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TABLE 1
Selected published clinical trials.*
Study
Author,
year
Phase N
Intervention
ORR (%) mPFS (months) Survival data
Immune-checkpoint blockade
-
Hodi, 2010 3
676 Ipilimumab 3 mg/kg vs.
Ipilimumab 3 mg/kg+gp
100 vs. gp100
10.9 x 5.7
x 1.5
2.86 x 2.76 x 2.76 mOS 10.1 mo x 10.0 mo
x 6.4 mo
-
Robert, 2011 3
502 Ipilimumab 10 mg/kg+DTIC
vs. DTIC
15.2 x 10.6 Not available
5y OS 18.2% x 8.8%
KEYNOTE 001 Ribas, 2016 1
655 Pembrolizumab
33
5,2
mOS 23 mo
KEYNOTE 002 Ribas, 2015 3
540 Pembrolizumab 2 mg/kg vs.
Pembrolizumab 10 mg/kg vs.
CT
38 x 46 x 8 4.2 x 5.6 x 2.6
NR
KEYNOTE 006 Robert, 2015 3
834 Pembrolizumab q 14d x
Pembrolizumab q 21d x
Ipilimumab
3 3 . 7 x
3 2 . 9 x
11.9
5.5 x 4.1 x 2.8
2y OS 55% x 55% x43%
-
Topalian, 2014 1
107 Nivolumab
31
3,7
mOS 16.8 mo
CheckMate 037 Weber, 2015 3
405 Nivolumab vs. CT
32 x 5
4.7 x 4.2
NR
CheckMate 066 Robert, 2015 3
418 Nivolumab vs. Dacarbazine 40 x 13.9 5.1 x 2.2
NR x 10.8 mo
CheckMate 069 Postow, 2015 2
142 Ipilimumab/Nivolumab vs.
Ipilimumab
61 x 11 NR x 4.4
NR
CheckMate 067 Larkin, 2015 3
945 Ipilimumab/Nivolumab vs.
Nivolumab vs. Ipilimumab
57.6 x 43.7
x 19
11.5 x 6.9 x 2.9
NR
MAPK pathway blockade
BRIM 3
McArthur,
2014
3
675 Vemurafenib vs. Dacarbazine 48 x 5
6.9 x 1.6
mOS 13.6 mo x 9.7 mo
BREAK 3
Hauschild,
2012
3
250 Dabrafenib vs. Dacarbazine 50 x 6
5.1 x 2.7
NR
METRIC
Flaherty, 2012 3
322 Trametinib vs. CT
22 x 8
4.8 x 1.5
6 mo OS 81% x 67%
coBRIM Ascierto, 2016 3
495 Vemurafenib + Cobimetinib
vs. Vemurafenib
70 x 50 12.3 x 7.2
mOS 22.3 mo x 17.4 mo
COMBI-v
Robert, 2015 3
704 Dabrafenib + Trametinib vs.
Vemurafenib
64 x 51 11.4 x 7.3
mOS 25.6 mo x 18.3 mo
COMBI-d
Long, 2015 3
423 Dabrafenib + Trametinib vs.
Dabrafenib
69 x 53 11.0 x 8.8
mOS 25.1 mo x 18.7 mo
*Data extracted from published manuscripts.
mo: months; N: number of patients enrolled; ORR: objective response rate; mPFS: median progression-free survival; OS: overall survival data; CT: chemotherapy; DTIC: dacarbazine; NR: not reached.
Besides alterations involving BRAF, other melanoma
gene mutations have been identified, which can also offer
significant therapeutic insights. NRAS, an upstream ef-
fector of the MAP and PI3K pathways, is mutated in about
20% of the cases.
9,24
Other less common mutations occur
in NF1 and c-KIT.
7,9
Initial results of a phase 3 trial com-
paring binimetinib, a MEKi, to dacarbazine in patients
with advanced NRAS mutation tumors, showed an in-
crease in PFS (median PFS 2.8 vs. 1.5 months; HR 0.62;
95CI 0.47-0.80; p<0.001). In this trial, there was no sig-
nificant difference in overall survival (11 vs. 10 months),
although survival data were still immature.
24
Although
infrequent, c-KIT mutations can be found in acral and
mucosal melanomas; in several case reports, a rapid, but
transient response was achieved with imatinib mesylate,
a small molecule inhibitor of KIT and other tyrosine ki-
nases.
25,26
These observations were confirmed in subse-
quent prospective, non-comparative phase 2 studies, in
which imatinib resulted in response rates of approxi-
mately 20%, despite relatively short PFS intervals ranging
from 2.8 to 3.7 months.
27,28
Taken together, although the
benefit of targeted approaches in patients with melanoma