A phase II, open-label, randomized, multicenter trial of encorafenib + binimetinib evaluating a standard-dose and a high-dose regimen in patients with BRAFV600-mutant melanoma brain metastasis (MBM) (POLARIS)

Abstract

Abstract Background Melanoma that metastasizes to the brain has a poor prognosis, and accounts for up to 54% of melanoma deaths. Clinical data show that treatment with BRAF-targeted agents induces responses in RAFV600-mutant MBM. Duration of response in the brain is shorter than that observed with extracranial disease. The BRAF/MEK-targeted combination encorafenib + binimetinib demonstrated favorable efficacy and safety for patients with BRAFV600-mutant melanoma in the COLUMBUS study, but excluded patients with active MBM. The aim of this study is to evaluate encorafenib + binimetinib in a population of patients with BRAFV600-mutated active MBM. A higher dose of combination therapy will be studied versus a standard dose to evaluate whether greater efficacy may be achieved with acceptable safety for patients with BRAFV600 MBM. Trial design This multicenter, randomized, open-label phase II study will evaluate two dosing regimens of encorafenib + binimetinib combination in adults with BRAFV600-mutant MBM. Eligible patients will have at least 1 measurable MBM, no prior local MBM therapy, no corticosteroids for MBM, and no prior BRAF or MEK inhibitors in the metastatic setting. One prior line of checkpoint inhibitor or prior adjuvant BRAF or MEK inhibitors is permitted. Patients will be randomized (1:1) to either the standard dose (450\xa0mg orally QD and binimetinib 45\xa0mg orally BID) or high-dose (encorafenib 300\xa0mg BID and binimetinib 45\xa0mg BID) stratified by baseline tumor burden (1 to 2 brain lesions vs. ≥ 3 brain lesions at baseline) and by prior checkpoint inhibitor (yes vs. no). The first 9 evaluable patients in the high-dose arm will constitute the safety lead-in cohort. If the high-dose is not tolerated, subsequent patients will receive standard-dose therapy. Assessments include intracranial response (assessed as per modified RECIST using gadolinium enhanced MRI), extracranial response, global response rate, DCR, DOR, PFS, OS, PK, and safety. The study will enroll approximately 100 patients. Clinical trial identification NCT03911869 Editorial acknowledgement JD Cox and Mayville Medical Communications, with funding from Array Biopharma. Legal entity responsible for the study Array BioPharma Inc. Funding Array BioPharma Inc. Disclosure M.A. Davies: Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: GSK; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Vaccinex; Advisory / Consultancy: Syndax; Non-remunerated activity/ies: Nanostring. J.S. Weber: Advisory / Consultancy, Research grant / Funding (institution): Array BioPharma; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech. K.T. Flaherty: Officer / Board of Directors: Clovis Oncology; Officer / Board of Directors: Strata Oncology; Officer / Board of Directors: Vivid Biosciences; Officer / Board of Directors: Checkmate Pharmaceuticals; Advisory / Consultancy: X4; Advisory / Consultancy: PIC Therapeutics; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Amgen; Advisory / Consultancy: Asana; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: Fount; Advisory / Consultancy: Aeglea; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: Shattuck Labs; Advisory / Consultancy: Tolero; Advisory / Consultancy: Apricity; Advisory / Consultancy: Oncoceutics; Advisory / Consultancy: Fog Pharma; Advisory / Consultancy: Neon; Advisory / Consultancy: Tyardi. G.A. McArthur: Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Pfizer. M.B. Reddy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Array BioPharma. A. Golden: Shareholder / Stockholder / Stock options, Full / Part-time employment: Array BioPharma. J.L. Culbertson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Array BioPharma. C.T. Thomas: Shareholder / Stockholder / Stock options, Full / Part-time employment: Array BioPharma. H.A. Tawbi: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Array BioPharma; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): GSK. G.V. Long: Advisory / Consultancy: Aduro; Advisory / Consultancy: Amgen; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Mass-Array; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Oncosec; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche.