inhibidores de braf y mek dirigida con terapia · inhibidores de braf y mek ... supervivencia con...
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TERAPIA DIRIGIDA CON INHIBIDORES DE BRAF Y MEK
Beatriz Nieto Mangudo
Unidad de Melanoma CAULE
El melanoma es una neoplasia conducida por la vía MAPK
NRAS
BRAF
Erk
MEK
SurvivalProliferation
KIT
La inhibición de RAF depende del estatus de BRAF
Adapted from Poulikakos PI, et al. Cancer Cell. 2011;19:11-15.
Wild-type BRAF (all other cells)Mutated BRAF V600 (tumor cells)
MutBRAF
MEK
Constitutively active High MEK activity
MutBRAF
DRUG
RAF inhibitor suppresses MEK activity
MEK
RAF RAF RAF RAFActive RAS DRUG DRUGDRUG ATP
All sites inhibitor-bound MEK activity inhibited
RAF Dimers = inhibitor–induced MEK activity
RAF
DRUG
MEK MEK MEK
RAF Dimers = Elevated MEK activity
RAF Monomers =Low MEK activity
Active RAS
RAF RAF RAF
MEK MEK
Without RAF Inhibitor
With RAF Inhibitor
Inhibidores vía MAPK disponibles en Melanoma
■ Inhibidores RAF : vemurafenib[1] y dabrafenib[2]
■ Altas tasas de respuesta■ Mediana de duración de la respuesta: 6-8 meses■ Respuesta en el cerebro[3]
■ Inhibidor MEK : trametinib[4] y Cobimetinib■ Moderada tasa de respuesta (~ 20%) y aumento de supervivencia en
melanoma BRAF-mutado■ No efectivo tras progresión a inhibidor RAF ■ Papel más importante en combinación con inhibición RAF[5]
1. Martin-Liberal J, et al. Future Oncol. 2015;11:579-589. 2. Khoja L, et al. Expert Rev Anticancer Ther. 2015;15:265-276. 3. Harding JJ, et al. Oncologist. 2015;20:789-797. 4. Chopra N, et al. Expert Rev Anticancer Ther. 2015;15:749-760. 5. Long GV, et al. Lancet. 2015;[Epub ahead of print].
Terapias dirigidas en Estadio IV: principales estudios
NRAS
CRAFBRAF
MEK
ERK
BRIM-3:BRAF•Vemurafenib vs DTIC
Melanoma IIIC ó IVBRAF V600E/V600KPrimera líneaPS 0-1Mtx cerebrales controladas 12 semanas tras ttoCrossover permitido
BREAK-3:BRAF•Dabrafenib vs DTIC
OSPFS
BRIM-3 Fase III Vemurafenib vs Dacarbazine en Melanoma: OS
BRAFi en Primera línea: PFS
Vemurafenib vs Dacarbacina Dabrafenib vs DTIC
Lancet Oncol 2014; 15: 323–32 Lancet. 2012 Jul 28;380(9839):358-65.
BRAF i en Primera línea: OS
Vemurafenib vs Dacarbacina Dabrafenib vs DTIC
Lancet Oncol 2014; 15: 323–32 Lancet. 2012 Jul 28;380(9839):358-65.
BRAF i en Primera línea : TR
Vemurafenib vs Dacarbacina Dabrafenib vs DTIC
Lancet Oncol 2014; 15: 323–32 Lancet. 2012 Jul 28;380(9839):358-65.
NRAS
CRAFBRAF
MEK
ERK
BREAK-3:BRAF•Dabrafenib vs DTIC•RR 59%,mPFS 6.9m•HR OS/PFS: 0.77/0.37
BRIM-3:BRAF•Vemurafenib vs DTIC•RR 57%,mPFS 6.9m•HR OS/PFS: 0.7/0.38
Metric: BRAF•Trametinib vs QT
Terapias dirigidas en Estadio IV: principales estudios
322 pacientesMelanoma avanzadoBRAF V600E/V600K1ª ó 2ª línea no BRAFiObj. Primario: SLPCrossover permitido
METRIC: Fase III Trametinib (MEKi) vs Dacarbazine o Paclitaxel
Flaherty KT, et al. N Engl J Med. 2012;367:107-114.
1.0
0.8
0.6
0.4
0.2
00 2 4 6 8
Mos Since Randomization
Prob
abili
ty o
f PFS
4.8 vs 1.5mesesHR: 0.47 (95% Cl: 0.34-0.65; P < .001)
Trametinib(n = 214)
Chemotherapy(n = 108)
Prob
abili
ty o
f OS
1.0
0.8
0.6
0.4
0.2
00 2 4 6 8 10
Trametinib(n = 214)
Chemotherapy(n = 108)
OS a 6 meses 81 vs 67%HR: 0.54 (95% Cl: 0.32-0.92; P = .01)
Mos Since Randomization
Eventos adversos más comunes con las nuevas terapias dirigidas en Melanoma Avanzado
AE (≥ Grade 2), % Vemurafenib[1] Dabrafenib[2] Trametinib[3]
Arthralgia 21 5 NRRash 18 NR 27Fatigue 13 6 9Cutaneous SCC/ keratoacanthoma
12/8 6 (combined) NR
Hyperkeratosis 6 13 NRPyrexia NR 11 NRHeadache 5 5 NRPhotosensitivity (any grade) 12 3 NRHypertension NR NR 12
1. Chapman PB, et al. N Engl J Med. 2011;364:2507-2516. 2. Hauschild A, et al. Lancet. 2012;380:358-365. 3. Flaherty KT, et al N Engl J Med. 2012;367:107-114.
