Practice Update | Onology

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Dabrafenib plus trametinib in patients
with BRAF(V600)-mutant melanoma brain
metastases (COMBI-MB)
The Lancet Oncology
Take-home message
• This multicenter, multicohort, open-label, phase 2 trial was designed to evaluate
the activity and safety of the dabrafenib plus trametinib combination in patients with
BRAF V600-mutant melanoma brain metastases. The primary analysis included
76 patients with asymptomatic brain metastases and no prior local therapy. After a
median of 8.5 months of follow-up, 58% patients had experienced an intracranial
response. The toxicity profile was acceptable.
• The authors conclude that the results of this trial support the safety and efficacy
profile of this treatment combination, which is consistent with prior studies con-
ducted in patients without the presence of intracranial disease. Further data are
needed to improve outcomes in this particular subpopulation.
Abstract
BACKGROUND Dabrafenib plus trametinib
improves clinical outcomes in BRAF(V600)-mu-
tant metastatic melanoma without brain
metastases; however, the activity of dabrafenib
plus trametinib has not been studied in active
melanoma brain metastases. Here, we report
results from the phase 2 COMBI-MB trial. Our
aimwas to build on the current body of evidence
of targeted therapy in melanoma brain metas-
tases through an evaluation of dabrafenib plus
trametinib in patients with BRAF(V600)-mutant
melanoma brain metastases.
METHODS This ongoing, multicentre, multico-
hort, open-label, phase 2 study evaluated
oral dabrafenib (150 mg twice per day) plus
oral trametinib (2 mg once per day) in four
patient cohorts with melanoma brain metasta-
ses enrolled from 32 hospitals and institutions
in Europe, North America, and Australia: (A)
BRAF(V600E)-positive, asymptomatic mela-
noma brain metastases, with no previous local
brain therapy, and an Eastern Cooperative
Oncology Group (ECOG) performance status
of 0 or 1; (B) BRAF(V600E)-positive, asympto-
matic melanoma brain metastases, with previous
local brain therapy, and an ECOG performance
status of 0 or 1; (C) BRAF(V600D/K/R)-positive,
asymptomatic melanoma brain metastases,
with or without previous local brain therapy,
and an ECOG performance status of 0 or 1; and
(D) BRAF(V600D/E/K/R)-positive, symptomatic
melanoma brain metastases, with or without
previous local brain therapy, and an ECOG
performance status of 0, 1, or 2. The primary
endpoint was investigator-assessed intracranial
response in cohort A in the all-treated-patients
population. Secondary endpoints included
intracranial response in cohorts B, C, and D.
FINDINGSBetween Feb 28, 2014, and Aug 5, 2016,
125 patients were enrolled in the study: 76 patients
in cohort A; 16 patients in cohort B; 16 patients in
cohort C; and 17 patients in cohort D. At the data
cutoff (Nov 28, 2016) after a median follow-up of
8.5months (IQR 5.5–14.0), 44 (58%; 95%CI 46–69)
of 76 patients in cohort A achieved an intracranial
response. Intracranial response by investiga-
tor assessment was also achieved in nine (56%;
95% CI 30–80) of 16 patients in cohort B, seven
(44%; 20–70) of 16 patients in cohort C, and ten
(59%; 33–82) of 17 patients in cohort D. The most
common serious adverse events related to study
treatment were pyrexia for dabrafenib (eight [6%]
of 125 patients) and decreased ejection fraction
(five [4%]) for trametinib. The most common grade
3 or worse adverse events, regardless of study
drug relationship, were pyrexia (four [3%] of 125)
and headache (three [2%]).
INTERPRETATION Dabrafenib plus trametinib was
active with a manageable safety profile in this
melanoma population that was consistent with
previous dabrafenib plus trametinib studies in
patients with BRAF(V600)-mutant melanoma
without brain metastases, but the median dura-
tion of response was relatively short. These
results provide evidence of clinical benefit with
dabrafenib plus trametinib and support the
need for additional research to further improve
outcomes in patients with melanoma brain
metastases.
Dabrafenib plus trametinib in patients with
BRAF(V600)-mutant melanoma brain metas-
tases (COMBI-MB): a multicentre, multicohort,
open-label, phase 2 trial. Lancet Oncol2017 Jun
02;[EPub Ahead of Print], MA Davies, P Saiag,
C Robert, et al.
COMMENT
By Manmeet Ahluwalia MD, FACP
Traditionally, the treatment for brain
metastases mostly focused on radi-
ation-based approaches, including
stereotactic radiosurgery. Recently, we
have seen a number of trials that have
looked at treating patients with brain
metastases either with targeted therapies
or immune checkpoint blockade. This is a
phase II trial of a combination of dabrafenib
and trametinib in four different cohorts of
patients with BRAF(V600)-mutant mela-
noma brainmetastases. As expected, most
of patients had the V600E BRAF mutation,
which is the most common type of BRAF
mutation seen in patients with melanoma.
The outcomes are impressive, with
response rates of 58% in patients who
were radiation-naïve and who had
asymptomatic brain metastases. This
is in comparison with the previously
reported response rates of around 30%
seen with dabrafenib alone in patients
with asymptomatic brain metastases as
reported in the BREAK-MB study. This
trial supports the use of targeted ther-
apy for oncogene-driven tumors such
as BRAF-mutated tumors in patients who
have asymptotic brain metastases. How-
ever, what this trial does not address is
that group of patients who have sympto-
matic brain metastases at presentation.
We know that a number of patients with
brain metastases have symptomatic dis-
ease at presentation and most of these
patients are treated with some form of
radiation. Because melanoma is a radi-
ation-resistant disease, a focus on
techniques such as stereotactic radiosur-
gery is often employed in themanagement
of these patients. The next set of clinical
trials may want to focus on the treat-
ment of patients with symptomatic brain
metastases using a combination of either
stereotactic radiosurgery with some form
of targeted therapy or immune checkpoint
blockade in these patients.
Dr Ahluwalia is the Dean
and Diane Miller Family
Endowed Chair in Neuro-
Oncology in the Rose Ella
Burkhardt Brain Tumor and
Neuro-Oncology Center,
Cleveland Clinic, where he
subspecializes in treatment
of patients with brain tumors and brain
metastases. He is also Associate Professor
in the Department of Medicine, Cleveland
Clinic Lerner College of Medicine of Case
Western Reserve University.
EDITOR’S PICKS 7
VOL. 1 • NO. 2 • 2017