Study design and treatment

coBRIM was a multicenter, randomized, double-blind, parallel, placebo-controlled Phase III study designed to evaluate the safety and efficacy of cobimetinib combined with vemurafenib, compared with vemurafenib, in patients with BRAF ^V600 mutation—positive unresectable locally advanced or metastatic melanoma. This trial was registered on clinicaltrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT01689519","term_id":"NCT01689519"}}NCT01689519. The primary end point was investigator-assessed PFS. Secondary end points included OS, objective response rate, duration of response, PFS as assessed by independent review, safety, pharmacokinetics, and health-related quality of life (HRQOL). Complete methodology of the study and primary efficacy and safety results have previously been published and the protocol is available online [6]. The study was approved by the institutional review board or ethics committee at each participating institution and was conducted in accordance with the provisions of the Declaration of Helsinki and the International Conference on Harmonisation guidelines for Good Clinical Practice. All the patients provided written informed consent.

Key eligibility criteria were age ≥18 years, histologically confirmed unresectable locally advanced stage IIIC or IV melanoma, BRAF ^V600 mutation detected using the cobas ^® 4800 BRAF V600 Mutation Test (Roche Molecular Systems Inc. USA), no history of systemic therapy for advanced disease, measurable disease according to Response Evaluation Criteria In Solid Tumors version 1.1, and Eastern Cooperative Oncology Group performance status 0–1. Because of the known ocular toxicities associated with MEK inhibitors, patients with a history or ophthalmic examination evidence of a retinal abnormality considered a risk factor for neurosensory retinal detachment/central serous retinopathy, retinal vein occlusion, or neovascular macular degeneration were excluded. Patients also were excluded if they had risk factors for retinal vein occlusion, including uncontrolled glaucoma with intraocular pressure >21 mmHg, grade ≥2 serum cholesterol, hypertriglyceridemia, or fasting hyperglycemia.

Patients were randomly assigned in a 1:1 ratio using an interactive response system [Perceptive Informatics (now Parexel International), USA] to receive oral vemurafenib (960 mg twice daily) in combination with either placebo or oral cobimetinib (60 mg once daily for 21 days followed by 7 days off). Treatment was administered in 28-day cycles and continued until disease progression, unacceptable toxicity, or withdrawal of consent. Patients were stratified according to the American Joint Committee on Cancer stage and geographic region. Dose modifications for management of specific adverse events were mandated by the protocol. For grade ≥2 visual symptoms, a complete ophthalmic examination was to be performed and treatment with cobimetinib combined with vemurafenib was to be interrupted until resolution to grade ≤1. Dose reduction of the implicated agent was employed if grade ≥2 visual symptoms recurred. Treatment was to be permanently discontinued in the case of retinal vein occlusion, lack of resolution of visual symptoms to grade ≤1 within 28 days, or recurrence of grade ≥2 visual symptoms despite dose reduction.