Resistencia a Inhibidores BRAF
Sosman J, et al. N Engl J Med. 2012;366:707-714.
BRIM-2 Fase II Vemurafenib en Melanoma Metastásico : PFS
Indi
vidu
al P
atie
nts
Trea
ted
With
Vem
uraf
enib
TTPTime to responseDiedAlive with response
Mos0 202 4 6 8 10 12 14 16 18
Resistencia a inhibidor BRAF
Intrínsecos
CDK 4cyclin D1 amplificada(CCN1)15-20%melanomasRESISTENCIAa BRAFi
Pérdida PTEN(corta PFS),bcl2a1 amplBraf fusion,GNAQ,RAC1P298,Pérdida NF1 RESISTENCIAa BRAFi
HGF, CMETRESISTENCIAa BRAFi
Adquiridos
No dependientes de ERK(ERK todavíainhibido)
ERK dependiente(ERKreactivado)
Sullivan et al. Eur J Cancer 2013: 1297-1304
Turajlic Annals 2014
Resistencia a inhibidor BRAF
Nazarian R, et al. Nature. 2010;468:973-977. Johannessen CM, et al. Nature. 2010;468:968-972. Villanueva J, et al. Cancer Cell. 2010;18:683-695. Wagle N, et al. J Clin Oncol. 2011;29:3085-3096. Shi H, et al. Nat Commun. 2012;3:724. Poulikakos PI, et al. Nature. 2011;480:387-390. Straussman R, et al. Nature. 2012;487:500-504. Whittaker SR, et al. Cancer Discov. 2013;3: 350-362. Maertens O, et al. Cancer Discov. 2013;3:338-349.
CRAF
BRAF
MEK
ERK
P
P
BRAF
BRAF
BRAF BR
AF
NRAS
COT
MEK
Alternative splicing
Amplification
PI3K
NF1
Espectro de resistencias
Datos de 3 grandes estudios de resistencias
100 pacientes con 132 muestras de resistencias adquiridas
Douglas Jonhson ASCO 2015
Espectro de resistencias
Douglas Jonhson ASCO 2015
Número PorcentajeMutación NRAS 23 17
Mutación KRAS 3 2
Splicing BRAF 21 16 (25)
Amplificación BRAF 17 13
Mutación MEK1/2 9 7
Otras alteraciones MAPK 3 2
Alteraciones no MAPK 14 11
Mecanismo no identificado
55 42
Espectro de resistencias
•Las mutaciones NRAS, variantes BRAF y mutaciones MEK1/2 ocurren más a menudo aisladas
•Las amplificaciones BRAF y las alteraciones no ligadas a la vía MAPK concurren con otras alteraciones más de manera más frecuente
•Varias mutaciones son mutuamente excluyentes
Douglas Jonhson ASCO 2015
Espectro de resistencias: asociaciones clínicas
•PFS fue similar independientemente del mecanismo de progresión
•Diferente patrón de progresión según mecanismo de resistencia:
NRAS más frecuente en cerebro, menos en pulmón
MEK 1/2 más frecuente en hígado
Douglas Jonhson ASCO 2015
¿Cómo frenar estas resistencias?
MEKi (Trametinib) en Melanoma Metastásico BRAF-Mutado/BRAFi-Nativo
Robert C, et al. ASCO 2012. Abstract LBA8509.
Disease Stage
39%
Trametinib (n = 214)
Confirmed RR: 22% (95% CI: 16.6-28.1)M1cM1bM1aIIIC
Unknown
100
80
60
40
200
-20
-40
-60
-80
-100
% C
hang
e Fr
om B
asel
ine
in
Dia
met
ers
of T
arge
t Les
ions
Inhibidor MEK en monoterapia tiene mínima actividad en pacientes refractarios a BRAFi
Unconfirmed RR: 5% (95% CI: 0.6-16.9) 1 CR, 1 PR, 11 SD
*Discontinued prior BRAFi due to toxicityK = V600K
M1cM1a M1bM Stage at Screening
KK
K
K
*
Max
imum
Red
uctio
n in
Tar
get L
esio
ns
From
Bas
elin
e (%
)
*
*
Kim KB, et al. J Clin Oncol. 2013;31:482-489.
100
80
60
40
20
0
-20
-40
-60
-80
-100
Inhibición combinada BRAF y MEK en Melanoma BRAFV600-Positivo
Flaherty KT, et al. N Engl J Med. 2012;367:1694-1703.
