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Combined BRAF and MEK Inhibition with
Vemurafenib and Cobimetinib for Patients
with Advanced Melanoma
Antonio M Grimaldi, Ester Simeone, Lucia Festino, Vito Vanella and Paolo A Ascierto
Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione “G. Pascale”, Napoli, Italy
A cquired resistance is the most common cause of BRAF inhibitor monotherapy treatment failure, with the majority of patients
experiencing disease progression with a median progression-free survival of 6-8 months. As such, there has been considerable
focus on combined therapy with dual BRAF and MEK inhibition as a means to improve outcomes compared with monotherapy. In
the COMBI-d and COMBI-v trials, combined dabrafenib and trametinib was associated with significant improvements in outcomes compared
with dabrafenib or vemurafenib monotherapy, in patients with BRAF-mutant metastatic melanoma. The combination of vemurafenib and
cobimetinib has also been investigated. In the phase III CoBRIM study in patients with unresectable stage III-IV BRAF-mutant melanoma,
treatment with vemurafenib and cobimetinib resulted in significantly longer progression-free survival and overall survival (OS) compared with
vemurafenib alone. One-year OS was 74.5% in the vemurafenib and cobimetinib group and 63.8% in the vemurafenib group, while 2-year
OS rates were 48.3% and 38.0%, respectively. The combination was also well tolerated, with a lower incidence of cutaneous squamous-cell
carcinoma and keratoacanthoma compared with monotherapy. Dual inhibition of both MEK and BRAF appears to provide a more potent and
durable anti-tumour effect than BRAF monotherapy, helping to prevent acquired resistance as well as decreasing adverse events related
to BRAF inhibitor-induced activation of the MAPK-pathway. Combined BRAF and MEK inhibition is the standard of care in patients with
advanced BRAF-mutant melanoma.
Keywords Metastatic melanoma, BRAF inhibitors, MEK
inhibitors, vemurafenib, cobimetinib,
Disclosure: Antonio M Grimaldi received honoraria from
BMS, MSD, Novartis and Roche Genentech, and had
consultant/advisory role for MSD and Novartis. Ester
Simeone recevied honoraria from BMS, Novartis and
Roche Genentech. Ester Simeone had consultant/
advisory role for BMS. Lucia Festino and Vito Vanella have
nothing to disclose in relation to this article. Paolo A
Ascierto received research founding form BMS, Roche
Genentech, Array Biopharma, and had consulting/
advisory role for BMS, Roche Genentech, MSD, Novartis,
Array Biopharma, Merck Serono and Pierre Fabre. This
study involves a review of the literature and did not
involve any studies with human or animal subjects
performed by any of the authors. No funding was
received for the publication of this article.
Authorship: All named authors meet the International
Committee of Medical Journal Editors (ICMJE) criteria
for authorship of this manuscript, take responsibility
for the integrity of the work as a whole, and have
given final approval to the version to be published.
Open Access: This article is published under the
Creative Commons Attribution Noncommercial License,
which permits any non-commercial use, distribution,
adaptation and reproduction provided the original
author(s) and source are given appropriate credit.
Received: 17 October 2016
Accepted: 18 January 2017
Citation: European Oncology & Haematology,
2017;13(1):61–5 Corresponding Author: Paolo A Ascierto, Melanoma,
Cancer Immunotherapy and Innovative Therapy Unit,
Istituto Nazionale Tumori Fondazione “G. Pascale”,
Via Mariano Semmola, 80131 Napoli, Italy.
TOU CH MED ICA L MEDIA
Metastatic melanoma management has been transformed in the past few years, with the
development of new therapeutic options that provide significant survival benefits replacing
palliative chemotherapy. One aspect of this advance has been an increased understanding of
molecular aberrations in melanoma, in particular, those associated with the mitogen-activated
protein kinase (MAPK) pathway. This has resulted in the identification of new oncogenic targets and
the development of targeted therapies, including the BRAF inhibitors, vemurafenib and dabrafenib,
and the MEK inhibitors, trametinib and cobimetinib.
Around 40–60% of cutaneous melanomas have mutations in BRAF that lead to constitutive
activation of downstream signalling through the MAPK pathway. 1 The majority of BRAF mutations
are V600E (glutamic acid substituted for valine), while 10% are V600K mutations with the remainder
involving rare mutations in V600D, V600R or V600M. BRAF V600 mutations significantly increase the
catalytic activity of the BRAF protein, leading to constitutive activation and phosphorylation of MEK
and ERK in the RAS-RAF-MAPK signalling cascade. 2 BRAF inhibitors and MEK inhibitors specifically
inhibit signal transduction by respectively targeting mutated BRAF or MEK.
The first BRAF inhibitor to be approved for unresectable or metastatic BRAF V600-mutant
melanoma was vemurafenib in 2011. In the phase III BRIM-3 trial of 675 patients with previously
untreated metastatic BRAF V600E-mutant melanoma, vemurafenib 960 mg twice daily resulted in
longer progression-free survival (PFS) (5.3 versus 1.6 months) and overall survival (OS) (13.6 versus
9.7 months) compared to chemotherapy with dacarbazine. 3 At a median follow up of 7 months,
the hazard ratio (HR) for death in the vemurafenib group was 0.37 (95% confidence interval [CI],
0.2–0.55; p<0.001) while the HR for tumour progression was 0.26 (95% CI, 0.20–0.33; p<0.001).
In a later analysis with a median follow-up of 12.5 months on vemurafenib and 9.5 months on
dacarbazine, vemurafenib maintained significantly longer median PFS (6.9 versus 1.6 months;
HR 0.38 [95% CI 0.32–0.46]; p<0.0001) and median OS (13.6 versus 9.7 months; HR 0.70 [95%
CI 0.57–0.87]; p=0.0008). 4 A second BRAF inhibitor, dabrafenib, was approved in 2013 having
achieved a similar improvement in PFS when compared with dacarbazine (5.1 versus 2.7 months;
HR 0.30 [95% CI, 0.18–0.51; p<0.0001) in the phase III BREAK-3 trial. 5 A third BRAF inhibitor,
encorafenib (LGX 818) is also in development.