Diapositiva 1 - Foro de Debate en Oncologia

Diapositiva 1 - Foro de Debate en Oncologia

Combinaciones Terapéuticas: el
principio del fin del melanoma o del SNS
Posibilidades ilimitadas de combinacion
Combinación con quimioterapia
• Estudios preclínicos han demostrado que
– La quimioterapia aumenta liberación de antígenos que inician
células T
– Quimioterapia sensibiliza células a la muerte por linfocitos T
– Quimioterapia destruye población Treg
• Algunas quimioterapias pueden por tanto aumentar eficacia de
ipilimumab
• Hay datos disponibles de la asociación con
– DTIC
– Temozolomida
– Fotemustina
– Cisplatino y etoposido
Reck M, et al. Ann Oncol. 2012 Aug 2. [Epub ahead of print]
Robert C, et al. N Engl J Med 2011;364(26):2517–26
Di Giacomo AM, Lancet Oncol 2012 ;13(9):879–86
Patel SP, et al. Presented at ESMO 2012. P1126
Combinación con radioterapia
• Modelo de ratón con carcinoma de mama muy poco inmunogenico
–
Bloqueo de CTLA-4 no afecta crecimiento ni supervivencia en el ratón
–
La radioterapia retrasa crecimiento tumoral tanto sola como asociada a
anti-CTLA-4
–
Supervivencia mejor para los tratados con combinación
–
El aumento de supervivencia se asocio a reducción de metástasis
pulmonares mediado por linfocitos T
lgG
9H10
RT+lgG
RT+9H10
125
CTLA-4 = cytotoxic T-lymphocyte-associated antigen-4; igG =
immunoglobulin isotype G; RT = radiotherapy;
9H10 = monoclonal antibody; against CTLA-4
Survival (%)
100
75
50
25
0
25
30
35
40
45
50
55
60
Days post-tumour inoculation
65
Demaria S, et al. Clin Cancer Res 2005;11:728–734
Efectos inmunológicos de la inhibición b-raf
Asociación dabrafenib + Ipilimumab
• Triplete se asoció a colitis
grado 3 con perforación
en 2/7
• Doblete sin DLT
Puzanov I et al. ASCO 2014
Combinación con agentes hipometilantes
Bases preclínicas de la combinación con inmunoterapia
• Los modelos preclínicos demuestran potenciación de la
combinación de inmunoterapias400
300
Hamster IgG
200
BL6/GM + Hamster IgG
Anti-CTLA4
BL6/GM + Anti-CTLA4
100
40
30
20
10
50
(0/5)
0
Day 4 Post-Challenge
Melanoma murino con GVAX
Davila E, et al. Cancer Res 2003;63(12):3281-8
Van Elsas A, et al. J Exp Med1999;190(3):355-66
Supervivencia Ipilimumab interleuquina
• El seguimiento a largo plazo de el estudio fase II con 36 pacientes tratados con
ipilimumab e interleuquina demuestra una tasa de respuestas completas
superior a la esperada con un 25% supervivientes a 5 años
Ipilimumab + gp100 vaccine
Ipilimumab + IL-2
Ipilimumab dose escalation
Peter A. Prieto et al. Clin Cancer Res 2012;18:2039-2047
Checkpoints actúan en diferentes compartimentos
Creelan BC. Cancer Control 2014:21;80-89
Sequenced
Therapy
Concurrent
Therapy
Diseño del estudio CA209-004
Cohort 1
(N = 14)
Nivo 0.3 + Ipi 3
Q3W
x4
Nivo 0.3
Q3W
x4
Nivo 0.3 + Ipi 3
Q12W
x8
Cohort 2
(N = 17)
Nivo 1 + Ipi 3
Q3W
x4
Nivo 1
Q3W
x4
Nivo 1 + Ipi 3
Q12W
x8
Cohort 2a
(N = 16)
Nivo 3 + Ipi 1
Q3W
x4
Nivo 3
Q3W
x4
Nivo 3 + Ipi 1
Q12W
x8
Cohort 3
(N = 6)
Nivo 3 + Ipi 3
Q3W
x4
Nivo 3
Q3W
x4
Nivo 3 + Ipi 3
Q12W
x8
Cohort 8
(N = 41)
Nivo 1 + Ipi 3
Q3W
x4
Cohort 6
(N = 17)
Cohort 7
(N = 16)
Prior standard
ipilimumab
therapy
Nivo 3
Q2W
x ≤48
Nivo 1
Q2W
x ≤48
Nivo 3
Q2W
x ≤48
All dose units are mg/kg.
