西罗莫司联合达卡巴嗪治疗转移性葡萄膜黑色素瘤患者的 III 期、多中心、随机试验（SUMIT）。
Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT).
机构信息
Richard D. Carvajal and Gary K. Schwartz, Columbia University Medical Center; Paul B. Chapman and Alexander N. Shoushtari, Memorial Sloan Kettering Cancer Center, New York, NY; Sophie Piperno-Neumann and Manuel J. Rodrigues, Institut Curie, Paris; Lauris Gastaud, Centre Antoine-Lacassagne, Nice, France; Ellen Kapiteijn, Leiden University Medical Center, Leiden, the Netherlands; Stephen Frank, Hebrew University Hadassah Medical School - The Sharett Institute of Oncology, Jerusalem; Jacob Schachter, Sheba Medical Center at Tel Hashomer, and Tel-Aviv University Medical School, Tel Aviv, Israel; Anthony M. Joshua, Princess Margaret Cancer Centre, Toronto, ON, Canada; Josep M. Piulats, Institut Catala d'Oncologia L'Hospitalet, L'Hospitalet de Llobregat, Barcelona, Spain; Pascal Wolter, University Hospitals Leuven, Leuven, Belgium; Veronique Cocquyt, Ghent University Hospital, Ghent, Belgium; Bartosz Chmielowski, University of California, Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, CA; T.R. Jeffry Evans, University of Glasgow, Glasgow; Delyth Clemett, Shirley Spratt, Susan Lovick, and Elaine Kilgour, AstraZeneca, Macclesfield; Dana Ghiorghiu and Gabriella Mariani, AstraZeneca, Cambridge; Paul Nathan, Mt Vernon Cancer Centre, Northwood, United Kingdom; Gerald Linette, Washington University School of Medicine, St Louis, MO; Carola Berking, University Hospital of Munich, Munich, Germany; Peter Barker, AstraZeneca, Gaithersburg, MD; and Zhongwu Lai, AstraZeneca, Waltham, MA.
出版信息
J Clin Oncol. 2018 Apr 20;36(12):1232-1239. doi: 10.1200/JCO.2017.74.1090. Epub 2018 Mar 12.
Purpose Uveal melanoma is the most common primary intraocular malignancy in adults with no effective systemic treatment option in the metastatic setting. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective MEK1/2 inhibitor with a short half-life, which demonstrated single-agent activity in patients with metastatic uveal melanoma in a randomized phase II trial. Methods The Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT) study was a phase III, double-blind trial ( ClinicalTrial.gov identifier: NCT01974752) in which patients with metastatic uveal melanoma and no prior systemic therapy were randomly assigned (3:1) to selumetinib (75 mg twice daily) plus dacarbazine (1,000 mg/m intravenously on day 1 of every 21-day cycle) or placebo plus dacarbazine. The primary end point was progression-free survival (PFS) by blinded independent central radiologic review. Secondary end points included overall survival and objective response rate. Results A total of 129 patients were randomly assigned to receive selumetinib plus dacarbazine (n = 97) or placebo plus dacarbazine (n = 32). In the selumetinib plus dacarbazine group, 82 patients (85%) experienced a PFS event, compared with 24 (75%) in the placebo plus dacarbazine group (median, 2.8 v 1.8 months); the hazard ratio for PFS was 0.78 (95% CI, 0.48 to 1.27; two-sided P = .32). The objective response rate was 3% with selumetinib plus dacarbazine and 0% with placebo plus dacarbazine (two-sided P = .36). At 37% maturity (n = 48 deaths), analysis of overall survival gave a hazard ratio of 0.75 (95% CI, 0.39 to 1.46; two-sided P = .40). The most frequently reported adverse events (selumetinib plus dacarbazine v placebo plus dacarbazine) were nausea (62% v 19%), rash (57% v 6%), fatigue (44% v 47%), diarrhea (44% v 22%), and peripheral edema (43% v 6%). Conclusion In patients with metastatic uveal melanoma, the combination of selumetinib plus dacarbazine had a tolerable safety profile but did not significantly improve PFS compared with placebo plus dacarbazine.
目的 葡萄膜黑色素瘤是成人中最常见的原发性眼内恶性肿瘤，在转移性疾病中没有有效的全身治疗方法。Selumetinib（AZD6244，ARRY-142886）是一种口服、有效且选择性的 MEK1/2 抑制剂，半衰期短，在转移性葡萄膜黑色素瘤患者的随机 II 期试验中表现出单药活性。
方法 Selumetinib（AZD6244：ARRY-142886）（Hyd-Sulfate）在转移性葡萄膜黑色素瘤（SUMIT）研究中是一项 III 期、双盲试验（ClinicalTrials.gov 标识符：NCT01974752），其中转移性葡萄膜黑色素瘤且无既往全身治疗的患者被随机分配（3:1）接受 selumetinib（75mg 每日两次）加达卡巴嗪（1000mg/m 静脉注射，每 21 天周期的第 1 天）或安慰剂加达卡巴嗪。主要终点是通过盲法独立中心放射学审查的无进展生存期（PFS）。次要终点包括总生存期和客观缓解率。
结果 共有 129 名患者被随机分配接受 selumetinib 加达卡巴嗪（n=97）或安慰剂加达卡巴嗪（n=32）。在 selumetinib 加达卡巴嗪组中，82 名患者（85%）发生 PFS 事件，而安慰剂加达卡巴嗪组为 24 名（75%）（中位数，2.8 个月比 1.8 个月）；PFS 的风险比为 0.78（95%CI，0.48 至 1.27；双侧 P=0.32）。selumetinib 加达卡巴嗪的客观缓解率为 3%，安慰剂加达卡巴嗪为 0%（双侧 P=0.36）。在 37%的成熟度（n=48 例死亡）时，总生存期分析的风险比为 0.75（95%CI，0.39 至 1.46；双侧 P=0.40）。最常报告的不良事件（selumetinib 加达卡巴嗪与安慰剂加达卡巴嗪）为恶心（62%与 19%）、皮疹（57%与 6%）、乏力（44%与 47%）、腹泻（44%与 22%）和外周水肿（43%与 6%）。
结论 在转移性葡萄膜黑色素瘤患者中，selumetinib 加达卡巴嗪联合治疗具有可耐受的安全性特征，但与安慰剂加达卡巴嗪相比，并未显著改善 PFS。
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