Tratamiento de combinación en el
melanoma irresecable o avanzado BRAF +
Dra. Ainara Soria Rivas
Servicio de Oncología Médica
EVOLUCIÓN DEL TRATAMIENTO DEL MELANOMA
Combinaciones de
quimioterapia (CVD, Dartmouth)
1975 1980s 1998
DACARBAZINA IL 2
ALTAS DOSIS
2011
IPILIMUMAB
VEMURAFENIB TRAMETINIB COBIMETINIB
DABRAFENIB
NIVOLUMAB PEMBROLIZUMAB
NIVOLUMAB- IPILIMUMAB
ENCORAFENIB BINIMETINIB
2017
HALLMARKS OF CANCER
Hanahan D, Weingerg RA. Cell 2000 Jan 7;100(1):57-70. Hanahan D, Weinberg RA. Cell 2011. Vol144 (5): 646-674.
VIA DE LAS MAP KINASAS
Dermatol Ther 2015 Sep 5
Salama A K , and Flaherty K T Clin Cancer Res 2013;19:4326-4334
N Engl J Med 2014
N Engl J Med 2015
COMBI-D: Supervivencia libre de progresión
Flaherty K. ASCO 2016
Robert C. ESMO 2016.
COMBI-D: Supervivencia global
Flaherty K. ASCO 2016 58% de los pacientes vivos, se encuentran en tratamiento con D +T
Robert C. ESMO 2016.
COMBI-v: Best Response
14
Best Confirmed Response
Dabrafenib + Trametinib (n = 352)
Vemurafenib (n = 352)a
Overall response rate, n (%) [95% CI]
236 (67) [62-72]
187 (53) [48-58]
Complete response (CR), n (%) 68 (19) 41 (12)
Partial response (PR), n (%) 168 (48) 146 (41)
Stable disease (SD), n (%) 83 (24) 109 (31)
Progressive disease, n (%) 22 (6) 37 (11)
Not evaluable, n (%) 11 (3) 18 (5)
Robert C. ESMO 2016.
COMBI-v: Duration of Response
15
● 36 of 68 patients (53%) with a CR on dabrafenib + trametinib are still in CR ● 21 of 41 patients (51%) with a CR on vemurafenib are still in CR
Pat
ien
ts
Survival, months
0 10 20 30 40
Dabrafenib + Trametinib
0 10 20 30 40
Survival, months
Pat
ien
ts
Vemurafenib
Median DOR (95% CI), months Dabrafenib + Trametinib Vemurafenib
All responders (CR + PR) 13.8 (11.3-17.7) 7.9 (7.4-9.3)
Complete responders 39.6 (26.5-NR) 29.9 (16.7-NR)
Partial responders 10.8 (9.2-12.0) 7.3 (5.8-7.5)
Complete response
Partial response
Complete response
Partial response
Robert C. ESMO 2016.
Robert C. ESMO 2016
Flaherty K. ASCO 2016
COMBI-v: Post-Progression Systemic Therapy
18
Post-Progression Systemic Therapy Dabrafenib + Trametinib
(n = 187) Vemurafenib
(n = 248)
Subsequent anticancer therapy, n (%)
Immunotherapy 108 (58) 123 (50)
Ipilimumab 88 (47) 100 (40)
Nivolumab 3 (2) 3 (1)
Pembrolizumab 14 (7) 13 (5)
Radiotherapy 102 (55) 120 (48)
Small-molecule targeted therapy 59 (32) 115 (46)a
Chemotherapy 43 (23) 71 (29)
Biologic therapy 14 (7) 12 (5)
Hormonal therapy 0 2 (< 1)
Median time from study treatment discontinuation to start of subsequent systemic therapy
12 days 11 days
● A total of 187 patients (53%) in the dabrafenib + trametinib arm and 248 patients (70%) in the vemurafenib arm received post-study anticancer therapy
a Includes patients who crossed over from vemurafenib to dabrafenib + trametinib. Robert C. ESMO 2016.
IMPACTO DE LOS FACTORES PRONÓSTICOS…
COMBI-v: Complete Responders—Baseline Characteristics
20
Dabrafenib + Trametinib (n = 68) Vemurafenib (n = 41)
Median age (range), years 59 (26-80) 50 (23-79)
Male sex, n (%) 35 (51) 15 (37)
ECOG PS, n (%) 0/1
62 (91)/5 (7)a
32 (78)/9 (22)
BRAF V600 mutation status, n (%) V600E mutation–positive V600K mutation–positive
64 (94)
4 (6)
40 (98)
1 (2)
Metastasis stage at screening, n (%)b M0 M1a M1b M1c
6 (9)
18 (27) 17 (25) 26 (39)
2 (5)
15 (37) 5 (12)
18 (44)
Baseline LDH, n (%) ≤ ULN/> ULN
64 (94)/4 (6)
36 (88)/5 (12)
Visceral disease at baseline, n (%) Yes/No
44 (66)/23 (34)
24 (59)/17 (41)
Number of organ sites with metastasis, n (%) < 3/≥ 3
57 (84)/11 (16)
37 (90)/4 (10)
a One patient had missing ECOG PS at baseline; b One patient in the Vem arm had a metastasis stage of MX at screening.
COMBI-v: Elevated LDH (> ULN)
23
OS PFS
OS
Pro
bab
ility
Dabrafenib + trametinib (n = 119) Median OS, 10.8 (95% CI, 8.9-14.4)
HR, 0.79 (95% CI, 0.59-1.07)
3-y OS, 20%
3-y OS, 14%
2-y OS, 27%
2-y OS, 25%
PFS
Pro
bab
ility
Months From Randomization
Dabrafenib + trametinib (n = 119) Median PFS, 5.5 (95% CI, 5.3-7.3)
Vemurafenib (n = 114) Median PFS, 4.0 (95% CI, 3.7-5.4)
3-y PFS, 6%
3-y PFS, 3%
2-y PFS, 13%
2-y PFS, 4%
HR, 0.70 (95% CI, 0.53-0.93)
Months From Randomization
1.00
0.75
0.50
0.25
0.00
0 6 12 18 24 30 36 42
1.00
0.75
0.50
0.25
0.00
0 6 12 18 24 30 36
119 114
90 77
52 37
38 31
27 23
20 16
15 10
3 3
119 114
49 32
26 12
15 7
13 3
12 3
4 2
Patients at risk, n D + T Vem
Patients at risk, n D + T Vem
Vemurafenib (n = 114) Median OS, 8.7 (95% CI, 7.3-10.7)
Robert C. ESMO 2016.
COMBI-v: Normal LDH (≤ ULN)
24
Patients at risk, n D + T Vem
Patients at risk, n D + T Vem
Months From Randomization
Dabrafenib + trametinib (n = 233) Median OS, NR (95% CI, 35.1-NR)
3-y OS, 56%
3-y OS, 39%
2-y OS, 66%
2-y OS, 46%
Months From Randomization
Dabrafenib + trametinib (n = 233) Median PFS, 17.5 (95% CI, 14.9-21.2)
Vemurafenib (n = 238) Median PFS, 9.2 (95% CI, 7.6-10.9)
HR, 0.56 (95% CI, 0.44-0.70)
3-y PFS, 33%
3-y PFS, 13%
2-y PFS, 39%
2-y PFS, 21%
OS
Pro
bab
ility
PFS
Pro
bab
ility
1.00
0.75
0.50
0.25
0.00
0 6 12 18 24 30 36 42
1.00
0.75
0.50
0.25
0.00
0 6 12 18 24 30 36 42
233 238
221 212
193 166
163 123
144 96
130 87
112 71
30 19
233 238
187 130
136 70
105 48
80 24
68 13
59 9
25 2
Vemurafenib (n = 238) Median OS, 21.6 (95% CI, 18.2-26.4)
HR, 0.61 (95% CI, 0.47-0.79)
NR, not reached.
OS PFS
Robert C. ESMO 2016.
COMBI-v: Normal LDH and < 3 Organ Sites With Metastasis
26
Patients at risk, n D + T Vem
OS
Pro
bab
ility
Months From Randomization
Vemurafenib (n = 161) Median OS, 26.4 (95% CI, 21.5-46.8)
HR, 0.47 (95% CI, 0.33-0.67)
3-y OS, 70%
3-y OS, 46% 2-y OS, 52%
2-y OS, 79%
Dabrafenib + trametinib (n = 141) Median OS, NR (95% CI, NR-NR)
141 161
135 146
125 125
115 91
104 75
96 68
83 58
21 16
1.00
0.75
0.50
0.25
0.00
0 6 12 18 24 30 36 42
Patients at risk, n D + T Vem
Months From Randomization
3-y PFS, 39%
3-y PFS, 16%
2-y PFS, 46%
2-y PFS, 27% Vemurafenib (n = 161) Median PFS, 10.7 (95% CI, 9.0-11.1)
HR, 0.52 (95% CI, 0.39-0.70)
PFS
Pro
bab
ility
Dabrafenib + trametinib (n = 141) Median PFS, 23.0 (95% CI, 18.1-29.7)
141 161
123 93
98 50
76 40
59 22
49 12
43 8
19 2
1.00
0.75
0.50
0.25
0.00
0 6 12 18 24 30 36 42
OS PFS
Robert C. ESMO 2016.
POOLED ANALYSIS DABRAFENIB-TRAMETINIB
27
• Phase 1/2: dabrafenib + trametinib1
• COMBI-d: dabrafenib + trametinib vs dabrafenib2
• COMBI-v: dabrafenib + trametinib vs vemurafenib3
Pooled
Analysis
Overall Survival (OS) Median (95% CI), mo
Phase 1/2 D + T 25.0 (17.5–36.5)
COMBI-d D + T 25.1 (19.2–NR)
COMBI-d D + P 18.7 (15.2–23.7)
COMBI-v D + T 25.6 (22.6–NR)
COMBI-v V 18.0 (15.6–20.7)
Months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48
OS
Pro
babili
ty
Long G, et al. Lancet Oncol Dec 2016
Methods: Patients
28
Study Randomize
d, na
PFS
Events, n
OS Events,
n
COMBI-v 352 215 155
COMBI-d 211 139 99
Phase 1/2 54 42 36
TOTAL 617 396 290
• Median duration of follow-up was 20.0 months
• 221 (36%) patients remained progression-free and alive
at analysis
BID, twice daily; PFS, progression-free survival; QD, once daily.
a Intention-to-treat population.
