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Avances en el tratamiento del melanoma metastásico.
José Antonio López Martín Oncología Médica H Universitario 12 de Octubre Madrid. España
2
Melanoma metastásico - 2010 • Incidencia global en ascenso • Edad de inicio menor que otros tumores • Mal pronóstico, opciones limitadas de tratamiento:
– Supervivencia 1 año ~25% / 2 años ~10%1
• No tratamientos aprobados para pacientes previamente tratados
• Ningún estudio aleatorizado ha mostrado incremento en la supervivencia
1Korn EL et al. J Clin Oncol. 2008;26:527-534
Survival curves of 7,635 patients with metastatic melanomas at distant sites (stage IV) subgrouped by (A) the site of metastatic
disease and (B) serum lactose dehydrogenase (LDH) levels.
Balch C M et al. JCO 2009;27:6199-6206 ©2009 by American Society of Clinical Oncology
Hasta 2010…
Interferón alfa-2b
Quimioterapia, IL-2
ADYUV
AVANZ
Efic
Tox
Diapositiva cedida por el Dr. E. Espinosa
Desde 2010…
iBRAF, iMEK
Ipilimumab, anti-PD1
ADYUV
AVANZ
Tox
Efic
Diapositiva cedida por el Dr. E. Espinosa
Subtipos clínico-moleculares de melanoma
Modificado de Curtin JA y cols. NEJM 2005
BRAF inhibitors Vemurafenib Dabrafenib/GSK2118436 LGX818 (encorafenib)
MEK inhibitors Trametinib Cobimetinib Binimetinib Pimasertib AZD6244 TAK, BAY,
ERK inhibitor
mTOR
PI3K
Akt
PI3K inhibitors mTOR inhibitors
PTEN
100 90 80 70 60 50 40 30 20 10 0
Prog
ress
ion-
free
sur
viva
l (%
)
0 6 12 18 24
338 337
63 186
22 77
3 16
0 0
100 269
37 113
14 49
0 3
No. at risk
1.6 6.9
Hazard ratio 0.38 (95% CI: 0.32–0.46)
Log-rank p<0.001 (post-hoc) Dacarbazine
(n=338)
Vemurafenib (n=337)
BRIM-3: Vemurafenib vs DTIC (1st line) PFS (censored at crossover)
Time (months)
Dacarbazine Vemurafenib
Chapman. ASCO 2012
100 90 80 70 60 50 40 30 20 10
0
Ove
rall
surv
ival
(%)
0 6 12 18 24
Vemurafenib (n=337) Median f/u 12.5 months
Dacarbazine (n=338) Median f/u 9.5 months
338 337
173 280
79 178
24 44
0 1
244 326
111 231
50 109
4 7
9.7 13.6
BRIM-3: Vemurafenib vs DTIC (1st line) Overall survival (censored at crossover)
Hazard ratio 0.70 (95% CI: 0.57–0.87) p<0.001 (post-hoc)
Time (months)
Dacarbazine Vemurafenib
No. at risk
Chapman. ASCO 2012
On randomized study treatment at cut-off: dabrafenib 57%, DTIC 27% Median follow-up time: 4.9 months (dabrafenib 5.1 mos, DTIC 4.8 mos.)
