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Cancer Therapy: Clinical
Phase I Dose-Escalation and -Expansion Study of
the BRAF Inhibitor Encorafenib (LGX818) in
Metastatic
BRAF
-Mutant Melanoma
Jean-Pierre Delord
1
, Caroline Robert
2
, Marta Nyakas
3
, Grant A. McArthur
4
,
Ragini Kudchakar
5
, Amit Mahipal
6
, Yasuhide Yamada
7
, Ryan Sullivan
8
,
Ana Arance
9
, Richard F. Kefford
10,11
, Matteo S. Carlino
10
, Manuel Hidalgo
12
,
Carlos Gomez-Roca
1
, Daniela Michel
13
, Abdelkader Seroutou
13
,
Vassilios Aslanis
13
, Giordano Caponigro
14
, Darrin D. Stuart
14
,
Laure Moutouh-de Parseval
13
, Tim Demuth
13
, and Reinhard Dummer
15
Abstract
Purpose:
Encorafenib, a selective BRAF inhibitor (BRAFi), has a
pharmacologic pro
fi
le that is distinct from that of other clinically
active BRAFis. We evaluated encorafenib in a phase I study in
patients with BRAFi treatment-na
€"
ve and pretreated
BRAF
-mutant
melanoma.
Experimental Design:
The pharmacologic activity of encor-
afenib was
fi
rst characterized preclinically. Encorafenib mono-
therapy was then tested across a range of once-daily (50
–
700 mg) or twice-daily (75
–
150 mg) regimens in a phase I,
open-label, dose-escalation and -expansion study in adult
patients with histologically con
fi
rmed advanced/metastatic
BRAF
-mutant melanoma. Study objectives were to deter-
mine the maximum tolerated dose (MTD) and/or recom-
mended phase II dose (RP2D), characterize the safety and
tolerability and pharmacokinetic pro
fi
le, and assess the pre-
and suppressed proliferation and tumor growth of
BRAF
V600E
–
mutant melanoma models. In the dose-escalation
phase, 54 patients (29 BRAFi-pretreated and 25 BRAFi-na
€"
ve)
were enrolled. Seven patients in the dose-determining set
experienced dose-limiting toxicities. Encorafenib at a dose of
300 mg once daily was declared the RP2D. In the expansion
phase, the most common all-cause adverse events were nausea
(66%), myalgia (63%), and palmar
–
plantar erythrodysesthesia
(54%). In BRAFi-na
€"
ve patients, the overall response rate (ORR)
and median progression-free survival (mPFS) were 60% and
12.4 months [95% con
fi
dence interval (CI), 7.4
–
not reached
(NR)]. In BRAFi-pretreated patients, the ORR and mPFS were
22% and 1.9 months (95% CI, 0.9
–
3.7).
Conclusions:
Once-daily dosing of single-agent encorafenib
had a distinct tolerability pro
fi
le and showed varying antitumor
Clinical
Cancer
Research
Published OnlineFirst June 13, 2017; DOI: 10.1158/1078-0432.CCR-16-2923
ü
Inhibidor BRAF altamente selectivo
ü
Menos efectos secundarios