Ipi = ipilimumab; Nivo = nivolumab; Q2W = every 2 weeks; Q3W = every 3 weeks; Q12W = every 12 weeks
CA209-004 Supervivencia
100
1-yr OS 94% 2-yr OS 88%
90
80
1-yr OS 85%
OS (%)
70
2-yr OS 79%
1-yr OS 70%
60
50
40
30
Censored
Cohorts 2 (Nivo 1 + Ipi 3)
Concurrent Cohorts 1–3
Sequenced Cohorts 6–7
20
10
0
0
Patients at Risk
Cohort 2 (Nivo 1 + Ipi 3)
Concurrent Cohorts 1–3
Sequenced Cohorts 6–7
17
53
33
3
6
17
52
31
9
17
49
25
12
16
47
25
15
16
45
23
18
21
14
42
20
14
37
12
24
14
30
8
27 30
Month
13
25
0
33
7
16
0
36
4
11
0
39
42
45
48
3
7
0
3
5
0
3
5
0
0
1
0
0
1
0
0
0
0
Cohort 2 dose is similar to the dose/schedule used in phase 3 clinical studies
June 2014 data analysis.
Kluger et all. Oral presentation. SMR 2014
CA209-004 toxicidad
Patients with an event, %
All drug-related AEs
Rash
Pruritus
Fatigue
Diarrhea
Nausea
Lipase increased
Pyrexia
AST increased
ALT increased
Amylase increased
All Concurrent Cohorts (N =
94)
Any Grade
Grade 3/4
97
64
64
6
52
0
45
1
38
7
23
2
22
15
22
0
19
11
18
12
17
6
All Sequenced Cohorts (N = 33)
Any Grade
85
24
21
21
12
9
18
3
0
3
9
Grade 3/4
24
0
0
0
0
0
12
0
0
0
2
Sorted from high to low by total AEs of any grade reported in all concurrent cohorts (1–3 and 8; N = 94).
ALT = alanine aminotransferase; AST = aspartate aminotransferase.
April 2014 data analysis
Kluger et all. Oral presentation. SMR 2014
Postow et all. NEJM. April 2015
CheckMate CA209-069: Estudio fase II randomizado
Eligible patients
with unresectable
stage III or IV
melanoma
•
•
•
Treatment-naïve
BRAF WT
(N =
100) or
MT (N = 50)
Stratified by BRAF
status
Arm
A
R
2:1
NIVO
1 mg/kg
+
IPI
3 mg/kg
Q3W
x4
NIVO
3 mg/kg
Q2W
Treat until:
disease
progressiona or
unacceptable
toxicity
Double-blind
Arm
B
Placebo
+
IPI
3 mg/kg
Q3W
x4
Placebo
Q2W
Primary endpoint:
aTreatment
beyond initial investigator-assessed RECIST v1.1- defined
progression is permitted in patients experiencing clinical benefit and tolerating
study therapy. Arm B patients have option to receive nivolumab monotherapy
after progression. Upon confirmed progression and change of treatment, all
patients are unblinded.
MT = mutation; PFS = progression-free survival; Q3W = every 3 weeks;
WT = wild type
• ORR in BRAF WT patients
Secondary endpoints:
• PFS in BRAF WT patients
• ORR and PFS in BRAF MT patients
• Safety
15
Respuestas objetivas
SLP en pacientes BRAF WT
Death or disease
progression, n/N
Median PFS,
mo (95% CI)
NIVO + IPI
30/72
NR
IPI monotherapy
25/37
4.4 (2.8-5.7)
Patients Alive and Progression-Free (%)
100
90
80
70
HR 0.40 (95% CI, 0.23, 0.68; P < 0.001)
60
50
NIVO + IPI (N = 72)
40
30
20
IPI (N = 37)
10
0
0
Patients at risk
3
6
NIVO + IPI
72
54
45
IPI
37
20
9
9
12
15
18
38
20
1
0
6
2
0
0
PFS (Months)
• Similar PFS among BRAF MT patients (8.5 mo for NIVO + IPI, 2.7 mo for IPI alone)
Database lock: January 30, 2015
Resumen de seguridad
NIVO + IPI (N = 94)a
Patients Reporting, n (%)
IPI (N = 46)a
Any
Grade
Grade
3–4
Any
Grade
Grade
3–4
Treatment-related AEs
86 (91)
51 (54)
43 (93)
11 (24)
Treatment-related AEs leading to
discontinuation
44 (47)
36 (38)
8 (17)
6 (13)
Treatment-related death
aSafety
3 (3)
0
was evaluated in all patients who received at least one dose of study treatment
• Summary of treatment-related deaths (n = 3)
‒ History of cardiac issues; death due to ventricular arrhythmia, 29 days after last treatment
‒ Sudden death 69 days after last treatment, while patient was clinically improving from
pneumonitis/iatrogenic pneumothorax
‒ Sudden death 3 days after resolution of grade 3 pneumonia and grade 4 hypercalcemia, 86
days after last treatment
Importantes costes
• Para el paciente
– Mas del doble de toxicidades grado 3-4
– Mas del doble de interrupciones de tratamiento
• Para el sistema sanitario
– Nivolumab (Opdivo) 12.500$ mes de tratamiento
(150.000$ año)
– Pembrolizumab (Keytruda) 12.500$ mes de
tratamiento (150.000$ año)
– Ipilimumab (Yervoy) 30.000$ ciclo de tratamiento
(120.000$ año)
¿Es mejor combinación que monoterapia?
KEYNOTE-006
(AACR 2014)
ORR
OS
Pembro
ipi-naïve
(SMR 2014)
ipi-nivo Cohort 8
ipi-naïve
(SMR 2014)
Pembro 10q2
Pembro 10q3
Ipi
34%
33%
12%
39%
40%
44% (vs 43% all
concurrent)
5% CR
6% CR
1% CR
10% CR
8% CR
7% CR (vs 13% all
concurrent)
74% at 12 mos
68% at 12 mos
58% at 12 mos
Nivolumab
74% at 12 mos
73% at 12 mos
~80% at 9 mos (16
pts at risk)
?? At 12 mos (0
pts at risk)
Grade 3-4 TRAEs
Grade 3-4 TRAEs
Grade 3-4 TRAEs
Grade 3-4 TRAEs
Grade 3-4 TRAEs
Grade 3-4 TRAEs
11%
7%
18%
15%
12%
66%
Discon due to AEs: Discon due to AEs: Discon due to AEs:
Safety
CheckMate 066
BRAF wt
(SMR 2014)
4%
7%
9%
Discon due to AEs: Discon due to AEs: Discon due to AEs:
6%
2%
23%
1 death
Población CheckMate 069 mas favorable
ChkMt 004
Cohort 8
CheckMate 069 (ph2)
BRAF WT Patients
All Randomized Patients
PEM
10q2
(N=279)
PEM 10q3
(N=277)
IPI
(N=278)
67
61
63
62
66/34
68/32
58/42
63/37
58/42
78
90
81
96
97
95
43
46
45
65
68
64
NIVO + IPI
(N = 41)
NIVO + IPI
(N = 72)
IPI
(N = 37)
NIVO + IPI
(N = 95)
