Vemurafenib and cobimetinib combination therapy for BRAFV600E-mutated melanoma favors posterior reversible encephalopathy syndrome
Authors: S. Engel, F. Luessi, B. Henning, S. Bittner, C. Loquai, F. Zipp
Journal: Annals of Oncology (2019)

Targeted therapy with a combination of serine/threonine-protein kinase B-raf (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors has recently become commonly used in the treatment of metastatic melanoma. This is the first report of the simultaneous occurrence of central serous retinopathy, an established adverse event, and posterior reversible encephalopathy syndrome (PRES), which has only been suspected to be related to BRAF inhibitor vemurafinib so far [1.Khurana A. Dasanu C.A. Posterior reversible encephalopathy syndrome due to targeted agents: vemurafinib among suspects!.J Oncol Pharm Pract. 2015; 21: 443-450Crossref PubMed Scopus (11) Google Scholar]. Additionally, we conducted a review of all previous reports of patients developing encephalopathy syndromes while being treated with BRAF- and MEK-inhibiting drugs. A 64-year-old woman was first diagnosed with BRAFV600E -mutated metastatic melanoma in August 2013. Intolerance and repeated disease progression demanded various therapy switches. In June 2018, treatment with vemurafenib and cobimetinib (an MEK inhibitor) was started. Three days after initiation, the patient developed bilateral visual impairment. Fundoscopic examination showed macular edema with serous neuroretinal detachment of the fovea, leading to a diagnosis of central serous retinopathy. Due to acute headaches, nausea, and recurrent vomiting, the patient was admitted to hospital 2 weeks later and vemurafenib and cobimetinib therapy was discontinued. Cranial magnetic resonance imaging (MRI) exhibited bilateral T2w-hyperintense lesions in the occipital regions without contrast-enhancement or restricted diffusion. There was no evidence of cerebral metastases. After treatment discontinuation, the patient’s condition improved gradually and the follow-up MRI in September 2018 demonstrated complete remission of the occipital edema. Reversal of the symptoms together with resolution of characteristic MRI-findings led us to diagnose PRES. We searched the literature for similar cases and identified three other cases of acute onset neurological syndromes following combined BRAF- and MEK-inhibitor treatment (Table 1). However, ours was the only case with simultaneous occurrence of PRES and central serous retinopathy.Table 1Demographic, clinical and imaging findings in four cases of acute encephalopathy and posterior reversible encephalopathy syndrome (PRES) upon combined BRAF- and MEK-inhibiting treatmentSex/age at onsetDiagnosisType of malignant diseaseChemotherapyPresenting symptomsTime interval between treatment initiation and symptom onset (days)Brain imagingTreatmentOutcomeReferenceM/75Acute encephalopathyBRAF mutation-positive metastatic adenocarcinoma of the lungDabrafenib and trametinibConfusion and disorientation, impaired speech, wheelchair dependency, and fever14MRI: no acute abnormalitiesDiscontinuation of chemotherapyReversal of symptomsRandhawa and Onyshchenko [6.Randhawa J. Onyshchenko M. Acute encephalopathy secondary to dabrafenib and trametinib in BRAF-positive metastatic adenocarcinoma of the lung.J Oncol Pharm Pract. 2018; (1078155218790331)PubMed Google Scholar]F/73Acute encephalopathyBRAF mutation-positive metastatic melanomaDabrafenib and trametinibAltered mental status, disorientation, impaired speech, limited oral intake, and progressive muscle tetany7CT: generalized volume loss without any other obvious intracranial abnormalities (MRI not possible due to pacemaker)Discontinuation of chemotherapyReversal of symptomsCooper et al. [7.Cooper J. Kodali D. Higa G.M. Acute encephalopathy with combination dabrafenib/trametinib therapy.J Oncol Pharm Pract. 