Full-dose BRAF/MEKFull-dose BRAF/half-dose MEKFull-dose BRAF
Full-Dose BRAF/MEK Full-Dose BRAFMedian PFS, mos 9.4 5.8HR 0.39 (P < .001)1.0
0.8
0.6
0.4
0.2
00 3 6 9 12 15 18
Mos Since Randomization
Prob
abili
ty o
f PFS
Resistencia retardada con la combinación BRAF/MEK vs monoterapia con BRAFi
Regresión tumoral con la combinación BRAF/MEK en pacientes refractarios a BRAFi
Max
imum
Per
cent
Red
uctio
nFr
om B
asel
ine
Mos Since Prior BRAFi
PRSDPD
Best Response on Prior BRAFiRR: 19%
M = Prior MEKi
Flaherty KT, et al. SMR 2011. Abstract LBA1-4.
--80
--60
--40
--20
0
20
40
1.0 0.4 0 0.6 4.2 -- 0.3 2.1 4.3 2.6 7.7 0.5 0.2 1.0 -- 6.2 0.5 1.0 0.2 7.4 9.21.1 1.1
M
M M M
M
Supervivencia con inhibición BRAF/MEK en función de inhibidor BRAF previo
0 6 12 18 24 30 36 420
0.2
0.4
0.6
0.8
1.0
Mos From Randomization/First Dose
Prop
ortio
n A
live
Part C 150/2 (n = 54)Part B 150/2 BRAFi naive (n = 24)Part B 150/2 BRAFi failure (n = 26)
Flaherty KT, et al. ASCO 2014. Abstract 9010.
Retratamiento con BRAFi
Thakur MD and Stuart D D Cancer Res 2013
Los tumores resistentes a BRAFi muestran dependencia contínua de la señalización BRAF(V600E)→MEK→ERK debido a sobreexpresión BRAF(V600E)
La discontinuación del tratamiento conduce a la regresión de tumores resistentes
Thakur MD Nature 2013
Retratamiento con BRAFi
Tratamiento discontínuo con IK/inmunoterapia
Los inhibidores kinasa pueden rescatar S100 durante el curso del tratamiento
Reinhard Dummer at 2015 ASCO Annual Meeting
Tratamiento combinado BRAFi + MEKi
Bases para la combinación
1.Hauschild A., et al. Lancet 2012;380:358. Updated in J Clin Oncol 2013 (suppl); ab 9013.
2.Flaherty KT., et al. N Engl J Med 2012;367:1694-1703.3.Long GV., et al. N Engl J Med 2014;371(20):1877-1888.4.Robert C., et al. N Engl J Med 2015;372(4):320-330.5.Larkin J., et al. N Engl J Med 2014;371(20):1867-1876.
BRAFi (dabrafenib/Vemurafenib)
PFS HR 0.37/0.38 v DTIC1
Hyperproliferative skin AEs
MEKi (trametinib)PFS HR 0.45 v
chemotherapy2
pERK
Proliferation SurvivalInvasion
Metastasis
RAS
MEK
BRAFi + MEKi ph3 studiesdabrafenib + trametinib
vemurafenib + cobimetinib
Decreased hyperproliferative skin AE3,4,5
BRAFmutBRAF
40%
NRAS
CRAFBRAF
MEK
ERK
BREAK-3:BRAF•Dabrafenib vs DTIC•RR 59%,mPFS 6.9m•HR OS/PFS: 0.77/0.37
BRIM-3:BRAF•Vemurafenib vs DTIC•RR 57%,mPFS 6.9m•HR OS/PFS: 0.7/0.38
Metric: BRAF•Trametinib vs DTIC•RR 22%, mPFS 4.8m•HR OS/PFS: 0.54/0.45
Terapias dirigidas en Estadio IV: principales estudios
COMBI-v:BRAF•D+T vs Vemurafenib
COMBI-v: Dabrafenib+Trametinib vs Vemurafenib en primera línea en melanoma BRAFV600E/K
BID, twice daily; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; ULN, upper limit of normal
• BRAF V600E/K mutation• Stages IIIC or IV cutaneous
melanoma• Treatment-naive in advanced
or metastatic• ECOG PS 0 or 1• No brain metastases, unless
– Treated– Stable > 12 weeks
Stratification• BRAF V600E vs V600K
mutation• LDH (> ULN vs ≤ ULN)
Vemurafenib (960 mg BID)
(n = 352)
Dabrafenib (150 mg BID) + trametinib (2 mg daily)
(n = 352)
Interim OS Analysis
(n = 202)
Final OS Analysis(n = 288)
N = 1,644 screened
n = 704
Primary endpoint: OSSecondary endpoints: progression-free survival (PFS), overall response rate (ORR), duration of response (DoR), safety
Dabrafenib+Trametinib vs Vemurafenib en primera línea en melanoma BRAFV600E/K :OS
Median Follow-up: D + T = 11 months and Vem = 10 months
Análisis OS por subgrupos (ITT)
HRFavours D +
TFavours
Vem
3.0
2.5
2.0
1.5
1.0
0.5
0
Baseline LDH > ULN
(n = 232)
Baseline LDH ≤ ULN
(n = 471)
≥ 65 years (n = 166)
< 65 years (n = 538)
Female (n = 316)
Male (n = 388)
V600E (n = 629)
V600K (n = 68)
0.75
0.68
0.81
