Transient MEK inhibitor-associated retinopathy in metastatic melanoma
Transient MEK inhibitor-associated retinopathy in metastatic melanoma
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DOI：
10.1093/annonc/mdu169
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发表时间：
2014-07-01
影响因子：
50.5
通讯作者：
Goldinger, S. M.
中科院分区：
文献类型：
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作者：
Urner-Bloch, U.;Urner, M.;Goldinger, S. M.
使用binimetinib观察到的MEK受体相关视网膜病变具有自限性，且具有剂量和时间依赖性。在光学相干断层扫描中，观察到神经视网膜的双侧多灶性隆起，但荧光素血管造影未见渗漏。重要的是要了解这种特定的，通常是温和的条件的过程和管理。由于其短暂的特征，视网膜病变不应该成为停止治疗的原因。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中心性浆液性脉络膜视网膜病变的眼部疾病。本文讨论了这些MEK受体相关视网膜综合征的临床特点和管理。32例晚期皮肤黑色素瘤患者在三个不同的1b期或2期临床试验中接受了选择性MEK抑制剂binimetinib（MEK 162）治疗。20名接受binimetinib单药治疗的患者和12名接受binimetinib + RAF抑制剂[泛激酶RAF抑制剂RAF 265（n = 7）或选择性BRAF抑制剂恩科拉非尼（LGX 818）（n = 5）]联合治疗的患者定期接受眼科检查，包括确定最佳矫正视力、视野检查、色觉测试、散瞳眼底检查、在接受比尼替尼单一疗法的20名患者中的13名、接受比尼替尼加RAF 265组合疗法的7名患者中的4名和接受比尼替尼加恩科拉非尼组合疗法的5名患者中的2名中观察到具有多个病变的1-2级双侧视网膜病变。在本研究人群中，发生率范围为40%至65%。视网膜病变事件发生在治疗的前4周，在某些情况下，发生在治疗的前几天。患者报告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隆起。开始治疗后，中央视网膜厚度和体积呈剂量依赖性增加，随后尽管继续治疗，但仍显著降低，这与症状缓解相关。荧光素和吲哚菁绿绿色血管造影未发现血管异常。选择性MEK抑制剂比尼美替尼作为单一药物或与RAF抑制剂联合治疗可诱导某些患者出现短暂性视网膜病变，伴有多处双侧病变。Binimetinib诱导的视网膜病变通常为轻度、自限性和可耐受，因为视觉功能未严重受损。
MEK inhibitor-associated retinopathy observed with binimetinib was self-limiting and dose- and time-dependent. In optical coherence tomography, bilateral multifocal elevations of the neuroretina were observed, but no leakage was seen by fluorescein angiography. It is important to be aware of the course and management of this specific, generally mild condition. Due to its transient features, retinopathy should not be a reason for discontinuing treatment.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.