Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study
Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study
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DOI：
10.1186/s40425-019-0800-0
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发表时间：
2019-11-13
影响因子：
10.9
通讯作者：
Berking, Carola
中科院分区：
文献类型：
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作者：
Heppt, Markus, V;Amaral, Teresa;Berking, Carola
背景葡萄膜黑色素瘤(UM)是一种难治性疾病，晚期预后较差。联合检查点阻断与CTLA-4和PD-1抑制在转移性UM中的价值目前尚不清楚。方法收集来自德国16个皮肤癌中心的转移性或不能切除的UM患者，用ipilimumab联合PD-1抑制剂进行治疗。分析病例的有效率、无进展生存期(PFS)、总生存期(OS)和安全性。用COX回归模型和Logistic回归分析确定与OS和治疗反应相关的临床参数和血清生物标志物。结果联合检查站封锁总有效率为15.6%，完全有效率为3.1%，部分有效率为12.5%。中位有效时间为25.5个月(9.0~65.0)。21.9%的患者病情稳定，疾病控制率为37.5%，中位临床受益时间为28.0个月(7.0~65.0)。中位PFS为3.0个月(95%可信区间2.4~3.6)。中位OS估计为16.1个月(95%可信区间12.9~19.3)。在安全性方面，根据CTCAE标准，39.1%的接受治疗的患者经历了与治疗相关的严重不良事件(3级：37.5%；4级：1.6%)。最常见的不良反应是结肠炎(20.3%)、肝炎(20.3%)、甲状腺炎(15.6%)和垂体炎(7.8%)。不良的脑电地形图表现状态是OS降低的独立危险因素(p=0.007)。结论联合检查点阻断治疗UM的耐受性可能优于皮肤黑色素瘤试验。这项研究表明，联合检查点阻断是迄今为止在临床试验之外可用于转移性UM的最有效的治疗选择。
Background Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear. Methods Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression. Results The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0-65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0-65.0). The median PFS was 3.0 months (95% CI 2.4-3.6). The median OS was estimated to 16.1 months (95% CI 12.9-19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007). Conclusions The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.