0.46
0.71
0.61
0.58
0.78
Dabrafenib+Trametinib vs Vemurafenib en primera línea en melanoma BRAFV600E/K :PFS
Dabrafenib+Trametinib vs Vemurafenib en primera línea en melanoma BRAFV600E/K : Respuesta
Best confirmed responseDabrafenib + trametinib
(n = 351)Vemurafenib
(n = 350)
Complete response, n (%) 47 (13) 27 (8)
Partial response, n (%) 179 (51) 153 (44)
Stable disease, n (%) 92 (26) 106 (30)
Progressive disease, n (%) 22 (6) 38 (11)
Not evaluable, n (%) 11 (3) 26 (7)
Response rate, n (%)(95% CI)
226 (64)(59.1–69.4)
180 (51)(46.1–56.2)
Difference in ORR, % (95% CI)
13 (5.7–20.2)
P-value < 0.001
DoR, months (95% CI) 13.8 (11.0–NR) 7.5 (7.3–9.3)
NRAS
CRAFBRAF
MEK
ERK
BREAK-3:BRAF•Dabrafenib vs DTIC•RR 59%,mPFS 6.9m•HR OS/PFS: 0.77/0.37
BRIM-3:BRAF•Vemurafenib vs DTIC•RR 57%,mPFS 6.9m•HR OS/PFS: 0.7/0.38
Metric: BRAF•Trametinib vs DTIC•RR 22%, mPFS 4.8m•HR OS/PFS: 0.54/0.45
Terapias dirigidas en Estadio IV: principales estudios
COMBI-d:BRAF•D+T vs Dabrafenib
COMBI-v:BRAF•D+T vs Vemurafenib•RR 64%, mPFS 11,4m•HR OS/PFS:0.69/0.56
COMBI-d: DiseñoN = 947 screened
Primary Endpoint: Investigator-assessed PFSSecondary Endpoints: OS, overall response rate (ORR), duration of response, safety
N = 423
• BRAF V600E/K• Unresectable stage IIIC/IV• Treatment naïve• ECOG PS 0/1• No brain mets, unless:
▪ Treated▪ Stable ≥ 12 weeks
Stratification• BRAF mut V600E v K• LDH (>ULN v ≤ ULN)
dabrafenib + trametinib150 mg BID + 2 mg QD
n = 211
dabrafenib + placebo150 mg BID + placebo QD
n = 212
Pre-planned interim OS[95 events]
Primary Analysis
(PFS)[213 events]
Aug 2013
Final Analysis
(OS)[222 deaths]
Jan 2015
Long GV, et al. Lancet epub 31 May 2015.
No crossover to combination allowedSite staff and patients remained blinded
COMBI-d: Supervivencia Libre de Progresión
Time (months)
Dabrafenib + PlaceboEvents: 162 (76%)Median PFS 8.8 mo (95% CI:5.9–9.3)
HR 0.67 (95% CI: 0.53, 0.84)P < 0.001
Prop
ortio
n Pr
ogre
ssio
n-fr
ee1.0
0.8
0.6
0.4
0.2
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
211 196 164 137 125 96 84 80 71 70 65 61 38 26 6 0 0 0
212 177 139 109 96 81 65 52 47 40 35 31 19 16 4 0 0 0
Dabrafenib + trametinibNumber at risk
Dabrafenib + placebo
Dabrafenib + TrametinibEvents: 139 (66%)Median PFS 11.0 mo (95% CI:8.0–13.9)
Long GV, et al. Lancet epub 31 May 2015.
PFS y OS en pacientes con LDH aumentada
COMBI-d: Supervivencia
Time (months)
211 208 200 187 174 159 144 135 124 112 106 103 88 53 21 3 0 0
212 206 191 175 159 147 138 127 111 104 95 88 70 42 10 2 1 0
Dabrafenib + trametinibNumber at risk
Dabrafenib + placebo
Dabrafenib + TrametinibDied: 99 (47%)Med OS = 25·1 mo (95% CI:19.2-NR)
DabrafenibDied: 123 (58%)Median OS = 18.7 mo (95% CI:15.2–23.7)
HR 0.71 (95% CI: 0.55, 0.92)P = 0.011
2-yr OS 51%
2-yr OS 42%Prop
ortio
n A
live
1.0
0.8
0.6
0.4
0.2
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
1-yr OS = 74%
1-yr OS = 68%
Dabrafenib+Trametinib med follow up 20 mo (range 0-30 mo); Dabrafenib med follow up 16 mo (range 0-32 mo).
Long GV, et al. Lancet epub 31 May 2015.
COMBI-d: Tratamiento tras la progresiónDabrafenib +
Placeboa
n = 212n (%)
Dabrafenib + Trametinibb
n = 211n (%)
Study treatment continued post progressionc 65 (31) 62 (29)
Subsequent anti-cancer therapyd 108 (51) 70 (33)
Ipilimumab 59 (28) 37 (18)
BRAF inhibitor (vemurafenib and/or dabrafenib)
29 (14) 18 (9)
Pembrolizumab or nivolumab 14 (7) 6 (3)
Chemotherapy regimens 66 (31) 45 (21)
Other 14 (7) 4 (2)a35 (17%) remained on study treatment at data cut.b64 (30%) remained on study treatment at data cut.cReceived study treatment for at least 15 days after disease progression.dStudy treatment is not included.
