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.