binimetinib and Retinal-Diseases

The treatment options for patients with metastatic melanoma (MM) have been dramatically expanded in recent years with the approval of new drugs. The MEK (mitogen-acitvated protein kinase kinase) and BRAF (serine/threonine-protein kinase B-Raf coding gene) inhibitor combination therapy is currently part of the standard of care for stage IIIC/IV of BRAF mutant melanoma. The MEK inhibitor-associated retinopathy (MEKAR) is observed in patients with MM who are treated (or have been treated) with such a combination therapy. This article reports the case of a 72-year-old male patient, who suffered from such a pathological condition under treatment with binimetinib in combination with nivolumab. This case study illustrates the importance of interdisciplinary collaboration in the treatment of MM patients.. Die Behandlungsmöglichkeiten für Patienten mit metastasierendem Melanom (MM) wurden in den letzten Jahren mit der Zulassung von neuen Medikamenten dramatisch erweitert. Die MEK(mitogen-aktivierte Proteinkinase-Kinasen)- und BRAF(Serin/Threonin-Kinase B-Raf kodierendes Gen)-Hemmer-Kombinationstherapie gehört aktuell zum Versorgungsstandard für das Stadium IIIC/IV des BRAF-mutierten Melanoms. MEKAR (MEK-Inhibitor-assoziierte Retinopathie) werden bei Patienten mit metastasierendem Melanom beobachtet, die mit einer solchen Kombinationstherapie behandelt werden bzw. wurden. Wir berichten über den Fall eines 72-jährigen Patienten, der eine solche Pathologie unter der Therapie mit Binimetinib in Kombination mit Nivolumab erlitt. Diese Kasuistik verdeutlicht die Wichtigkeit einer interdisziplinären Zusammenarbeit bei der Behandlung von MM-Patienten.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Humans; Male; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Retinal Diseases

Topics: Antineoplastic Agents; Astrocytoma; Benzimidazoles; Brain Neoplasms; Carbamates; Female; Humans; MAP Kinase Kinase Kinase 1; MAP Kinase Kinase Kinase 2; Middle Aged; Proto-Oncogene Proteins B-raf; Retinal Diseases; Subretinal Fluid; Sulfonamides

Recently, treatment with MEK inhibitors has been shown to be an effective treatment option for metastatic melanoma. Treatment efficacy is dependent on inhibition of MAPK-related melanoma proliferation. However, targeting of MEK can be accompanied by a time-dependent and reversible serous retinopathy of unknown origin.We analyzed the molecular mechanism by which the MEK inhibitor binimetinib may lead to retinopathy, using neuroretina and cell models of retinal pigment epithelium (RPE).Binimetinib inhibited the MAPK pathway while discontinuation of treatment resulted in reactivation. However, cell proliferation was not inhibited correspondingly during binimetinib treatment of ARPE19 cells. Remarkably, post-mitotic neuroretinal tissue displayed a strong MAPK activation that was lost after binimetinib treatment.We propose that binimetinib-associated retinopathy is correlated with inhibition of the MAPK pathway in multiple retinal components. Retinal cells are able to regain the activation after binimetinib treatment, mimicking the reversibility of the retinopathy. As most retinal cells are nonregenerating, other mechanisms than stimulation of proliferation must be involved.

Topics: Antineoplastic Agents; Benzimidazoles; Cell Proliferation; Cells, Cultured; Humans; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Melanoma; Mitogen-Activated Protein Kinases; Neoplasm Metastasis; Retinal Diseases; Retinal Pigment Epithelium

Mitogen-activated protein kinase kinase (MEK) inhibitors have aroused considerable interest in oncology. Activity has been demonstrated in various types of cancer, especially melanoma. MEK inhibitors induce a transient retinopathy, considered to be a class effect. At present, only sparse data are available on retinal effects with long-term MEK inhibition.. In this prospective, observational study, patients with advanced melanoma participating in different phase 1/2 or phase 3 clinical trials were treated with the MEK inhibitor binimetinib, with a v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor, or with combination therapy. They underwent regular ophthalmological examinations including determination of visual function, biomicroscopy, dilated fundoscopy and optical coherence tomography (OCT) for a period of up to 2 years. Retinopathy was diagnosed on defined OCT criteria.. Sixty-two patients were investigated between 1st October 2011 and 31st July 2015: 13 were treated with the MEK inhibitor binimetinib alone, 10 with a selective BRAF inhibitor, and 39 with combination therapy. In 92% of patients on monotherapy and 100% of those on combination treatment, binimetinib caused dose-related lesions with serous neuroretinal detachments and oedema, strongly dependent on the time after medication. With continued treatment, retinal volume and thickness decreased to levels below baseline, without any apparent functional deficits or changes in structural integrity.. Binimetinib induces a specific retinopathy with daily fluctuations depending on the time interval after medication. The retinopathy partially recovers, but can still be detected many months later. Retinal thinning, possible first signs of retinal atrophy have been observed after long-term treatment, but, so far, without functional relevance.

Topics: Aged; Antineoplastic Agents; Benzimidazoles; Dose-Response Relationship, Drug; Female; Humans; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Retinal Diseases; Skin Neoplasms