Long GV, et al. Lancet epub 31 May 2015.
COMBI-d: OS por subgrupos
Hazard ratio and 95% confidence interval
Factor Number of patients
Favors Dabrafenib + trametinib
Favors Dabrafenib + placebo
0.71
0.79
0.65
0.76
0.73
0.70
0.74
0.72
0.62
0.84
0.59
0.0 0.5 1.0 1.5 2.0
All patients 423
Age: < 65 years 305
≥ 65 years 118
BRAF mutation: V600E 360
V600K 61
Stage: IIIc/M1a/M1b 142
M1c 280
LDH: ≤ ULN 273
> ULN 148
No disease sites ≤ 2 228
≥ 3 193
Long GV, et al. Lancet epub 31 May 2015.
COMBI-d: RespuestaDabrafenib + Placebo
(n = 210a)n (%)
Dabrafenib + Trametinib (n = 210a)
n (%)P-valueb
Best response
CR 28 (13) 33 (16)
PR 84 (40) 111 (53)
SD 66 (31) 50 (24)
PD 19 (9) 13 (6)
NE 13 (6) 3 (1)
Response rate
CR+PR 112 (53) 144 (69) 0.001 95% CI (46.3, 60.2) (61.8, 74.8)
Duration of response
Progressed or died, n (%) 79 (70) 86 (60)
Median, months (95% CI)
10.6 (9.1–13.8)
12.9 (9.4–19.5)
aNumber of patients with measurable disease at baseline.bChi-square test was used to calculate the P-value for difference between response rates.
Long GV, et al. Lancet epub 31 May 2015.
NRAS
CRAFBRAF
MEK
ERK
COMBI-d:BRAF•D+T vs Dabrafenib•RR 69%, mPFS 11 m•HR OS/PFS:0.71/0.67
COMBI-v:BRAF•D+T vs Vemurafenib•RR 64%, mPFS 11,4m•HR OS/PFS:0.69/0.56
coBRIM: BRAF•V+Cobimetinib vs Vemura
BREAK-3:BRAF•Dabrafenib vs DTIC•RR 59%,mPFS 6.9m•HR OS/PFS: 0.77/0.37
BRIM-3:BRAF•Vemurafenib vs DTIC•RR 57%,mPFS 6.9m•HR OS/PFS: 0.7/0.38
Metric: BRAF•Trametinib vs DTIC•RR 22%, mPFS 4.8m•HR OS/PFS: 0.54/0.45
Terapias dirigidas en Estadio IV: principales estudios
coBRIM
Primary end pointPFS, investigator assessed1
Secondary end pointsOS, objective response rate, duration of response, PFS, IRC assessed, safety, pharmacokinetics, quality of life: QLQ-C30 and EQ-5D
1:1®
•Melanoma, unresectable locally advanced or metastatic (n = 495)
•BRAFV600 mutation (cobas® 4800)
•No prior systemic therapy for advanced disease
•ECOG PS 0/1
Vemurafenib 960 mg BID × 28 days (Days 1-28) +
Cobimetinib 60 mg QD × 21 days (Days 1-21)
Vemurafenib 960 mg BID × 28 days (Days 1-28) +
Placebo
Disease progression, unacceptable
toxicity, or withdrawal of
consent
BID, two times daily; ECOG, Eastern Cooperative Oncology Group; EQ, EuroQol; HR, hazard ratio; IRC, independent review committee; OS, overall survival; PS, performance status; QD, once daily; QLQ, quality-of-life questionnaire.1. Larkin J et al. N Engl J Med. 2014;371:1867-1876.
Stratification•Geographic region•Extent of disease (M1c vs other)
Primary analysis for PFS: Performed in 2014 with the data cutoff as May 9, 2014. Protocol-specified first OS interim analysis was also performed1
Updated analysis for PFS: Presented here with the data cutoff as January 16, 2015.
coBRIM: Supervivencia libre de Progresión
ITT Population Cobi + Vemn = 247
Pbo + Vemn = 248
PFS events, n (%) 143 (57.9) 180 (72.6)
Median PFS, months(95% CI)
12.25b
(9.46-13.37) 7.20b
(5.55-7.49)
HRa (95% CI)
0.58b
(0.460-0.719)
aStratified HR. bThe median PFS was 6.2 months in Pbo + Vem, and 9.9 months in Cobi + Vem (HR, 0.51; 95% CI, 0.39-0.68) at the May 9, 2014 data cutoff.Larkin J et al. N Engl J Med. 2014;371:1867-1876.