• Treatment-naive patients randomized to dabrafenib 150mg
BID + trametinib 2mg QD:
PRESENTED BY GV LONG AT SMR 2015
Five Baseline Factors Influenced OS
29
ECOG = 0 ECOG ≥ 1
N = 93
1Y = 71%
2Y = 43%
3Y = NE
N = 56
1Y = 42%
2Y = 19%
3Y = 16%
LDH Normal LDH ≥ ULN N = 617
Disease Sites ≥ 3 Disease Sites < 3
N = 161
1Y = 76%
2Y = 55%
3Y = 38%
N = 237
1Y = 90%
2Y = 75%
3Y = 70%
LDH >1-≤ 2 × ULN LDH ≥ 2 × ULN
N = 70
1Y = 40%
2Y = 7%
3Y = 7%
N = 149
1Y = 60%
2Y = 33%
3Y = 9%
N = 219
1Y = 54%
2Y = 25%
3Y = 7%
N = 398
1Y = 85%
2Y = 67%
3Y = 57%
a Regression tree analysis.
NE, not estimable. PRESENTED BY GV LONG AT SMR 2015
OS by LDH, Number of Disease Sites, and ECOG
30
Normal LDH, Disease Sites < 3 Normal LDH, Disease Sites ≥ 3
LDH > 1 x ULN, ECOG = 0 LDH > 1 x ULN, ECOG ≥ 1
LDH > 2 x ULN
a Factors identified by the regression tree analysis.
237 206 103 14
161 119 58 5
93 61 15 0
56 23 9 1
70 22 1 0
No. at risk
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36
OS
Pro
ba
bili
ty
Months
Normal LDH, Disease Sites < 3
Normal LDH, Disease Sites ≥ 3
LDH >1-≤ 2 x ULN, ECOG = 0
LDH >1-≤ 2 x ULN, ECOG ≥ 1
LDH > 2 x ULN
PRESENTED BY GV LONG AT SMR 2015
Four Baseline Factors Influenced PFS
31
LDH Normal LDH ≥ ULN
N = 617
LDH >1-≤ 2 × ULN
LDH ≥ 2 × ULN
N = 149
1Y = 32%
2Y = 18%
3Y = 18%
N = 70
1Y = 8%
2Y = 2%
3Y = 2%
Disease Sites < 3 Disease Sites ≥ 3
N = 161
1Y = 50%
2Y = 29%
3Y = 17%
N = 237
1Y = 68%
2Y = 46%
3Y = 42%
N = 219
1Y = 24%
2Y = 13%
3Y = 13%
N = 398
1Y = 61%
2Y = 40%
3Y = 33%
a Regression tree analysis. PRESENTED BY GV LONG AT SMR 2015
PFS by LDH and Number of Disease Sites
32
No. at risk
Normal LDH, Disease Sites < 3 Normal LDH, Disease Sites ≥ 3
LDH > 1 x ULN
LDH > 2 x ULN
a Factors identified by the regression tree analysis.
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36
237 149 53 8
161 69 23 2
149 40 9 0
70 4 0 0
PF
S P
rob
ab
ility
Months
Normal LDH, Disease Sites < 3
Normal LDH, Disease Sites ≥ 3
LDH >1-≤ 2 x ULN
LDH > 2 x ULN
PRESENTED BY GV LONG AT SMR 2015
ENSAYOS POR VENIR…
Dabrafenib and Trametinib Followed by Ipilimumab and Nivolumab or Ipilimumab and Nivolumab Followed by
Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAFV600 Melanoma
National Cancer Institute (NCI)
NCT02224781
IPILIMUMAB + NIVOLUMAB
DABRAFENIB + TRAMETINIB
IPILIMUMAB + NIVOLUMAB
DABRAFENIB + TRAMETINIB
Progresión o toxicidad
Progresión o toxicidad
Primary Outcome: OS rate, defined as the proportion of patients alive after 2 years of follow-up time. Secondary Outcome: PFS, evaluated based on RECIST version 1.1 Response rate according to RECIST version 1.1 Toxicity rate
Arm A
Arm B
CONCLUSIONES
• Dabrafenib y Trametinib han demostrado:
– Aumentar la SLP (12,1 meses).
– Aumentar la supervivencia global (26,1 meses).
• Alta tasa de respuestas: ORR 69% (16% RC) y 24% EE.
• Factores de buen pronóstico: LDH normal y menos de 3 localizaciones preciden un beneficio más prolongado del tratamiento y mayor probabilidad de respuesta completa.
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