inmunoterapia del melanoma maligno: rompiendo...
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Inmunoterapia del Melanoma Maligno: Rompiendo Barreras
Alfonso Berrocal
Servicio Oncología Medica
Hospital General de Valencia
McArthur GA, Ribas A. J Clin Oncol 2013
Avances por mejor conocimiento de la biología
Teoría de las tres señales
2003
Mecanismos de escape tumoral
Tumour cells
CD8+ T cell
A. Presentación ineficaz de
antígenos al Sistema
inmune
Treg MDSC
Adaptado de: Vesely MD, et al. Ann Rev Immunol 2011;29:235–271
B. Atracción células
inmunosupresoras
(Tregs, MDSCs, otras)
CD8+ T cell
CD4+ T cell
TGF-β
IL-10
TGF-β
ARG1
iNOS
C. Secreción factores
inmunosupresores
VEGF APC
TGF-β
IDO
IL-10
D. Alteración
Checkpoints
PD-1
P-DL1 PD-1
PD-L1
CTLA-4 TCR
MHC
Respuesta del huésped al tumor
Pacientes en Riesgo
Ipilimumab 4846 1786 612 392 200 170 120 26 15 5 0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 12 24 36 48 60 72 84 96 108 120
Ipilimumab
CENSURADO
¿De donde partimos?
Mediana de supervivencia meses (95% CI): 9.5 (9.0–10.0)
Tasa SG a 3 años, % (95% CI): 21 (20–22)
Pro
po
rció
n v
ivo
s
Meses
Schadendorf D, et al. Eur J Cancer 2013;49(suppl 2): abstract 24LBA
CTLA4: Respuesta inicial al antígeno
Ipilimumab y T-regs
Necesidades no cubiertas en Melanoma
• Baja tasa de respuestas • Latencia de acción • Duración de la respuesta • Porcentaje de largos
supervivientes
• Tratamiento de segunda línea
CheckMate 066 KeyNote 006
CheckMate 037 KeyNote 002
PD1/PDL1: Regulación de linfocitos T efectores
PD-1 “también” es terapia dirigida
Primera línea
CheckMate 066: Diseño del estudio
1. Robert C, Long GV, Brady B, et al. N Engl J Med 2015;372(4):320-30.
Estudio de fase III, aleatorizado, doble ciego
La TRO resultó casi 3 veces mayor con OPDIVO
que con dacarbacina1
1. Robert C, Long GV, Brady B, et al. N Engl J Med 2015;372(4):320-30.
2. Atkinson V, Ascierto PA, Long GV, et al. Two-Year Survival and Safety Update in Patients With Treatment-Naïve Advanced Melanoma (MEL) Receiving Nivolumab or Dacarbazine
in CheckMate 066. Presented at Society for Melanoma Research (SMR) 2015 International Congress; November 18–21, 2015; San Francisco, California, USA
CheckMate 066: Respuestas
Mediana de tiempo hasta la respuesta de 2,1 meses (intervalo de 1,2–7,6 meses)
CheckMate 066: Tiempo hasta respuesta
1. Robert C, Long GV, Brady B, et al. N Engl J Med 2015;372(4):320-30.
La mediana del tiempo hasta la respuesta de la dacarbacina también fue de 2,1 meses (intervalo: 1,8-3,6)1
CheckMate 066: Supervivencia global
1. Atkinson V, Ascierto PA, Long GV, et al. Two-Year Survival and Safety Update in Patients With Treatment-Naïve Advanced Melanoma (MEL) Receiving Nivolumab or
Dacarbazine in CheckMate 066. Presented at Society for Melanoma Research (SMR) 2015 International Congress; November 18–21, 2015; San Francisco, California, USA
IC: Intervalo de confianza. HR: Hazard ratio; NC: no calculado
Diseño Keynote 006
Antoni Ribas AACR 2015 Abstract CT101
Respuestas Keynote 006
Antoni Ribas AACR 2015 Abstract CT101
Supervivencia Keynote 006
Robert et all. NEJM. April 2015
CA-209-003. Supervivencia a 5 años P
rob
abili
ty o
f Su
rviv
al
Months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 12 24 36 48 60 72 84 6 18 30 42 54 66 78
Database lock Oct 2015
107 64 86 51 49 41 29 0 3 15 43 36 17 12 1
Number of Patients at Risk
All Patients
All Patients (events: 69/107), median and 95% CI: 17.3 (12.5–37.8)
NIVO 3 mg/kg (events: 11/17), median and 95% CI: 20.3 (7.2–NR)
17 11 15 9 8 7 6 1 6 7 6 6 6 0 NIVO 3 mg/kg
OS Rate, % (95% CI)*
Landmark timepoint All Patients (N = 107)
NIVO 3 mg/kg (n = 17)
12-month 63 (53–71) 65 (38–82)
24-month 48 (38–57) 47 (23–68)
36-month 42 (32–51) 41 (19–63)
48-month 35 (26–44) 35 (15–57)
60-month 34 (25–43) 35 (15–57)
Median OS, months (95% CI) 17.3 (12.5–37.8) 20.3 (7.2-NR)
Hodi FS. AACR 2016 Abstract CT001
Segunda línea
Diseño Keynote 002
Antoni Ribas SMR Meeting 2014
Respuestas Keynote 002
Antoni Ribas SMR Meeting 2014
SLP Keynote 002 (Revisión Central)