2017; 23: 313-317Crossref PubMed Scopus (5) Google Scholar]M/68PRESBRAF mutation-positive metastatic melanomaVemurafenib and cobimetinibConfusion, acute headache, altered mental status, impaired speech, and stage 2 hypertension12MRI: cortical/subcortical high signal intensity on fluid-attenuated inversion recovery (FLAIR)-weighted imaging of both parietal and occipital areas with micronodular cortical enhancementDiscontinuation of chemotherapy and intravenous nicardipineReversal of symptomsBoukari F et al. [8.Boukari F. Dugourd P.M. Chassang M. Posterior reversible encephalopathy syndrome due to combination of vemurafenib and cobimetinib for metastatic melanoma.Pigment Cell Melanoma Res. 2017; 30: 262-264Crossref PubMed Scopus (6) Google Scholar]F/64PRESBRAF mutation-positive metastatic melanomaVemurafenib and cobimetinibImpaired visual acuity, nausea, vomiting, and headache14MRI: hyperintensity in T2-weighted imaging of both occipital areasDiscontinuation of chemotherapyReversal of symptomsOur caseCT, computed tomography; MRI, magnetic resonance imaging. Open table in a new tab CT, computed tomography; MRI, magnetic resonance imaging. MEK-inhibitor-associated central serous retinopathy is hypothesized to be caused by a disruption of the mitogen-activated protein kinase (MAPK) pathway, which leads to endothelial dysfunction of the blood–retina barrier and consecutively to retinal detachment by subretinal fluid accumulation [2.de la Cruz-Merino L. Di Guardo L. Grob J.J. et al.Clinical features of serous retinopathy observed with cobimetinib in patients with BRAF-mutated melanoma treated in the randomized coBRIM study.J Transl Med. 2017; 15: 146Crossref PubMed Scopus (27) Google Scholar]. Endothelial dysfunction also plays a crucial role in the development of PRES. It might arise from direct effects of excessive circulating cytokines, e.g. IFN-γ and tumor necrosis factor-α, which activate endothelial cells to secrete vasoactive factors, increase vascular permeability, and may lead to interstitial brain edema [3.Fugate J.E. Rabinstein A.A. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions.Lancet Neurol. 2015; 14: 914-925Abstract Full Text Full Text PDF PubMed Scopus (590) Google Scholar]. BRAF inhibitors were shown to increase serum levels of IFN-γ and tumor necrosis factor-α [4.Wilmott J.S. Haydu L.E. Menzies A.M. et al.Dynamics of chemokine, cytokine, and growth factor serum levels in BRAF-mutant melanoma patients during BRAF inhibitor treatment.J Immunol. 2014; 192: 2505-2513Crossref PubMed Scopus (56) Google Scholar], offering one possible link between its usage and the occurrence of PRES [1.Khurana A. Dasanu C.A. Posterior reversible encephalopathy syndrome due to targeted agents: vemurafinib among suspects!.J Oncol Pharm Pract. 2015; 21: 443-450Crossref PubMed Scopus (11) Google Scholar]. In addition, targeted cancer therapies may damage the endothelium directly, leading to release of endothelin-1, thromboxane A2, and prostacyclin, and subsequent disruption of the blood–brain-barrier and cerebral blood flow autoregulation [5.Vaughn C. Zhang L. Schiff D. Reversible posterior leukoencephalopathy syndrome in cancer.Curr Oncol Rep. 2008; 10: 86-91Crossref PubMed Scopus (81) Google Scholar]. BRAF and MEK inhibitors were also shown to decrease vascular endothelial growth factor expression and, therefore, could damage the endothelium by disrupting the vascular endothelial growth factor signaling pathway. Our novel finding of simultaneous occurrence of PRES and central serous retinopathy upon combined treatment with two protein kinase inhibitors strengthens the direct link between PRES and these therapies. Their known impact on endothelial damage, together with the involvement of endothelial dysfunction in the pathophysiology of both central serous retinopathy and PRES, indicates PRES as an adverse event of combined cobimetinib and vemurafenib therapy. The authors thank Rosalind Gilchrist for proofreading and editing the manuscript. Informed consent: The patient was informed of the intent to publish the case report and gave the written consent. This study was supported by a grant from the German Research Foundation (DFG) (CRC-TR-128 to FZ).