title: Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study.
abstract: 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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  F Hoffmann-La Roche/Genentech.
authors.affiliation: Jonsson Comprehensive Cancer Center at University of California, Los Angeles, CA, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: University of Colorado Comprehensive Cancer Center, Aurora, CO, USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Gonzalez
authors.affiliation: New York University Medical Center, New York, NY, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Pavlick
authors.affiliation: The Angeles Clinic and Research Institute, Los Angeles, CA, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Hamid
authors.affiliation: University of Chicago, Chicago, IL, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
authors.affiliation: Hematology/Oncology Division, University of California, San Francisco, CA, USA.
authors.forename: Adil
authors.initials: A
authors.lastname: Daud
authors.affiliation: Karmanos Cancer Institute, Detroit, MI, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Flaherty
authors.affiliation: Indiana University, Indianapolis, IN, USA.
authors.forename: Theodore
authors.initials: T
authors.lastname: Logan
authors.affiliation: Jonsson Comprehensive Cancer Center at University of California, Los Angeles, CA, USA.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Chmielowski
authors.affiliation: University of Colorado Comprehensive Cancer Center, Aurora, CO, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Lewis
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Damien
authors.initials: D
authors.lastname: Kee
authors.affiliation: The Angeles Clinic and Research Institute, Los Angeles, CA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Boasberg
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Yin
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Iris
authors.initials: I
authors.lastname: Chan
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Luna
authors.initials: L
authors.lastname: Musib
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Choong
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Electronic address: grant.mcarthur@petermac.org.
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
mesh_terms: D000328:Adult; D000368:Aged; D001384:Azetidines / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D018579:Patient Selection; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D048493:Proto-Oncogene Proteins B-raf / Q000187:drug effects* / Q000235:genetics; D018570:Risk Assessment; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D015996:Survival Rate; D016896:Treatment Outcome; D000077484:Vemurafenib
chemical_list: D001384:Azetidines; D007211:Indoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf; C574276:cobimetinib