Hauschild ASCO 2012
BREAK-3: Dabrafenib vs DTIC PFS Investigator-assessed
Vemurafenib and Dabrafenib show similar efficacy
Dabrafenib in untreated CNS metastases BRAFV600E: Maximal intracranial target lesion reduction
Cohort B
Cohort A
Kirkwood. ASCO 2012
Vemurafenib: Selected adverse events (% of patients)
Vemurafenib, n= 336 Dacarbazine, n= 282
Adverse events All Grade 3 Grade≥ 4 All Grade 3 Grade ≥4
Arthralgia 49 3 - 3 <1 - Rash 36 8 - 1 - - Fatigue 33 2 - 31 2 - Photosensitivity 30 3 - 4 - - ↑LFTs 18 7 <1 5 1 - Cutaneous SCC 12 12 - <1 <1 - Keratoacanthoma 8 6 - - - - Skin papilloma 18 <1 - - - - Nausea 30 1 - 41 2 - Neutropenia <1 - <1 11 5 3
Discontinuations due to AE: 6% Vemurafenib; 4% Dacarbazine
Chapman. ASCO 2012
Dabrafenib: Adverse Events in > 5% patients
Fotosensibilidad: dabrafenib (3%), DTIC (5%)
010203040506070
CR+PR SD PD
Assessment of Tumor Response Rate to vemurafenib: Independent Review Committee
• ORR 53% by IRC • ORR 57% by investigator assessments (INV) • RR, including unconfirmed, 69% (INV) • PR in 4 of 10 BRAFV600K patients
Res
pons
e ra
te (%
)
n=70 n=38 n=18
53% CR+PR
5% CR
29%
14%
Error bars represent 95% confidence intervals
Response and Relapse with vemurafenib 10/02/08 (Pre) 11/26/08 (2+ mo) 02/20/09 (4+ mo)
Pt #43, UCLA
melanoma
stroma
A. Ribas
Mechanisms of Resistance to BRAF Inhibitors
Survival
BRAFV600E
MEK
ERK
P
P
BRAF inh
PDGFRb or IGF1R
PI3K
AKT
Nazarian et al. Nature 2010 Villanueva et al. Cancer Cell 2010
MEK-independent progression
Nazarian et al. Nature 2010
NRASQ61
COT
Johannessen et al. Nature 2010
CRAF
Wagle et al. JCO 2011
MEK-dependent progression
Poulikakos et al. Nature 2012 Shi et al. Nature Com 2012
MEKi
PI3Ki or AKTi
A. Ribas
METRIC: Trametinib vs CT – Overall Survival
BRAFi + MEKi : Enhanced Antitumor Activity with Combination
Mea
n tu
mor
vol
ume
(m
m3 )
+ SE
M
BRAFV600E human melanoma xenograft
2000
1500
1000
500
0
0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0
Treatment period (days)
A375PF11 Untreated control Trametinib (0.3 mg/kg) Dabrafenib (30 mg/kg) Dabrafenib (300 mg/kg)
Dabrafenib+trametinib (30/0.3 mg/kg)
Weber. ASCO 2012
MEKi Blocks BRAFi-Induced Skin Lesions in Rats
Control BRAFi (150 mg/kg) BRAFi + MEKi (1.5 mg/kg)
BRAFi alone results in thickening & hyperkeratosis
Co-dosing with MEKi attenuates lesion formation
Weber. ASCO 2012
COMBI-d: Progression-free Survival
Presented By Keith Flaherty at 2016 ASCO Annual Meeting
COMBI-d: Overall Survival
Presented By Keith Flaherty at 2016 ASCO Annual Meeting
COMBI-v: Dabrafenib + Trametinib vs Vemurafenib Overal Survival
COMBI-v: Vemurafenib + Cobimetinib vs Vemurafenib Overal Survival
COMBI-v / Co-BRIM: Safety of the combination vs monotherapy
Ras mutated melanoma
Binimetinib vs DTIC (NEMO)
Progression-Free Survival
Binimetinib vs DTIC (NEMO)
Progression-Free Survival by Prior Immunotherapy Stratum
Binimetinib vs DTIC (NEMO)
GNAQ/GNA11 melanoma
c-KIT activated melanoma
Imatinib in KIT-abnormal melanoma
M1b M1c M1a
-80
-60
-40
-20
0
20
40
60
80
100
120
Guo J et al, ASCO 2010
KIT status (Exon 9:11:13:17:18: amplif) 2:14:8:3:5:3
Correlations of response and KIT aberrations
KIT Status PR SD PR+SD
KIT Amp 1/3 0/3 1/3
Exon11 2/12 8/12 10/12
Exon13 3/8 1/8 4/8
Exon17 0/3 1/3 1/3
Exon18 0/4 2/4 2/4
Multiple gene aberrations* 3/4 1/4 4/4
* 4 patients respectively harbored multiple KIT aberrations as following: (13)K642E+Amplification ; (13) I817T(T2450C); (18)F848L(T2542C) ; (11)L576P+Amplification ;
Guo J et al, ASCO 2010
70%
Paradigmas de tratamiento farmacológico del melanoma avanzado
Diana= sistema inmune
Diana=tumor Inmunoterapia Tratamiento Anti-diana
Cortesía del Dr. Ribas
Melero … Ascierto. Clin Cancer Res 2013
Ipilimumab en melanoma avanzado: Supervivencia en ensayos de Fase 2
O´Day et al. ASCO 2009: 9033
Hodi, NEJM 2010 Robert, NEJM 2011
Supervivencia global
IPILIMUMAB vs vacuna (pretratados) o DTIC (1ª Línea)
41
Eventos adversos relacionados con activación linfocitaria (irAEs)
Pooled survival analysis from all phase I-III, including BMS EAP
Nivo CA209-003
Hodi, SMR 2014
Nivolumab CA209-003
52% IPI previo, 17% iBRAF previo Mediana seguimiento 15 m.
