The development of the BRAF inhibitor encorafenib (LGX818) and mitogen-activated protein kinase kinase inhibitor binimetinib (MEK162) in patients with metastatic melanoma

R. Dummer, K. Flaherty, R. Kefford, P. A. Ascierto, L. Moutouh-de Parseval, E. Wasserman, D. Schadendorf

Research output: Contribution to journalMeeting abstract


Activating mutations in BRAF and NRAS account for 40–50%
and 15–25% of mutations in cutaneous melanoma, respec-
tively, and treatment is rapidly evolving with the recent
approval of immunotherapies and agents targeting the mito-
gen-activated protein kinase (MAPK) signalling pathway. Here,
a summary of the data supporting clinical development of the
BRAF inhibitor encorafenib (LGX818) and the MAPK kinase
(MEK) inhibitor binimetinib (MEK162) for the treatment of
metastatic cutaneous melanoma will be presented. Encorafe-
nib, a potent, highly selective BRAF inhibitor, has demon-
strated phase 1 single-agent clinical activity in BRAF inhibitor-
naive patients with BRAF V600-mutant metastatic melanoma
[overall response rate (ORR) 65%, 17 of 26; and BRAF inhibi-
tor-pretreated ORR 11%, three of 28]. Common adverse
events associated with encorafenib included cutaneous toxici-
ties (palmoplantar erythrodysesthesia syndrome, hyperkerato-
sis, keratosis pilaris, alopecia, dry skin), arthralgia and fatigue.
Currently, there are no approved specific therapies for patients
with NRAS mutant melanoma. In a phase 2 study, the MEK
inhibitor binimetinib was the first targeted agent to show clin-
ical activity in the NRAS mutant subset, with 20% of patients
with melanoma with NRAS mutations (six of 30) achieving
partial response. Adverse events commonly associated with
binimetinib included dermatitis acneiform, peripheral oedema,
diarrhoea, increased creatine phosphokinase and retinal events.
A phase 3 trial evaluating binimetinib vs. dacarbazine in NRAS
mutant melanoma (NEMO; NCT01763164) is currently
recruiting worldwide. To increase the duration of patient
response to encorafenib monotherapy and potentially improve
single-agent safety profiles, the combination of encorafenib
and binimetinib in BRAF V600 mutant melanoma was investi-
gated in a phase 1b/2 study. Clinical response was achieved
with the combination in both BRAF inhibitor-naive (ORR
89%, eight of nine) and BRAF inhibitor-pretreated patients
(ORR 21%, three of 14). The combination of encorafenib plus
binimetinib was well tolerated with no substantial increase in
adverse events for the combination compared with single-
agent therapy. The combination also mitigated some on-target
BRAF inhibitor-associated adverse events, including cutaneous
toxicities (hyperkeratosis, keratoacanthoma, squamous cell car-
cinoma, palmoplantar erythrodysesthesia syndrome), myalgia
and arthralgia. Only low incidences of febrile events, photo-
sensitivity and rash have been reported in this study to date. A
phase 3 trial assessing the combination of encorafenib plus
binimetinib or encorafenib alone vs. the BRAF inhibitor vemu-
rafenib in BRAF V600 mutant melanoma (COLUMBUS;
NCT01909453) is currently enrolling globally.
Original languageEnglish
Article number150 (PP17)
Pages (from-to)e80-e80
Number of pages1
JournalBritish Journal of Dermatology
Issue number3
Publication statusPublished - Sep 2014
Externally publishedYes
Event15th World Congress on Cancers of the Skin - Edinburgh, United Kingdom
Duration: 3 Sep 20146 Sep 2014

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