100
80
60
40
20
0
Surv
ival
Dis
trib
utio
n Fu
nctio
n (%
)
Cobimetinib + vemurafenib (n=247)Placebo + vemurafenib (n=248)Censored+
No. of patients at riskVemurafenib + cobimetinibVemurafenib + placebo
238240
215205
190150
168115
14287
11667
7945
4630
2117
83
1
1 Months 5 Months 9 Months 13 Months 17 Months 21 Months 25 Months
Time
++
+
Kaplan-Meier Plot for PFSIntent-to-Treat Population
+++++
+
+++++++
++++++++++++++++++++
++++++++
+
+
+
+ +
+++
+
++
++
+++
+ +++
++++ ++ +++ +++++
+++++
Data cutoff of January 16, 2015 was 1 year from enrollment of last patient
Baseline Risk
FactorsTotal
n
Placebo + vemurafeni
b(n=248)
Cobimetinib + vemurafenib
(n=247)
nEvent
sMedian
(months) nEvent
sMedian
(Months)
Hazard
Ratio
95%Wald
CI
Disease Stage (IIIc/M1a/M1b, or M1c)
Age Group (yr)
Sex
Geographic Region
ECOG Performance Status
Screening Serum LDH
Prior Adjuvant Therapy
BRAFV600 Mutation Status
All Patients
495
248
180
7.2
247
143
12.3
0.59
(0.47, 0.73)
M1C
299
153
128
5.5
146
94
9.5
0.52
(0.40, 0.68)
Europe
366
138
6.0
182
107
11.2
0.58
(0.45, 0.75)
184
Unresectable Stage IIIC/M1A/M1B
196
52
11.0
101
49
13.4
0.73
(0.49, 1.08)
95
< 65
362
128
7.2
183
107
12.6
0.61
(0.47, 0.79)
179≥ 65 13
352
5.6
64
36
11.2
0.52
(0.34, 0.80)
69
Female
209
72
7.5
101
52
12.9
0.57
(0.40, 0.82)
108Mal
e286
108
5.7
146
91
11.1
0.58
(0.44, 0.77)
140
Australia/New Zealand/Others
78
26
7.4
40
20
13.3
0.57
(0.32, 1.03)
38
N. America
51
16
7.5
25
16
11.2
0.57
(0.28, 1.17)
26
0 348
110
7.6
184
100
12.9
0.65
(0.49, 0.85)
1641 13
866
5.5
58
41
10.0
0.53
(0.35, 0.78)
80
Elevated
216
85
5.4
112
78
8.2
0.57
(0.42, 0.78)
104Norma
l268
90
7.8
130
65
13.4
0.59
(0.43, 0.81)
138
Yes
48
16
7.2
24
12
16.5
0.60
(0.28, 1.27)
24No 44
7164
7.2
223
131
11.2
0.59
(0.47, 0.74)
224
V600E
344
126
7.2
170
102
10.6
0.64
(0.49, 0.83)
174V600
K56
32
24
6.0
24
14
12.4
0.52
(0.27, 1.02)
Cobimetinib + vemurafenib
better
Placebo + vemurafenib
better
1/100
1/10
1 10
100
PFS por subgrupos
coBRIM : Tasa de Respuestas
Cobimetinib + Vemurafenib
n = 247
Placebo + Vemurafenib
n = 248
Complete response (CR), n (%) 39 (15.8) 26 (10.5)
Partial response, n (%) 133 (53.8) 98 (39.5)
Objective response rate (ORR), n (%) 172 (69.6)(95% CI, 63.49-75.31)
124 (50.0)(95% CI, 43.61-56.39)
Difference in ORR, % 19.64a
(95% CI, 10.95-28.32)
Duration of response Patients with event, n (%) Median (95% CI) Range
84 (48.8)12.98 (11.10-16.62)
2.86-20.11
73 (58.9)9.23 (7.52-12.78)
1.77-17.68
aAt the primary analysis ORR was 68% and 45%, respectively, and CR was 10% and 4%, respectively. Larkin J et al. N Engl J Med. 2014;371:1867-1876.Data cutoff was January 16, 2015.