Respuestas 33%
Pembro KEYNOTE 001: resultado global
Daud, ASCO 2015, abs 9005
Pembrolizumab KEYNOTE 001
Pembrolizumab (MK-3475)
Hamid NEJM 2013.
Ribas SMR 2014 Ribas A. Lancet Oncol.2015
Pembrolizumab tras Ipilimumab KEYNOTE-002
Respuestas 21-25% frente a 4%
Nivolumab tras Ipilimumab CHEKMATE-037
Weber, Lancet 2015
Nivolumab Resp. 31%
DTIC o Taxol-Carbo Resp. 10%
Nivolumab vs DTIC en 1ª Línea (BRAFwt)
Robert, NEJM 2014
Supervivencia global
Pembrolizumab vs ipilimumab (1ª Línea) KEYNOTE-006
Robert C, N Engl J Med. 2015;372(26):2521-2532. 1. Ficha técnica de KEYTRUDA™ (pembrolizumab). Julio de 2015.
Grupo de tratamiento RRIb
(IC del 95%)
Valor P c
Pembro 10 mg/kg cada 2 semanas
0,63 (0,47, 0,83) 0,00052
Pembro 10 mg/kg cada 3 semanas
0,69 (0,52, 0,90) 0,00358
Ipilimumab — —
Tiempo, meses
100
90
80
70
60
50
40
30
20
10
0
Supe
rviv
enci
a gl
obal
, %
0 2 4 6 8 10 12 14 16 18
Kaplan-Meier OS (población IT)
212 202
279 277 278
266 266 242
248 251 212
233 238 188
219 215 169 157
177 158 117
67 71 51
N.º en riesgo 19 18 17
0 0 0
74% 68%
58%
Fecha de corte de los datos para el análisis: 3 de marzo de 2015.
12
Pembrolizumab vs Ipilimumab KEYNOTE-006: PFS
Grupo de tratamiento RRIc
(IC del 95%)
Valor P d
Pembro 10 mg/kg cada 2 semanas
0,58 (0,46, 0,72) <0,00001
Pembro 10 mg/kg cada 3 semanas
0,58 (0,47, 0,72) <0,00001
Ipilimumab — —
100
90
80
70
60
50
40
30
20
10
0
Supe
rviv
enci
a lib
re d
e pr
ogre
sión,
%
0 2 4 6 8 10 12 14 Tiempo, meses
Fecha de corte de los datos para el análisis:
3 de septiembre de 2014.
Kaplan-Meier PFS (población IT)
279 231 147 98 49 7 2 0 277 235 133 95 53 7 1 1 278 186 88 42 18 2 0 0
N.º en riesgo
47%
46%
27%
6
Robert C, N Engl J Med. 2015;372(26):2521-2532. 1. Ficha técnica de KEYTRUDA™ (pembrolizumab). Julio de 2015.
