• Should patients expect prolonged overall survival, prolonged progression-free survival, or simply palliation without chance of a cure?

What are the main benefits of BRAF inhibitors in

metastatic melanoma?

Vemurafenib in previously untreated Stage IV BRAFV600 mutant melanoma

(BRIM3 trial): Overall survival

Chapman et al, ASCO 2012; #8502

Overall survival (%)

Vemurafenib (n = 337)Median f/u 12.5 months

DTIC (n = 338)Median f/u 9.5 months

338337

173280

79178

2444

01

244326

111231

50109

47

9.7 13.6

Hazard ratio 0.70 (95% CI, 0.57–0.87)P<0.001 (post-hoc)at February 1, 2012 cutoffCensored at crossover

MonthsDacarbazineVemurafenib

No. at risk

1009080706050403020100

0 6 12 2418

Vemurafenib in previously treated Stage IV BRAFV600 mutant melanoma

(BRIM2 trial): Progression-free survival

Sosman et al, N Engl J Med 2012; 366: 707–14

Treatment duration (weeks)

Months

Progression-free Survival (%)

12 246 18

No. at risk

132 88 48 31118 67 33 22 12 5 0

100

80

60

40

20

0

90

70

50

30

10 6.9

Vemurafenib in previously treated Stage IV BRAFV600 mutant melanoma

(BRIM2 trial): Overall survival

Sosman et al, N Engl J Med 2012; 366: 707–14

Treatment duration (weeks)

Months

Overall Survival (%)

126 18

No. at risk 132 118 83 70128 97 77 39 18 1 0

100

80

60

40

20

0

90

70

50

30

10

24

60

15.9

Dabrafenib in previously untreated Stage IV BRAFV600 mutant melanoma

(BREAK3 trial):Progression-free survival (independent

review)

Hauschild et al, ASCO 2012; LBA8500Hauschild et al, Lancet 2012; 380: 358–65

0 1 2 3 4 5 6 7 8 9

187 182 167 112 98 39 28 7 4 063 53 32 16 12 5 4 2 0 0

Dabrafenib

DTIC

Hazard ratio 0.35 (95% CI, 0.20–0.61) (Dec 19, 2011 cut-off)

Proportion Alive Without Progression

MonthsNo. at risk

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

6.72.9

Median

(mos)

HR(95% CI)

P 12 mo. PFS (%)

Mono D

5.8 9

D150/T1

9.20.56 (0.37, 0.87)

0.006 26

D150/T2

9.4 0.39 (0.25, 0.62)

<0.0001

41

Open label study of combined BRAF/MEK inhibition in stage IV

melanoma: Progression-free survival

Long et al, ESMO 2012; LBA27Flaherty et al, N Engl J Med 2012; 367: 1694–703

Estimated survival function

Patients at risk

Months

1.0

0.8

0.6

0.4

0.2

0.0

0 3 6 9 12 15 18

54 46 25 13 2 054 47 33 26 11 154 52 36 29 15 1

Median follow up time 14 mo

5.8 9.2 9.4

Benefits of BRAF inhibition

Front line BRAF inhibitors provide Significant PFS (5–7 months) Prolonged survival (13–18 months)

There are few data on cures <10% of the BRIM2 patients are

alive free of disease 3–5 years from treatment

The drugs provide significant palliation, especially in patients with rapidly growing or symptomatic disease