Supervivencia
Vemurafenib + Placebo
Vemurafenib + Cobimetinib
OS events, n 51 34Median OS NE NE
9-month OS (95% CI), % 72.5 (65.2-79.8)
81.1 (74.7-87.5)
HR (95% CI)P value two-sided
0.65 (0.42-1.00) P = 0.046*
Data Cutoff: May 9, 2014
Ove
rall
Surv
ival
, %
No. at Risk
243
245
229
227
182
166
112
101
62
53
20
21
6
2 1
1814 1610 126 82 4Time, months
Vemurafenib + cobimetinibVemurafenib + placebo
0
100
80
60
40
20
0
Vemurafenib + cobimetinib (n = 247)Vemurafenib + placebo (n = 248)Censored++
CI, confidence interval; NE, not estimable.* Descriptive p-value. Did not cross the pre-specified stopping boundary for the interim analysis (boundary p <0.0000037)
0
Update of Progression-Free Survival and Correlative Biomarker Analysis From coBRIM: Phase 3 Study of Cobimetinib Plus Vemurafenib in Advanced BRAF-
Mutated Melanoma
James Larkin, Yibing Yan, Grant McArthur, Paolo Ascierto, Gabriella Liszkay, Michele Maio, Mario Mandalà, Lev Demidov,
Daniil Stoyakovskiy, Luc Thomas, Luis de la Cruz-Merino,
Victoria Atkinson, Caroline Dutriaux, Claus Garbe, Matthew Wongchenko, Isabelle Rooney, Ilsung Chang,
Stephen P. Hack, Brigitte Dréno, Antoni Ribas
coBRIM Oncogenic Mutation ProfilingSequencing Targets
Gene Codon Range
HRAS 9-20, 59-76
KRAS 4-15, 55-65, 137-148
NRAS 9-20, 55-67
BRAF 581-615
EGFR 709-722, 737-749, 744-754, 757-761, 767-779, 788-798, 849-861
FGFR1 123-136, 250-262
FGFR3 363-374, 638-650
FLT3 829-840
KIT 557-579, 815-826
MET 1245-1256
PDGFRa 560-572, 840-853
RET 916-926
ABL1 249-258, 303-319
AKT1 16-27
AKT2 16-26
JAK2 607-618
PIK3CA 540-551, 1038-1049
RA
S/R
AF
RTK
Materiales
• DNA de tejido previo al tratamiento
Métodos
• Se analizaron mutaciones BRAF y 528 mutaciones conocidas activantes en 17 proteínas kinasas oncogénicas (Ion Torrent next generation sequencing)
• 423 muestras secuenciadas
• La mutación fue positiva cuando la frecuencia del alelo mutado fue detectada en >3% de las lecturas
• Los datos se correlacionaron con PFS y ORR
• En 46 de 423 muestras de pacientes (11%) se demostraron mutaciones coexistentes en RAS, RAF, y/o RTK
Distribution of Mutations in Assayed Oncogenes*60
50
40
30
20
10
0
Num
ber o
f Pat
ient
s
Coe
xist
ing
mut
atio
nR
AS
/RA
F/R
TKR
AS
/RA
FH
RA
SK
RA
SN
RA
SB
RA
F N
on-V
600
EG
FRFG
FR3
FLT3 KIT
PD
GFR
aJA
K2
PIK
3CA
RAS/RAF RTK*Includes patients with ≥1 coexisting mutation.
Baseline Oncogene Mutations Coexist With BRAFV600 Mutations in coBRIM Patients
#Allelic frequencies of co-existing oncogene mutations in baseline tumor tissues ranged from 5 – 99 % with median of 8.6%
Kaplan-Meier Plot of PFS for Sequenced Patients in Both Treatment Arms
Coexisting mutations were not associated with worse PFS in either treatment arm
pERK in Available Samples by RPPA1
RAS/RAF/RTK co-mutants have higher MAPK pathway activity, as measured by pERK
1RPPA, reverse-phase protein array.
RAS/RAF/RTK WT
RAS/RAF/RTK Mut
ORR 60% 61%
Coexisting Baseline RAS/RAF/RTK Mutations Were Not Associated With Worse PFS or ORR in coBRIM Patients
55
Greater Clinical Benefit Obtained in Advanced BRAFV600-mutated Melanoma with Cobimetinib/Vemurafenib Over
Vemurafenib Is Consistent Across Mutation Subtypes
ESMO 2015
Resumen eficacia BRAFi+MEKi
TR SLP SG %LDH elevado
Dabrafenib-Trametinib(Combi-d)
69% 11m 25,1m 36%
Dabrafenib-Trametinib(Combi-v)
64% 11,4m NA 34%
Vemurafenib-CobimetinibCo-BRIM
69,6% 12,25m NA 46%
Resumen Eventos Adversos
Vem Vem+Cobi Dabra Dabra+Trame
EA (total) 98% 98% 97% 97%EA >=G3 59% 65% 30% 32%EA que conducen a la discontinuación del tto
12% 13% 7% 11%
Long GV, et al. Lancet epub 31 May 2015.
Larkin J et al. N Engl J Med. 2014;371:1867-1876
COMBI-d: Eventos Adversos en ≥20% de pacientes
Preferred TermDabrafenib + Placeboa
n = 211 n (%)
Dabrafenib + Trametinibb
n = 209n (%)
All Grades Grade 3 All Grades Grade 3
All Events 189 (90) 63 (30) 181 (87) 66 (32)Pyrexia 52 (25) 4 (2) 108 (52) 15 (7)Chills 29 (14) 1 (<1) 58 (28) 0Fatigue 59 (28) 2 (<1) 56 (27) 4 (2)Rash 42 (20) 1 (<1) 50 (24) 0Nausea 31 (15) 1 (<1) 41 (20) 0Arthralgia 49 (23) 0 34 (16) 1 (<1)Hyperkeratosis 70 (33) 1 (<1) 13 (6) 0Hand-foot syndromec 57 (27) 1 (<1) 13 (6) 1 (<1)
Alopecia 55 (26) 0 10 (5) 0aThree grade 4 events; 1 grade 5 event, treatment-related (bile duct adenocarcinoma).bOne grade 4 event; 5 fatal SAEs, not treatment related (3 intracranial hemorrhage,1 pneumonia,1 drowning).cCombined terms of palmar-plantar erythrodysesthesia and palmoplantar keratoderma. Long GV, et al. Lancet epub 31 May 2015.