IPI
(N = 47)
Age, median (yr)
55
66
69
64
Male/female (%)
44/56
67/33
62/38
AJCC stage IV (%)
89
M1c stage (%)
ECOG performance
status (%)
0
47
1
≥2
Baseline LDH levels
(%)
≤ULN
>ULN
History of brain
metastases (%)
BRAF V600 mutant
(%)
No prior systemic
therapy (%)
KEYNOTE-006 (ph3)
Total
(N = 142)
46
67/33
66
86
81
83
79
82
87
68
68
29
13
19
15
21
17
30
32
32
-
1
0
2
0
1
-
-
-
61
79
81
74
77
75
64
63
64
39
21
19
25
23
25
33
35
33
6
0
4
0
3
8
10
10
29
0
0
24
21
23
35
35
39
49
100
100
100
100
100
58
60
57
Tasas de Respuesta
CheckMate 69 “investigator assessed” vs Keynote 006 “Central review”
ChkMt
004
Cohort
8
ORR, %
(95% CI)
CheckMate 069
BRAF WT Patients
KEYNOTE-006
BRAF MT Patients
NIVO + IPI
(N=72)
IPI
(N=37)
NIVO + IPI
(N=23)
IPI
(N=10)
PEM 10q2
(N=279)
PEM 10q3
(N=277)
IPI
(N=278)
PEM vs
IPI
PEM vs
IPI
44
61
(49, 72)
11
(3, 25)
52
(31, 73)
10
(0, 45)
34
(28, 40)
33
(27, 39)
12
(8, 16)
41
vs 13
21
vs 6
0.00013
0.00002
5
6
<0.001
Not evaluated
Best overall
response, %
22
0
22
0
Partial response
39
11
30
10
Stable disease
12
35
13
10
14
41
22
70
12
14
13
10
Progressive
disease
Unable to
determine
BRAF
MT
prior
NIVO +
IPI
(N=41)
P value for
comparison
Complete
response
BRAFM
T naive
7
1
Supervivencia libre de progresión
Keynote 006 incluye pacientes de primera y segunda línea
ChkMt
004
Cohort 8
NIVO + IPI
(N=41)
Median PFS, months
(95% CI)
HR (95% CI)
P value for
comparison
6 month PFS rate
(95% CI)
?
CheckMate 069
BRAF WT Patients
KEYNOTE-006
BRAF MT Patients
NIVO + IPI
(N=72)
IPI
(N=37)
NIVO +
IPI
(N=23)
IPI
(N=10)
PEM 10q2
(N=279)
PEM 10q3
(N=277)
IPI
(N=278)
NR
4.4
(2.85.7)
8.5
(?)
2.7
(?)
5.5
(3.4, 6.9)
4.1
(2.9, 6.9)
2.8
(2.8, 2.9)
0.58
(0.47,
0.72)
-
0.40 (0.23, 0.68)
?
0.58
(0.46,
0.72)
-
0.0006
?
0.00001
0.00001
47.3
(41.2,
53.2)
46.4
(40.3,
52.3)
?
~68%
(est)
~30%
(est)
?
?
26.5
(20.9,
32.4)
Seguridad
CheckMate 069
Patients
Reporting, n (%)
NIVO + IPI
(N = 94)a
KEYNOTE-006
IPI
(N = 46)a
PEM 10q2
(N=278)
PEM 10q3
(N=277)
IPI
(N=256)
Any
Grade
Grade
3–4
Any
Grade
Grade
3–4
Any
Grade
Grade
3–4
Any
Grade
Grade
3–4
Any
Grade
Grade
3–4
Treatment-related
AEs
86
(91)
51
(54)
43
(93)
11
(24)
221
(80)
31
(11)
202
(73)
18
(7)
187
(73)
45
(18)
Treatment-related
AEs leading to
discontinuation
44
(47)
36
(38)
8 (17)
6 (13)
24 (9)
19 (7)
11 (4)
9 (3)
19 (7)
12 (4)
Treatment-related
death
3 (3)
0
0
0
1 (<1)
Supervivencia a largo plazo CA209-003 de Nivolumab
Mas de un tercio de los pacientes se sobre-tratarían y
expondrían a toxicidad de forma innecesaria
Hodi, S. SMR 2014
Conclusiones
• Las terapias de combinación son extraordinariamente
atractivas en el tratamiento del melanoma metastásico
• Los incrementos de supervivencia parece que corren
parejos a incrementos en la toxicidad
• Para no sobre-tratar a una considerable proporción de
pacientes es necesario
– Abordaje secuencial
– Identificación de factores predictivos