Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial.
Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial.
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DOI：
10.1001/jama.2014.6096
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发表时间：
2014-06-18
影响因子：
120.7
通讯作者：
Schwartz, Gary K.
中科院分区：
文献类型：
--
作者：
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.
葡萄膜黑色素瘤的特点是 GNAQ 和 GNA11 突变，导致 MAPK 通路激活。旨在评估司美替尼（MEK1 和 MEK2 的选择性非 ATP 竞争性抑制剂）在葡萄膜黑色素瘤中的疗效。比较司美替尼与化疗的随机开放标签 II 期临床试验。接受化疗的患者可以在放射学进展时接受司美替尼治疗。十五个学术肿瘤学中心。 120 名转移性葡萄膜黑色素瘤患者。 101 名患者按照 1:1 的比例随机接受司美替尼 75 mg 口服，每日两次，连续治疗 (n=50) 或化疗（替莫唑胺 150 mg/m2，每日口服，每 28 天 5 次，或 DTIC 1000 mg/m2，每 21 天静脉注射；研究者选择；n=51），直至疾病进展、死亡、不可耐受的毒性或撤回同意。主要结果分析后，继续以非随机方式入组至优越疗法。截至 2013 年 4 月 22 日评估了主要终点无进展生存期的最终分析。截至 2013 年 12 月 31 日评估了其他终点，包括总生存期、缓解率和安全性/毒性。随机接受化疗和司美替尼治疗组的中位无进展生存期为 7（95% CI，4.3 – 8.4；中位治疗持续时间为 8 周（IQR，4.3-16）），并且15.9 周（95% CI，8.4 – 21.1；中位治疗持续时间为 16.1 周（IQR，8.1–25.3））（风险比 0.46；95% CI，0.30 – 0.71；p < 0.001）。随机接受化疗和司美替尼治疗组的中位总生存期分别为 9.1（95% CI，6.1-11.1）和 11.8 个月（95% CI，9.8-15.7）（风险比 0.66；95% CI，0.41-1.06；p=0.09）。化疗没有观察到客观反应。 49% 的接受司美替尼治疗的患者实现了肿瘤消退，其中 14% 的患者实现了客观的放射学治疗反应。在接受司美替尼治疗的 97% 患者中观察到与治疗相关的不良事件，其中 37% 需要至少减少一次剂量。在这项针对晚期葡萄膜黑色素瘤患者的假设生成研究中，与化疗相比，司美替尼可适度改善无进展生存期和缓解率；然而，没有观察到总体生存率的改善。临床结果的改善伴随着较高的不良事件发生率。
Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in MAPK pathway activation. To assess the efficacy of selumetinib, a selective, non-ATP competitive inhibitor of MEK1 and MEK2, in uveal melanoma. Randomized open-label phase II clinical trial comparing selumetinib versus chemotherapy. Those receiving chemotherapy could receive selumetinib at the time of radiographic progression. Fifteen academic oncology centers. 120 patients with metastatic uveal melanoma. 101 patients were randomized on a 1:1 ratio to 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 DTIC 1000 mg/m2 intravenously every 21 days; investigator choice; n=51) until disease progression, death, intolerable toxicity, or withdrawal of consent. Following primary outcome analysis, enrollment continued in a non-randomized fashion to the superior therapy. Final analysis of progression-free survival, the primary endpoint, was assessed as of April 22, 2013. Additional endpoints, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013. Median progression-free survival for those randomized to chemotherapy and selumetinib was 7 (95% CI, 4.3 – 8.4; median treatment duration of 8 weeks (IQR, 4.3–16)) and 15.9 weeks (95% CI, 8.4 – 21.1; median treatment duration of 16.1 weeks (IQR, 8.1–25.3)), respectively (hazard ratio 0.46; 95% CI, 0.30 – 0.71; p < 0.001). Median overall survival was 9.1 (95% CI, 6.1 – 11.1) and 11.8 months (95% CI, 9.8 – 15.7) for those randomized to chemotherapy and selumetinib, respectively (hazard ratio 0.66; 95% CI, 0.41–1.06; p=0.09). No objective responses were observed with chemotherapy. 49% 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% patients treated with selumetinib, with 37% requiring at least one 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 adverse event rate.
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影响因子：
11.2
作者：
Nissan MH;Pratilas CA;Jones AM;Ramirez R;Won H;Liu C;Tiwari S;Kong L;Hanrahan AJ;Yao Z;Merghoub T;Ribas A;Chapman PB;Yaeger R;Taylor BS;Schultz N;Berger MF;Rosen N;Solit DB
通讯作者：
Solit DB
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
DOI：
10.1056/nejmoa1209288
发表时间：
2013-02-14
期刊：
The New England journal of medicine
影响因子：
--
作者：
Ho AL;Grewal RK;Leboeuf R;Sherman EJ;Pfister DG;Deandreis D;Pentlow KS;Zanzonico PB;Haque S;Gavane S;Ghossein RA;Ricarte-Filho JC;Domínguez JM;Shen R;Tuttle RM;Larson SM;Fagin JA
通讯作者：
Fagin JA
影响因子：
4.4
作者：
Onken MD;Worley LA;Long MD;Duan S;Council ML;Bowcock AM;Harbour JW
通讯作者：
Harbour JW
影响因子：
51.1
作者：
Robert, Caroline;Dummer, Reinhard;Middleton, Mark R.
通讯作者：
Middleton, Mark R.