HyperkeratosisPhotosensitivity reactionDermatologi
cAlopecia
Vomiting
Increased AST
Increased ALT
Pyrexia
Increased CPK
Fatigue
Arthralgia
Rash
NauseaDiarrhea
Other
Laboratory
GI
Percentage
Co-BRIM: Eventos Adversos en ≥20% de pacientes
Grade 1
Grade 2
Grade 3
Grade 4
Vemurafenib + Placebo (n = 239)
Vemurafenib + Cobimetinib (n = 254)
Data Cutoff: May 9, 2014Larkin J et al. N Engl J Med. 2014;371:1867-1876
EA relacionados con BRAFi o MEKi
Vemurafenib+Cobimetinib(%)
Dabrafenib + Trametinib
n (%)EA relacionados con BRAFi
cuSCC + KA 3+1 3EA relacionados con MEKi
Pirexia 9 52 (G3-4:7%)
Disminución Fracción eyección 7 4
Chorioretinopathyb 20 (G3-4 <3%) <1
Long GV, et al. Lancet epub 31 May 2015.Larkin J et al. N Engl J Med. 2014;371:1867-1876
NRAS
CRAFBRAF
MEK
ERK
COMBI-d:BRAF•D+T vs Dabrafenib•RR 69%, mPFS 11 m•HR OS/PFS:0.71/0.67
COMBI-v:BRAF•D+T vs Vemurafenib•RR 64%, mPFS 11,4m•HR OS/PFS:0.69/0.56
coBRIM: BRAF•V+Cobimetinib•RR 69,6%, mPFS 12,2m•HR OS/PFS: 0,65/0,58
BREAK-3:BRAF•Dabrafenib vs DTIC•RR 59%,mPFS 6.9m•HR OS/PFS: 0.77/0.37
BRIM-3:BRAF•Vemurafenib vs DTIC•RR 57%,mPFS 6.9m•HR OS/PFS: 0.7/0.38
Metric: BRAF•Trametinib vs DTIC•RR 22%, mPFS 4.8m•HR OS/PFS: 0.54/0.45
Terapias dirigidas en Estadio IV: principales estudios
Fase II NRAS•Binimetinib (MEK 162)•ORR 63%
Phase I/II Study: LEE011 + Binimetinib (MEK162) in NRAS-Mutant Melanoma
■ LEE011: oral selective CDK4/6 inhibitor■ Binimetinib: oral selective MEK1/2 inhibitor■ Phase Ib endpoints
■ Primary objective: determine the MTD and/or recommended phase II dose using a Bayesian logistic regression model with overdose control principle
■ Secondary objectives: safety and tolerability, PK, and clinical efficacy
Sosman JA, et al. ASCO 2014. Abstract 9009.
Metastatic or Locally Advanced NRAS-Mutant
Melanoma (N ≈ 40)
Phase II/Dose ExpansionPhase Ib/Dose Escalation
LEE011 + Binimetinib
Metastatic or Locally Advanced NRAS-Mutant
Melanoma •(N ≥ 15)
MTD and/orRP2D
*LEE011 for 21 consecutive days followed by a 7-day planned break and binimetinib on a continuous dosing schedule.
Cohort Binimetinib, mg BID
LEE011, mg QD
Patients, n
1 45 200 9
2 45 250 3
3 30 300 4
4 45 300 6
Phase Ib Doses and Schedule*
LEE011 + Binimetinib (MEK162) in NRAS-Mutant Melanoma: Responses
■ Several patients had early tumor shrinkage with major symptomatic improvementSosman JA, et al. ASCO 2014. Abstract 9009.
Response, n (%) LEE011 + Binimetinib
(N = 22)
CR 0
PRConfirmed PRUnconfirmed PR
7 (33)3 (14)4 (19)
SD 11 (52)*
20% to 30% tumor mass decrease by RECIST 1.1
7 (33)
Clinical benefit rate(CR + PR + SD)
18 (86)
PD 3 (14)
Unevaluable 1 (NA)
Overall Response Individual Patient Responses
*Includes 1 patient with KRAS-mutant pancreatic cancer.
-100
n = 21
* * * * * * * * * * **
-80
-60
-40
-20
0
20
40
60
80
100
Treatment Group
K
LEE 200 mg + MEK 45 mgLEE 250 mg + MEK 45 mg
LEE 300 mg + MEK 30 mgLEE 300 mg + MEK 45 mg
Best
Per
cent
age
Cha
nge
From
Bas
elin
e
*Ongoing as of April 14, 2014 K denotes patient with KRAS-mutant pancreatic cancer
Selumetinib (melanoma uveal)
R Carvajal et al JAMA. 2014 Jun 18; 311(23): 2397–2405.
Selumetinib Misses Endpoint in
Phase III Uveal Melanoma Study-
SUMMIT
Conclusiones
■ Para el 50% de los pacientes con melanoma, la inhibición combinada BRAF y MEK mejora las respuestas y la SLP
■ Aumento en la supervivencia con medianas aún no alcanzadas y supervivencias prolongadas (51% a 2 años)
■ Tratamiento en primera línea, pendiente de establecer su papel en combinación/secuenciación con inmunoterapia
■ Es preciso mayor conocimiento de los mecanismos de resistencia y estrategias para revertirlos/retrasarlos