CheckMate 037: Diseño
†
Estudio de fase III aleatorizado, controlado, abierto
1. Weber J, D’Angelo SP, Minor D et al. Lancet Oncol 2015;16:375-84.
CheckMate 037: Respuestas globales
1. Weber J, D’Angelo SP, Minor D et al. Lancet Oncol 2015;16:375-84.
Gráfica extraída de 1. Weber et al. 2015
Otros farmacos
T-VEC
1. Hawkins LK, et al. Lancet Oncol 2002;3:17–26; 2. Fukuhara H, Todo T. Curr Cancer Drug Targets 2007;7:149–55;
3. Amgen. Imlygic® Summary of Product Characteristics. Section 5.1; 4. Pol JG, et al. Virus Adapt Treat 2012;4:1–21;
5. Melcher A, et al. Mol Ther 2011;19:1008–16; 6. Dranoff G. Oncogene 2003;22:3188–92; 7. Liu BL, et al. Gene Ther 2003;10:292–303;
8. Andtbacka RHI, et al. J Clin Oncol 2015;33:2780–8.
Proposed mechanism of action for T-VEC.
TDA, tumour-derived antigen.
Tumour cells rupture for an oncolytic effect1–4
GM-CSF
Tumour cell lysis TDAs
2
T-VEC replication in tumour tissue1–3
Local effect: virus-induced tumour-cell lysis
T-VEC Tumour
cells
Healthy cells
1
Systemic antitumour immune
response3,5,6
Systemic effect: antitumour immune response
TDAs
CD8+ cytotoxic
T cell
CD4+ helper T cell
Dendritic cell activated by
GM-CSF
3
Death of distant cancer cells5–8
Distant dying tumour cell
4
Objetivo principal: DRR
Andtbacka RHI, et al. J Clin Oncol 2015;33:2780–8.
*CIs for DRR and ORR were calculated using asymptotic normal approximation; †DRR per EAC between treatment arms was evaluated using unadjusted Fisher’s exact test;
‡No α was allocated for this evaluation of statistical significance. CI, confidence interval.
ITT set
GM-CSF
n = 141
T-VEC
n = 295 Difference (95% CI)
DRR, % (95% CI)* 2.1 (0–4.5) 16.3 (12.1–20.5) Unadjusted odds ratio, 8.9
(2.7–29.2); P < 0.001†
ITT set
GM-CSF
n = 141
T-VEC
n = 295 P-value
ORR, % (95% CI)* 5.7 (1.9–9.5) 26.4 (21.4–31.5) P < 0.001‡
CR, % < 1 10.8
PR, % 5.0 15.6
ORR
DRR (primary endpoint)
0
20
50
75
100
SG por estadio de la enfermedad
Andtbacka RHI, et al. J Clin Oncol 2015;33:2780–8.
NE, not evaluable.
Time (months)
Log rank: P = 0.71 (descriptive) HR, 1.07 (95% CI, 0.75–1.52)
Stage IV M1b/c Stage IIIB/C, IV M1a
5 10 15 20 25 30 35 40 45 50 55 60
Time (months)
Log rank: P < 0.001 (descriptive) HR, 0.57 (95% CI, 0.40– 0.80)
Kapla
n–M
eie
r (%
)
163 157 146 129 113 104 93 73 51 23 10 1 0
86 78 65 55 43 35 30 22 17 10 2 0
T-VEC
GM-CSF
Risk set, n
0
T-VEC
Risk set, n
131 112 84 58 46 41 32 22 15 13 6 1 0
GM-CSF 55 46 35 28 20 17 16 14 10 5 3 0 0
T-VEC 41.1 (30.6–NE)
GM-CSF 21.5 (17.4–29.6)
80/163 (49)
57/86 (66)
T-VEC 13.4 (11.4–16.2)
GM-CSF 15.9 (10.2–19.7)
109/131 (83)
44/55 (80)
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0
20
50
75
100
0 5 10 15 20 25 30 35 40 45 50 55 60
Events/n, % Median (95% CI), months Events/n, % Median (95% CI), months
0
Kapla
n–M
eie
r (%
)
1
T-VEC
Systemic effect
3
Mature dendritic cell
T cell
GM-CSF
TDA MHC TCR
CD80/ CD86
CD28
4 T cell
5
TDA MHC TCR
PD-L1 PD-1
Cancer Immunity
Cycle
Local effect
2
Healthy cells
T-VEC
GM-CSF
TDA
Immature dendritic cell
Tumour cells
TDA
Combinación de T-VEC
Anti CTLA-4
Anti PD-1
¿Que es lo siguiente?
