Private Ophthalmic Practice in Cooperation with the Skin Cancer Unit, University Hospital of Zurich, Zurich.
Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich.
Ann Oncol. 2014 Jul;25(7):1437-1441. doi: 10.1093/annonc/mdu169. Epub 2014 May 26.
Melanoma is one of the most aggressive skin cancers. Recently, selective MEK inhibitors have shown efficacy in patients with advanced BRAF- and NRAS-mutant melanoma. Soon after the initiation of clinical oncology trials with MEK inhibitors, it was observed that some participants developed an eye condition resembling central serous chorioretinopathy. The present article addresses the clinical features and management of these MEK inhibitor-associated retinal syndromes.
Thirty-two patients with advanced cutaneous melanoma were treated with the selective MEK inhibitor binimetinib (MEK162) in three different Phase 1b or 2 clinical trials. Twenty patients on binimetinib monotherapy and 12 on binimetinib plus RAF inhibitor [pan-kinase RAF inhibitor RAF265 (n = 7) or selective BRAF inhibitor encorafenib (LGX818) (n = 5)] combination therapy underwent ophthalmological examinations at regular intervals, including determination of best corrected visual acuity, perimetry, colour vision testing, dilated fundus examination, and multimodal imaging.
Grade 1-2 bilateral retinopathies with multiple lesions were observed in 13 of 20 patients on binimetinib monotherapy, 4 of 7 patients on binimetinib plus RAF265 combination therapy, and 2 of 5 patients on binimetinib plus encorafenib combination therapy. In this study population, the rate ranged from 40% to 65%. Retinopathy events appeared during the first 4 weeks, and in some cases, during the first few days of treatment. Patients reported mild and only short-lived visual symptoms. Optical coherence tomography revealed neuroretinal elevations. Central retinal thickness and volume showed dose-dependent increases after the start of treatment, followed by a marked decrease despite continued treatment, which was associated with symptom resolution. No vascular abnormalities were found with fluorescein and indocyanine green angiography.
Treatment with the selective MEK inhibitor binimetinib as a single agent or in combination with RAF inhibitors induced transient retinopathy with multiple bilateral lesions in some patients. Binimetinib-induced retinopathy was usually mild, self-limiting, and tolerable as visual function was not seriously impaired.
黑色素瘤是最具侵袭性的皮肤癌之一。最近，选择性 MEK 抑制剂在晚期 BRAF 和 NRAS 突变型黑色素瘤患者中显示出疗效。在开始进行 MEK 抑制剂的临床肿瘤学试验后不久，观察到一些参与者出现了类似于中心性浆液性脉络膜视网膜病变的眼部疾病。本文介绍了这些 MEK 抑制剂相关的视网膜综合征的临床特征和治疗方法。
在三项不同的 1b 期或 2 期临床研究中，32 名晚期皮肤黑色素瘤患者接受了选择性 MEK 抑制剂 binimetinib（MEK162）治疗。20 名接受 binimetinib 单药治疗的患者和 12 名接受 binimetinib 加 RAF 抑制剂[泛激酶 RAF 抑制剂 RAF265（n=7）或选择性 BRAF 抑制剂 encorafenib（LGX818）（n=5）]联合治疗的患者定期进行眼科检查，包括最佳矫正视力、视野检查、色觉测试、散瞳眼底检查和多模态成像。
在 20 名接受 binimetinib 单药治疗的患者中，有 13 名出现了 1-2 级双侧视网膜病变，伴有多个病变；在 7 名接受 binimetinib 加 RAF265 联合治疗的患者中，有 4 名出现了这种情况；在 5 名接受 binimetinib 加 encorafenib 联合治疗的患者中，有 2 名出现了这种情况。在本研究人群中，发生率为 40%至 65%。视网膜病变事件出现在治疗的前 4 周，在某些情况下，出现在治疗的最初几天。患者报告了轻微且仅短暂的视觉症状。光学相干断层扫描显示神经视网膜抬高。中央视网膜厚度和体积在治疗开始后呈剂量依赖性增加，尽管继续治疗，但随后显著下降，与症状缓解相关。荧光素和吲哚青绿血管造影未发现血管异常。
选择性 MEK 抑制剂 binimetinib 单药治疗或与 RAF 抑制剂联合治疗可引起一些患者出现短暂性、双侧多发性视网膜病变。binimetinib 诱导的视网膜病变通常较轻，自限性，且可耐受，因为视力未受到严重损害。
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