BACKGROUND The rationale for the evaluation of trametinib in advanced biliary cancer (BC) is based on the presence of mitogen-activated protein kinase alterations and on earlier promising results with MEK inhibitors in BC. METHODS Patients with histologically proven BC who progressed on gemcitabine/platinum were randomised to trametinib daily (arm 1) versus fluoropyrimidine therapy (infusional 5-fluorouracil or oral capecitabine, arm 2). The primary end-point was overall survival (OS). Secondary end-points included progression free survival (PFS) and response rate. A planned interim futility analysis of objective response was performed on the first 14 patients registered to the trametinib arm. RESULTS The study was stopped early based on the lack of measurable response in the trametinib arm. A total of 44 eligible patients were randomised (24 patients in arm 1 and 20 patients in arm 2). Median age was 62 years and the primary sites of tumour were cholangiocarcinoma (68%) and gallbladder (32%). The overall response rate was 8% (95% CI 0%-19%) in arm 1 versus 10% (95% CI 0%-23%) in arm 2 (p > .99) Median OS was 4.3 months for arm 1 and 6.6 months for arm 2. The median PFS was 1.4 months for arm 1 and 3.3 months for arm 2. CONCLUSIONS This is the first prospective randomised study of a targeted agent versus chemotherapy for the second-line treatment of BC. In this unselected population, the interim analysis result of unlikely benefit with trametinib resulted in early closure.

中文翻译：

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单药 MEK 抑制剂曲美替尼与 5-氟尿嘧啶或卡培他滨治疗难治性晚期胆道癌的随机 II 期试验 (SWOG S1310)。


背景 评估曲美替尼治疗晚期胆道癌 (BC) 的基本原理是基于丝裂原激活蛋白激酶改变的存在以及 MEK 抑制剂在 BC 中的早期有希望的结果。方法 经组织学证实的 BC 患者在接受吉西他滨/铂类药物治疗后出现进展，被随机分配至每天接受曲美替尼（第 1 组）与氟嘧啶治疗（输注 5-氟尿嘧啶或口服卡培他滨，第 2 组）。主要终点是总生存期（OS）。次要终点包括无进展生存期（PFS）和缓解率。对注册到曲美替尼组的前 14 名患者进行了计划的客观反应中期无效分析。结果 由于曲美替尼组缺乏可测量的反应，该研究提前停止。共有 44 名符合条件的患者被随机分组​​（第 1 组 24 名患者，第 2 组 20 名患者）。中位年龄为 62 岁，肿瘤原发部位为胆管癌 (68%) 和胆囊癌 (32%)。第 1 组的总体缓解率为 8% (95% CI 0%-19%)，第 2 组的总体缓解率为 10% (95% CI 0%-23%) (p > .99) 第 1 组的中位 OS 为 4.3 个月第 2 组为 6.6 个月。第 1 组的中位 PFS 为 1.4 个月，第 2 组为 3.3 个月。 结论 这是针对 BC 二线治疗的靶向药物与化疗的第一项前瞻性随机研究。在这个未经选择的人群中，曲美替尼不太可能获益的中期分析结果导致了早期关闭。