1. What are the main benefits of BRAF inhibitors in metastatic melanoma?
Should patients expect prolonged overall survival, prolonged progression-free survival, or simply palliation without chance of a cure?

2. Vemurafenib in previously untreated Stage IV BRAFV600 mutant melanoma (BRIM3 trial): Overall survival
Overall survival (%)
Hazard ratio 0.70
(95% CI, 0.57–0.87)
P<0.001 (post-hoc)
at February 1, 2012 cutoff Censored at crossover
100 90 80 70 60 50 40 30 20 10 6 12 24 18
Vemurafenib (n = 337)
Median f/u 12.5 months
DTIC (n = 338)
Median f/u 9.5 months
9.7
13.6
Months
No. at risk
Dacarbazine
Vemurafenib
338
337
244
326
173
280
111
231 79
178 50
109 24 44 4 7 1
Chapman et al, ASCO 2012; #8502

3. Sosman et al, N Engl J Med 2012; 366: 707–14
Vemurafenib in previously treated Stage IV BRAFV600 mutant melanoma (BRIM2 trial): Progression-free survival
Progression-free Survival (%)
100 80 60 40 20 90 70 50 30 10
6.9 12 24 6 18
Months
No. at risk
132
118 88 67 48 33 31 22 12 5
Treatment duration (weeks)
Sosman et al, N Engl J Med 2012; 366: 707–14

4. Sosman et al, N Engl J Med 2012; 366: 707–14
Vemurafenib in previously treated Stage IV BRAFV600 mutant melanoma (BRIM2 trial): Overall survival
Overall Survival (%)
100 80 60 40 20 90 70 50 30 10
15.9 12 6 18 24
Months
No. at risk
132
128
118 97 83 77 70 60 39 18 1
Treatment duration (weeks)
Sosman et al, N Engl J Med 2012; 366: 707–14

5. Dabrafenib in previously untreated Stage IV BRAFV600 mutant melanoma (BREAK3 trial): Progression-free survival (independent review)
Proportion Alive Without Progression
Hazard ratio (95% CI, 0.20–0.61) (Dec 19, 2011 cut-off)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Dabrafenib
DTIC
2.9
6.7 1 2 3 4 5 6 7 8 9
187
182
167
112 98 39 28 63 53 32 16 12
Months
No. at risk
Hauschild et al, ASCO 2012; LBA8500
Hauschild et al, Lancet 2012; 380: 358–65

6. Flaherty et al, N Engl J Med 2012; 367: 1694–703
Open label study of combined BRAF/MEK inhibition in stage IV melanoma: Progression-free survival
Estimated survival function
Median (mos)
HR (95% CI) P
12 mo. PFS (%)
Mono D
5.8 9
D150/T1
9.2
0.56 (0.37, 0.87)
0.006 26
D150/T2
9.4
0.39 (0.25, 0.62)
<0.0001 41
1.0
0.8
0.6
0.4
0.2
Median follow up time 14 mo
5.8
9.2
9.4
0.0 3 6 9 12 15 18
Patients at risk
Months 54 46 25 13 2 47 33 26 11 1 52 36 29 15
Long et al, ESMO 2012; LBA27
Flaherty et al, N Engl J Med 2012; 367: 1694–703

7. 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