Nivolumab vs Ipilimumab 1ª Línea CHECKMATE 067
NIVO + IPI (N=314)
NIVO (N=316)
IPI (N=315)
Mediana SLP, meses (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)** -- --
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
Meses
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Prop
orti
on a
live
and
prog
ress
ion-
free
Sup. libre progresión
Larkin, NEJM 2015
Talimogene Laherparepvec - T-VEC (Amgen) OncoVex-GMCSF (Biovex)
1 Liu BL, et al. Gene Therapy. 2003;10:292-303.
• Herpes simplex virus type 1 (HSV-1)
• engineered to selectively replicate in tumor cells and to express h-GM-CSF
– ICP34.5 deletion (neurovirulence factor)
– ICP47 deletion
– Insertion of GM-CSF
– Created in JS1 virus strain
ICP34.5
pA hGM-CSF CMV
ICP34.5 ICP47
CMV hGM-CSF pA
Talimogene laherparepvec (JS1/ICP34.5-/ICP47-/hGM-CSF)
HSV: Herpes simplex virus; ICP: Infected cell protein; CMV: Cytomegalovirus promoter
Talimogene Laherparepvec: Oncolytic Immunotherapy Platform
Local Effect: Tumor Cell Lysis
Systemic Effect: Tumor-Specific Immune Response
Selective viral replication in tumor tissue
Tumor cells rupture for an oncolytic effect
Systemic tumor-specific immune response
Death of distant cancer cells
Product is not suitable for systemic administration. This mechanism of action is investigational. 1. Varghese S, et al. Cancer Gene Ther. 2002;9:967-978. 2. Hawkins LK, et al. Lancet Oncol. 2002;3:17-26. 3. Fukuhara H, et al. Curr Cancer Drug Targets. 2007;7:149-155. 4. Sobol PT, et al. . Mol Ther. 2011;19:335-344. 5. Liu BL, et al. Gene Ther. 2003;10:292-303. 6. Melcher A, et al. Mol Ther. 2011;19:1008-1016. 7. Fagoaga OR In: McPherson RA, Pincus MR, eds. Henry’s Clinical Diagnosis and Management by Laboratory Methods, 22nd ed. Philadelphia, PA: Elsevier; 2011:933-953. 8. Dranoff G. Oncogene. 2003;22:3188-3192.
Oncology
Baseline Midway through treatment After 4 months of treatment
= Lesion injected
Examples of Responses Seen With Talimogene Laherparepvec
1 Senzer NN, et al. J Clin Oncol. 2009;27:5763-5771.
Midway through treatment After 4 months of treatment
Uninjected area
1 Senzer NN, et al. J Clin Oncol. 2009;27:5763-5771.
Examples of Responses Seen With Talimogene Laherparepvec
3 months
6 months
Response in the liver – uninjected
1 Senzer NN, et al. J Clin Oncol. 2009;27:5763-5771.
Examples of Responses Seen With Talimogene Laherparepvec
Ove
rall
Surv
ival
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Months
0 5 10 15 20 25 30 35 40
GM-CSF T-VEC
141 295
101 229
63 154
25 62
3
10
Log Rank: P = 0.07* HR: 0.79 (0.61, 1.02)
45
19.0 (16.0, 24.0) months
23.3 (19.4, 29.7) months
Median (95% CI)
GM-CSF (N = 141)
T-VEC (N = 295)
OPTIM_ TVEC Interim Overall Survival
Interim OS data represent 85% of the required 290 events
Survival T-VEC GM-CSF Difference %
24-month 49.6% 41.3% 8.3
36-month 40.6% 27.8% 12.8
Difference: 4.3 months
*P-value is not significant at the planned nominal 0.0001
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Kaufman HL et al. LBA and oral presentation at SMR 2013 Annual Meeting, November 17 – 20, Philadelphia, PA
Stage IIIB/IIIC/IVM1a disease: HR 0.56; 95% CI: 0.38-0.81 Descriptive Log Rank p = 0.002
Interim OS by Stage at Enrollment Stage IIIB/C
Stage IV M1a
Hazard Ratio = 0.46 (0.26, 0.83) Descriptive Log Rank p=0.008
Median (95% CI)
T-VEC (N=88) NE (NE, NE) mos
GM-CSF (N=43) 24.3 (18.6, NE) mos
