuvieron una mediana de la dosis de 31,1 mg/m2 en comparación con 30 mg/m2 en la población de biomarcadores negativos. Además el número total de dosis, la duración de la exposición, la intensidad de la dosis, la intensidad relativa de dosis y el número máximo de ciclos recibidos mostraron diferencias muy similares.
Los sujetos tratados con bortezomib + rituximab mantuvieron PFS más larga cuando el biomarcador fue positivo y se estratificaron por cualquiera de la puntuación FLIPI, por la carga tumoral, por la puntuación de Ann Arbor, por la edad, por la región, por el sexo y por la raza. En los pacientes con mayor riesgo y mal pronóstico, por ejemplo, alta carga tumoral, medio o alto FLIPI, mayores de 65 años, o con tratamiento previo con rituximab, se observaron mejoras mayores de PFS en pacientes cuando el biomarcador es positivo en comparación a cuando el biomarcador es negativo. La PFS más larga se mantuvo independientemente del tiempo a partir del último tratamiento o el número de tratamientos previos por rituximab previo o el número de tratamientos con rituximab menores o iguales a
2.
Los sujetos tratados con bortezomib + rituximab mantuvieron una supervivencia global más larga cuando el biomarcador fue positivo y se estratificaron por la puntuación de FLIPI, por la carga tumoral, por la puntuación de Ann Arbor, por la edad, por la región, por el sexo y por la raza. Los sujetos tratados con Velcade + rituximab mantuvieron una PFS más larga cuando fueron positivos para CD68 bajo (0-50) y se estratificaron por cualquiera de la puntuación FLIPI, por la carga tumoral, por la puntuación de Ann Arbor, por la edad, por la región, por el sexo y
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Tabla 6. Pares marcadores significativos
Marcador A
Marcador B PFS Vc+R vs. R media meses N Vc+R vs. R Logrank Valor-p FDR
PSMB5/R24C C/T
P65 Intensidad de señal citoplasmica <=1+ 27 mo vs. 10.4 mo 16.6 mo mejora 5 vs. 7 0.0439 0.489
PSMB1/P11A C/G
20S % SEÑALCITOPLASMICA POSTIVA: >90 18.9 mo vs. 9.5 mo 9.4 mejora 50 vs50 0.0145 0.447
PSMB1/P11A C/G
CD68 Positivo folicular 0-50 16.6 mo vs. 9.1 mo 7.5 mejora 57 vs61 0.0001 0.051
PSMB1/P11A C/G
CD68 Positivo peri – folicular: >50 16.6 mo vs. 9.2 mo 7.4 Mo mejora 24 vs28 0.0365 0.471
PSMB9/R60H G/G
P65 % TINCIÓN NUCLEAR: >0 16.2 mo vs. 9.5 mo 6.7 mejora 35 vs28 0.0303 0.455
PSMB5/R24C C/T
CD68 Positivo folicular 0-50 13.7 mo vs. 7.2 mo 6.5 mo mejora 18 vs21 0.0220 0.447
HI Tumor BD NO
CD68 Positivo global 0-50 22.8 mo vs. 16 mo 6.8 mo mejora 64 vs68 0.0177 0.447
HI Tumor BD NO
CD68 Positivo folicular 0-50 20.5 mo vs. 13.8 mo 6.7 mo mejora 64 vs66 0.0310 0.455
Prior RX: 1
CD68 Positivo folicular 0-50 18.2 mo vs. 9.3 mo 8.9 mo mejora 63 vs69 0.0129 0.447
PSMB1/P11A C/G
Tiempo desde último Rx: > 1 año 18.2 mo vs. 10.7 mo 7.5 mo mejora 72 vs74 0.0198 0.447
Prior Ritutux NO
CD68 Positivo folicular 0-50 15.9 mo vs. 9.2 mo 6.7 mo mejora 73 vs88 0.0066 0.437
PSMB1/P11A C/G
Grupo edad <=65 15.3 mo vs. 9.2 mo 6.1 mo mejora 86 vs96 0.0071 0.437
Sexo Masculino
20S % TINCION NUCLEAR: >20 13.7 mo vs. 7.7 mo 6 mo mejora 63 vs48 0.0050 0.437
Grupo carrera OTRO
20S % TINCION NUCLEAR: >20 11.4 mo vs. 3.8 mo 7.6 mo mejora 11 vs 7 0.0320 0.455
PSMB1/P11A C/G
PSMB5/R24C C/T 13.7 mo vs. 7.8 mo 5.9 mo mejora 7 vs. 7 0.0221 0.4468
Tabla 7 Pares marcadores significativos
Combinación
PFS Vc-R vs. R media meses Logrank Valor-p
P65 Señal Citoplasmica >90% & 1
23.6 vs. 10.6 mo (13mo) 0.0132
tratamiento anterior*
16 vs. 8.9 mo (7.1mo) n.s.
CD68 Pos Folico (0-50) & P11A[C/G]**
14.2 vs 8.5 mo (5.7 mo) 0.0025
14.4 vs 9.2 mo (5.2 mo)
n.s.
10 Arif A (2009), Jamal S, Mushtaq S, Ahmed S, Mubarik A. Frequency of bcl-2 gene rearrangement in B-Cell NonHodgkin’s lymphoma. Asian Pacific J Cancer Prev 2009; 10(2): 237-240.
Binstadt BA (2003), Geha RS, Bonilla FA. IgG Fc receptor polymorphisms in human disease: Implications for intravenous immunoglobulin therapy. J Allergy Clin Immunol 2003; 111(4): 697-703.
15 Cartron G (2002), Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRllla gene. Blood 2002; 99(3): 754-758.
20 Chen P (1996), Hochstrasser M. Autocatalytic subunit processing couples active site formation in the 20S proteasome to completion of assembly. Cell 1996; 86: 961-972.
Chen S (2010), Blank JL, Peters T, Liu XJ, Rappoli DM, Pickard MD, Menon S, Driscoll DL, Lingaraj T, Burkhardt AL,
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Apéndice 2, Tabla 2.2: OS variante genética de la línea germinal nd por covariable, revisión IRC (significativa [p≤0,05], frecuencia de ≥10 % o superior)
Vc-R Marcador: Subgrupo N
Marcador: Nivel Subgrupo HR (Escala log) R Media
Media total
3Lineas prioritarias de la terapita
Puntuación intermedia FLIPI
Ann Arbor Etapa IV
5
Apéndice 2, Tabla 2.3: OS por mutación somática y por covariable, revisión IRC (significativa [p≤0,05], frecuencia de ≥10 % o superior)
10 Marcador: Nivel Subgrupo HR ( Escala log) R Media Vc-R Media
2Lineas prioritarias de la terapia
No carga alta de tumor
15
Carga alta de tumor
Puntuacion FLIPI alta
Terapia no prior 20 Rituximab
Resto del Mundo
>65 Años de edad
25
Femenino
Masculino
30 Masculino
Masculino
Ann Arbor Etapa IV
35
40
45
50
20
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Claims (1)

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ES12754124.1T 2011-08-11 2012-08-08 Factores predisponentes para el tratamiento del cáncer Active ES2586328T3 (es)

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