BACKGROUND: Addition of a MEK inhibitor to a BRAF inhibitor enhances tumour 
growth inhibition, delays acquired resistance, and abrogates paradoxical 
activation of the MAPK pathway in preclinical models of BRAF-mutated melanoma. 
We assessed the safety and efficacy of combined BRAF inhibition with vemurafenib 
and MEK inhibition with cobimetinib in patients with advanced BRAF-mutated 
melanoma.
METHODS: We undertook a phase 1b study in patients with advanced 
BRAF(V600)-mutated melanoma. We included individuals who had either recently 
progressed on vemurafenib or never received a BRAF inhibitor. In the 
dose-escalation phase of our study, patients received vemurafenib 720 mg or 960 
mg twice a day continuously and cobimetinib 60 mg, 80 mg, or 100 mg once a day 
for either 14 days on and 14 days off (14/14), 21 days on and 7 days off (21/7), 
or continuously (28/0). The primary endpoint was safety of the drug combination 
and to identify dose-limiting toxic effects and the maximum tolerated dose. 
Efficacy was a key secondary endpoint. All patients treated with vemurafenib and 
cobimetinib were included in safety and efficacy analyses (intention-to-treat). 
The study completed accrual and all analyses are final. This study is registered 
with ClinicalTrials.gov, number NCT01271803.
FINDINGS: 129 patients were treated at ten dosing regimens combining vemurafenib 
and cobimetinib: 66 had recently progressed on vemurafenib and 63 had never 
received a BRAF inhibitor. Dose-limiting toxic effects arose in four patients. 
One patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 80 
mg once a day 14/14 had grade 3 fatigue for more than 7 days; one patient on a 
schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg once a day 21/7 
had a grade 3 prolongation of QTc; and two patients on a schedule of vemurafenib 
960 mg twice a day and cobimetinib 60 mg 28/0 had dose-limiting toxic 
effects-one developed grade 3 stomatitis and fatigue and one developed 
arthralgia and myalgia. The maximum tolerated dose was established as 
vemurafenib 960 mg twice a day in combination with cobimetinib 60 mg 21/7. 
Across all dosing regimens, the most common adverse events were diarrhoea (83 
patients, 64%), non-acneiform rash (77 patients, 60%), liver enzyme 
abnormalities (64 patients, 50%), fatigue (62 patients, 48%), nausea (58 
patients, 45%), and photosensitivity (52 patients, 40%). Most adverse events 
were mild-to-moderate in severity. The most common grade 3 or 4 adverse events 
were cutaneous squamous-cell carcinoma (12 patients, 9%; all grade 3), raised 
amounts of alkaline phosphatase (11 patients, 9%]), and anaemia (nine patients, 
7%). Confirmed objective responses were recorded in ten (15%) of 66 patients who 
had recently progressed on vemurafenib, with a median progression-free survival 
of 2·8 months (95% CI 2·6-3·4). Confirmed objective responses were noted in 55 
(87%) of 63 patients who had never received a BRAF inhibitor, including six 
(10%) who had a complete response; median progression-free survival was 13·7 
months (95% CI 10·1-17·5).
INTERPRETATION: The combination of vemurafenib and cobimetinib was safe and 
tolerable when administered at the respective maximum tolerated doses. The 
combination has promising antitumour activity and further clinical development 
is warranted in patients with advanced BRAF(V600)-mutated melanoma, particularly 
in those who have never received a BRAF inhibitor; confirmatory clinical testing 
is ongoing.
FUNDING: F Hoffmann-La Roche/Genentech.