Hazard Ratio = 0.67 (0.41, 1.10) Descriptive Log Rank p = 0.11
Median (95% CI)
T-VEC (N=75) 25.8 (18.1, NE) mos
GM-CSF (N=43) 19.0 (13.3, 29.6) mos
88 87 81 75 68 46 25 10 4 0
0 5 10 15 20 25 30 35 40 45
0%
20%
40%
60%
80%
100%
Kapl
an-M
eier
Per
cent
GM-CSF 88 87 81 75 68 46 25 10 4 0
Study Month
Number of Patients at Risk:
75 70 65 54 43 29 17 9 2 0
0 5 10 15 20 25 30 35 40 45 Study Month
0%
20%
40%
60%
80%
100%
75 70 65 54 43 29 17 9 2 0 43 41 32 26 20 13 7 3 1 0 43 41 32 26 20 13 7 3 1 0
Number of Patients at Risk: Kapl
an-M
eier
Per
cent
T-VEC
GM-CSF T-VEC
43 37 33 29 22 14 9 3 0 43 37 33 29 22 14 9 3 0
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Kaufman HL et al. LBA and oral presentation at SMR 2013 Annual Meeting, November 17 – 20, Philadelphia, PA
Interim OS by Stage at Enrollment Stage IV M1b
Stage IV M1c
Hazard Ratio = 0.97 (0.57, 1.66) Descriptive Log Rank p = 0.92
Median (95% CI)
T-VEC (N=64) 13.5 (11.8, 19.4) mos
GM-CSF (N=26) 13.2 (6.1, 26.4) mos
Hazard Ratio = 1.14 (0.69, 1.90) Descriptive Log Rank p = 0.61
Median (95% CI)
T-VEC (N=67) 12.6 (9.1, 17.3) mos
GM-CSF (N=29) 16.2 (10.2, 32.1) mos
0 5 10 15 20 25 30 35 40 45 Study Month
0%
20%
40%
60%
80%
100%
Kapl
an-M
eier
Per
cent
Number of Patients at Risk: 67 57 40 28 23 15 10 5 2 0 67 57 40 28 23 15 10 5 2 0 29 26 21 17 10 8 4 3 1 0 29 26 21 17 10 8 4 3 1 0 GM-CSF
T-VEC
|
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0 5 10 15 20 25 30 35 40 45
0%
20%
40%
60%
80%
100%
Kapl
an-M
eier
Per
cent
Study Month
Number of Patients at Risk: 64 55 43 29 20 15 10 7 2 0 64 55 43 29 20 15 10 7 2 0 26 21 15 12 11 7 5 3 1 0 26 21 15 12 11 7 5 3 0 GM-CSF
T-VEC
|
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Kaufman HL et al. LBA and oral presentation at SMR 2013 Annual Meeting, November 17 – 20, Philadelphia, PA
Interim OS by Line of Therapy
Second-line or greater
Hazard Ratio = 0.49 (0.33, 0.74) Descriptive Log Rank p < 0.001
Median (95% CI) T-VEC (N=138) NE (24.5, -) mos GM-CSF (N=65) 16.7 (12.8, 21.1) mos
Hazard Ratio = 1.13 (0.80, 1.60) Descriptive Log Rank p = 0.48
Median (95% CI)
T-VEC (N=157) 17.1 (14.3, 22.5) mos
GM-CSF (N=76) 23.7 (16.2, 32.4) mos
0 5 10 15 20 25 30 35 40
0%
20%
40%
60%
80%
100%
Kapl
an-M
eier
Per
cent
Study Month
Number of Patients at Risk:
0 5 10 15 20 25 30 35 40 Study Month
0%
20%
40%
60%
80%
100%
Kapl
an-M
eier
Per
cent
Number of Patients at Risk:
45
157 139 114 89 69 55 35 26 10 0 157 139 114 89 69 55 35 26 10 0 76 69 57 49 40 29 22 12 3 0 76 69 57 49 40 29 22 12 3 0
13 8 13 0 11 5 9 7 8 5 5 0 2 7 5 0 6 5 5 6 4 4 3 5 2 3 1 3 3 0 GM-CSF
T-VEC
GM-CSF T-VEC
First-line
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Kaufman HL et al. LBA and oral presentation at SMR 2013 Annual Meeting, November 17 – 20, Philadelphia, PA
Melanoma, volumen mutacional y efecto de ipilimumab
Snyder, NEJM 2014
Melanoma- NRAS e inmunoterapias Best Response to Any Line of Immune Therapy, n (%)
NRAS Mutant (n = 60)
BRAF Mutant (n = 53)
Wild Type (n = 116)
P
Value*
CR/PR 19 (32) 12 (23) 22 (19) .068
SD/ PD 41 (68) 41 (77) 94 (81)
CR/PR/SD 30 (50) 16 (30) 34 (29) .004
PD 30 (50) 37 (70) 82 (71)
Response to First-line Immune Therapy
CR/PR 17 (28) 8 (15) 19 (16) .037
SD/PD 43 (72) 45 (85) 97 (84)
CR/PR/SD 27 (45) 13 (25) 31 (27) .006
PD 33 (55%) 40 (75) 85 (73)
Johnson DB, et al. Cancer Immunol Res. 2015;3:288-295. *Pearson χ2 test P value for NRAS-mutant vs non-NRAS-mutant pts.
