Carvajal Richard D, Sosman Jeffrey A, Quevedo Jorge Fernando, Milhem Mohammed M, Joshua Anthony M, Kudchadkar Ragini R, Linette Gerald P, Gajewski Thomas F, Lutzky Jose, Lawson David H, Lao Christopher D, Flynn Patrick J, Albertini Mark R, Sato Takami, Lewis Karl, Doyle Austin, Ancell Kristin, Panageas Katherine S, Bluth Mark, Hedvat Cyrus, Erinjeri Joseph, Ambrosini Grazia, Marr Brian, Abramson David H, Dickson Mark Andrew, Wolchok Jedd D, Chapman Paul B, Schwartz Gary K
Memorial Sloan-Kettering Cancer Center, New York, New York2Weill Medical College of Cornell University, New York, New York.
Vanderbilt University Medical Center, Department of Hematology-Oncology, Nashville, Tennessee.
JAMA. 2014 Jun 18;311(23):2397-405. doi: 10.1001/jama.2014.6096.
Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation.
To assess the efficacy of selumetinib, a selective, non-adenosine triphosphate competitive inhibitor of MEK1 and MEK2, in uveal melanoma.
DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, phase 2 clinical trial comparing selumetinib vs chemotherapy conducted from August 2010 through December 2013 among 120 patients with metastatic uveal melanoma at 15 academic oncology centers in the United States and Canada.
One hundred one patients were randomized in a 1:1 ratio to receive selumetinib, 75 mg orally twice daily on a continual basis (n = 50), or chemotherapy (temozolomide, 150 mg/m2 orally daily for 5 of every 28 days, or dacarbazine, 1000 mg/m2 intravenously every 21 days [investigator choice]; n = 51) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression.
Progression-free survival, the primary end point, was assessed as of April 22, 2013. Additional end points, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013.
Median progression-free survival among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) and among those randomized to selumetinib was 15.9 weeks (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < .001). Median overall survival time was 9.1 months (95% CI, 6.1-11.1 months) with chemotherapy and 11.8 months (95% CI, 9.8-15.7 months) with selumetinib (hazard ratio, 0.66; 95% CI, 0.41-1.06; P = .09). No objective responses were observed with chemotherapy. Forty-nine percent of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction.
In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events.
clinicaltrials.gov Identifier: NCT01143402.
葡萄膜黑色素瘤的特征是GNAQ和GNA11发生突变，导致丝裂原活化蛋白激酶途径激活。
评估司美替尼（一种MEK1和MEK2的选择性、非三磷酸腺苷竞争性抑制剂）治疗葡萄膜黑色素瘤的疗效。
设计、地点和参与者：2010年8月至2013年12月在美国和加拿大的15个学术肿瘤中心对120例转移性葡萄膜黑色素瘤患者进行的一项随机、开放标签的2期临床试验，比较司美替尼与化疗。
101例患者按1:1比例随机分组，持续接受司美替尼口服，75mg，每日2次（n = 50），或化疗（替莫唑胺，150mg/m²，口服，每28天中的5天，或达卡巴嗪，1000mg/m²，静脉注射，每21天一次[研究者选择]；n = 51），直至疾病进展、死亡、出现无法耐受的不良反应或撤回同意书。在主要结局分析后，登记了19例患者，其中18例接受了司美替尼治疗但未随机分组，以完成计划的120例患者入组。化疗组患者在影像学进展时可接受司美替尼治疗。
无进展生存期作为主要终点，截至2013年4月22日进行评估。其他终点，包括总生存期、缓解率和安全性/毒性，截至2013年12月31日进行评估。
随机接受化疗的患者中位无进展生存期为7周（95%CI，4.3 - 8.4周；中位治疗持续时间，8周；四分位间距[IQR]，4.3 - 16周），随机接受司美替尼的患者为15.9周（95%CI，8.4 - 21.1周；中位治疗持续时间，16.1周；IQR，8.1 - 25.3周）（风险比，0.46；95%CI，0.30 - 0.71；P <.001）。化疗组的中位总生存时间为9.1个月（95%CI，6.1 - 11.1个月），司美替尼组为11.8个月（95%CI，9.8 - 15.7个月）（风险比，0.66；95%CI，0.41 - 1.06；P = 0.09）。化疗未观察到客观缓解。接受司美替尼治疗的患者中有49%实现了肿瘤退缩，其中14%对治疗有客观的影像学缓解。97%接受司美替尼治疗的患者观察到与治疗相关的不良事件，37%的患者至少需要减少1次剂量。
在这项针对晚期葡萄膜黑色素瘤患者的探索性研究中，与化疗相比，司美替尼使无进展生存期和缓解率略有改善；然而，总生存期未观察到改善。临床结局的改善伴随着高不良事件发生率。
clinicaltrials.gov标识符：NCT01143402。