Combinación anti CTLA-4 + anti PD1
Callahan MK et al. ASCO 2013, Abstract 3003.
1. Larkin J, Chiarion-Sileni V, Gonzalez R et al. N Engl J Med 2015; 373:23-34.
CheckMate 067: Diseño
Estudio de fase III, doble ciego y aleatorizado
Ficha técnica de Opdivo y de Yervoy disponible
CheckMate 067 PFS (Intent-to-Treat)
NIVO + IPI (N=314)
NIVO (N=316)
IPI (N=315)
Median PFS, months (95% CI)
11.5 (8.9–16.7)
6.9 (4.3–9.5)
2.9 (2.8–3.4)
HR (99.5% CI) vs. IPI
0.42 (0.31–0.57)*
0.57 (0.43–0.76)*
--
HR (95% CI) vs. NIVO
0.74 (0.60–0.92)**
-- --
*Stratified log-rank P<0.00001 vs. IPI
**Exploratory endpoint
No. at Risk
314 NIVO + IPI 173 151 65 11 1 219 0
316 NIVO 147 124 50 9 1 177 0
315 IPI 77 54 24 4 0 137 0
0 6 9 12 15 18 3 21
NIVO
NIVO + IPI
IPI
Months
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pro
po
rtio
n a
live
an
d p
rogr
ess
ion
-fre
e
1. Larkin J, Chiarion-Sileni V, Gonzalez R et al. N Engl J Med 2015; 373:23-34.
No. at Risk
IPI – 202 82 44 31 12 1
NIVO 208 108 88 74 31 5 2
NIVO + IPI 210 142 112 96 42 9 2
0 3 6 9 12 15 17
Months
1.0
0.8
0.6
0.4
0.2
0.0
0 3 6 9 12 15 17
No. at Risk
IPI 0 75 40 22 17 9 2
NIVO 80 57 51 43 16 4 0
NIVO + IPI 68 53 44 39 16 1 0
Months
NIVO + IPI NIVO IPI
NIVO + IPI NIVO IPI
CheckMate 067: PFS por PD-L1 (5%)
PD-L1 ≥5%* PD-L1 <5%*
*Per validated PD-L1 immunohistochemical assay based on PD-L1 staining of tumor cells in a section of at least 100 evaluable tumor cells.
Pro
po
rtio
n a
live
an
d p
rogr
ess
ion
-fre
e
Pro
po
rtio
n a
live
an
d p
rogr
ess
ion
-fre
e 1.0
0.8
0.6
0.4
0.2
0.0
mPFS HR
NIVO + IPI 14.0 0.40
NIVO 14.0 0.40
IPI 3.9 --
mPFS HR
NIVO + IPI 11.2 0.42
NIVO 5.3 0.60
IPI 2.8 --
1. Larkin J, Chiarion-Sileni V, Gonzalez R et al. N Engl J Med 2015; 373:23-34.
CheckMate 067: Seguridad
Patients Reporting Event, %
NIVO + IPI (N=313) NIVO (N=313) IPI (N=311)
Any Grade Grade
3–4 Any Grade Grade
3–4 Any Grade
Grade 3–4
Treatment-related adverse event (AE) 95.5 55.0 82.1 16.3 86.2 27.3
Treatment-related AE leading to discontinuation
36.4 29.4 7.7 5.1 14.8 13.2
Treatment-related death* 0 0.3 0.3
*One reported in the NIVO group (neutropenia) and one in the IPI group (cardiac arrest).
• 67.5% of patients (81/120) who discontinued the NIVO + IPI combination due to treatment-related AEs developed a response
1. Larkin J, Chiarion-Sileni V, Gonzalez R et al. N Engl J Med 2015; 373:23-34.
Ipilimumab + Pembrolizumab KN029
Diseño estudio CA-209-511
Previously Untreated Unresectable Stage III-IV Melanoma
Randomize (N = 346)
1:1 Stratify by • PD-L1 expression • M stage M0,M1a,M1b vs M1c
Arm A (n = 173) nivolumab 3 mg/kg IV + ipilimumab 1 mg/kg IV Every 3 weeks for 4 doses
Arm B (n = 173) nivolumab 1 mg/kg IV + ipilimumab 3 mg/kg IV Every 3 weeks for 4 doses
Nivolumab Flat Dose 480 mg Every 4 weeks
Nivolumab Flat Dose 480 mg Every 4 weeks
Double Blinded Part 1
Treat until progression** or unacceptable toxicity
Open-label Part 2***
6 weeks*
Conclusiones
• La inmunoterapia del melanoma ya es un tratamiento establecido de la enfermedad
• Las posibilidades de combinación y sinergias son muy importantes
• Ademas de haber sido el primer tratamiento en modificar la historia natural su pleno potencial esta aun por llegar