Expresión intratumoral de PD-L1 y respuesta a anti-PD1/PD-L1
Mahoney KM, et al. Oncology. 2014;28:39-48.
Setting Treatment Objective Response Rate, %
Assay (mAb) Unselected PD-L1+ PD-L1–
Solid tumors (n = 42) Nivo 21 36 0 Tumor (5H1)
Melanoma (n = 44) Nivo 32 67 19 Tumor (28-8)
Tumor (28-8) Melanoma (n = 34) Nivo 29 44 17 Melanoma (n = 113) Pembro 40 49 13 Tumor (22C3) NSCLC (n = 129) Pembro 19 37 11 Tumor (22C3) HNSCC (n = 55) Pembro 18 46 11 Tumor (22C3) Melanoma (n = 411) Pembro 40 49 13 Tumor (22C3) Solid tumors (n = 94) MPDL 21 36 13 TIL Melanoma (n = 30) MPDL 29 27 20 TIL NSCLC (n = 53) MPDL 23 46 15 TIL Bladder (n = 65) MPDL 26 43 11 TIL Solid tumors (n = 179) MEDI 11 22 4 NR (SP263)
Melanoma - PD-L1 tumoral y nivolumab
100
90
80
70
60
0
50
40
30
20
10
0 3 6 9 12 15 18 Meses
Nivolumab PD-L1+
Dacarbacina PD-L1+
Nivolumab PD-L1- (<5%)
Dacarbacina PD-L1-
Dacarbacina PD-L1-
Nivolumab PD-L1-
Dacarbacina PD-L1+
Nivolumab PD-L1+
74 128 74
126
69 108 64
107
56 88 44 78
39 63 30 52
18 26 11 11
1 7 1 2
0 0 0 0
%SG 1 año (95% CI)
82 (69–89)
67 (58–75)
52 (37–65)
37 (26–48)
Mediana SG (95% CI)
Nivolumab PD-L1+ NA
Nivolumab PD-L1- NA
Dacarbacina PD-L1+ 12,4 (9,2–NA)
Dacarbacina PD-L1- 10,2 (7,6–11,8)
Modificado de Long, SMR 2014
Gajewski, Curr Opin Immun 2011
Infiltrado celular inmuno-inflamatorio del tumor
FENOTIPO NO INFLAMADO: Alta expresión de marcadores vasculares, macrófagos, fibroblastos + Escasa inflamacion, quimioquinas y linfocitos = Escaso tráfico celular inmune
FENOTIPO INFLAMADO: Alta densidad de señales de inmunidad natural, quimioquinas para reclutamiento de células T, células T activadas específicas de tumor Pero dominan los reguladores negativos
Melanoma - Supervivencia (PFS, OS) con pembrolizumab, según score de firma
génica de IFN-γ
A Ribas. ASCO 2015
MM ALGORITHM 2016 ? (be aware that this may change shortly…)
METASTATIC MELANOMA
BRAF wild type
BRAF mutated
NIVOLUMAB PEMBROLIZUMAB
iBRAF+iMEK INMUNOTHERAPY 2L
???????
1st LINE THERAPY 2nd LINE THERAPY
iBRAF+iMEK iBRAFor iMEK
vs
NIVOLUMAB PEMBROLIZUMAB
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