Background

Biliary tract cancers are aggressive, rare, gastrointestinal malignancies with a poor prognosis; approximately half of patients with these cancers survive for less than 1 year after diagnosis with advanced disease. We aimed to evaluate the efficacy and safety of ramucirumab or merestinib in addition to first-line cisplatin–gemcitabine in patients with locally advanced or metastatic biliary tract cancer.

Methods

We did a randomised, double-blind, phase 2 study at 81 hospitals across 18 countries. We enrolled patients with histologically or cytologically confirmed, non-resectable, recurrent, or metastatic biliary tract adenocarcinoma, who were treatment-naive, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, estimated life expectancy of 3 months or more, and measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1. Eligible participants were randomly assigned (2:1:2:1) to receive either intravenous ramucirumab 8 mg/kg or placebo (on days 1 and 8 in 21-day cycles) or oral merestinib 80 mg or placebo (once daily) until disease progression, unacceptable toxicity, death, or patient or investigator request for discontinuation. All participants received intravenous cisplatin 25 mg/m² and gemcitabine 1000 mg/m² (on days 1 and 8 in 21-day cycles), for a maximum of eight cycles. Randomisation was done by an interactive web response system using a permuted block method (blocks of six) and was stratified by primary tumour site, geographical region, and presence of metastatic disease. Participants, investigators, and the study funder were masked to treatment assignment within the intravenous and oral groups. The primary endpoint was investigator-assessed progression-free survival (in the intention-to-treat population). The safety analysis was done in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02711553, and long-term follow-up is ongoing.

Findings

Between May 25, 2016, and Aug 8, 2017, 450 patients were assessed for eligibility and 309 (69%) were enrolled and randomly assigned to ramucirumab (n=106), merestinib (n=102), or pooled placebo (n=101); 306 received at least one dose of study treatment. The median follow-up time for progression-free survival at data cutoff (Feb 16, 2018) was 10·9 months (IQR 8·1–14·1). Median progression-free survival was 6·5 months (80% CI 5·7–7·1) in the ramucirumab group, 7·0 months (6·2–7·1) in the merestinib group, and 6·6 months (5·6–6·8) in the pooled placebo group (ramucirumab vs placebo hazard ratio 1·12 [80% CI 0·90–1·40], two-sided stratified p=0·48; merestinib vs placebo 0·92 [0·73–1·15], two-sided stratified p=0·64). The most common grade 3 or worse adverse events were neutropenia (51 [49%] of 104 patients in the ramucirumab group; 48 [47%] of 102 in the merestinib group; and 33 [33%] of 100 in the pooled placebo group), thrombocytopenia (36 [35%]; 19 [19%]; and 17 [17%]), and anaemia (28 [27%]; 16 [16%]; and 19 [19%]). Serious adverse events occurred in 53 (51%) patients in the ramucirumab group, 56 (55%) in the merestinib group, and 48 (48%) in the pooled placebo group. Treatment-related deaths (deemed related by the investigator) occurred in one (1%) of 104 patients in the ramucirumab group (cardiac arrest) and two (2%) of 102 patients in the merestinib group (pulmonary embolism [n=1] and sepsis [n=1]).

Interpretation

Adding ramucirumab or merestinib to first-line cisplatin–gemcitabine was well tolerated, with no new safety signals, but neither improved progression-free survival in patients with molecularly unselected, locally advanced or metastatic biliary tract cancer. The role of these targeted inhibitors remains investigational, highlighting the need for further understanding of biliary tract malignancies and the contribution of molecular selection.

Funding

Eli Lilly and Company.

中文翻译：

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在局部晚期或转移性胆道癌的标准一线化疗中添加雷莫芦单抗或 Merestinib：一项随机、双盲、多中心 2 期研究

 背景

胆道癌是一种侵袭性、罕见的胃肠道恶性肿瘤，预后较差；大约一半患有这些癌症的患者在诊断为晚期疾病后存活时间不到一年。我们的目的是评估除一线顺铂-吉西他滨外，雷莫芦单抗或 Merestinib 对局部晚期或转移性胆道癌患者的疗效和安全性。

 方法

我们在 18 个国家的 81 家医院进行了一项随机、双盲、2 期研究。我们招募了经组织学或细胞学证实的、不可切除的、复发性或转移性胆道腺癌的患者，这些患者未接受过治疗，年龄为 18 岁或以上，东部肿瘤合作组表现状态为 0 或 1，估计预期寿命为3 个月或更长时间，并且根据实体瘤反应评估标准 1.1 版可测量疾病。符合条件的参与者被随机分配 (2:1:2:1) 接受静脉注射 ramucirumab 8 mg/kg 或安慰剂（在 21 天周期的第 1 天和第 8 天）或口服 Merestinib 80 mg 或安慰剂（每天一次），直至疾病进展、不可接受的毒性、死亡或患者或研究者要求停药。所有参与者均接受静脉注射顺铂 25 mg/m ²和吉西他滨 1000 mg/m ² （在 21 天周期的第 1 天和第 8 天），最多 8 个周期。随机化是通过交互式网络响应系统使用置换块方法（六个块）进行的，并根据原发肿瘤部位、地理区域和转移性疾病的存在进行分层。参与者、研究人员和研究资助者对静脉注射组和口服组的治疗分配情况不知情。主要终点是研究者评估的无进展生存期（在意向治疗人群中）。安全性分析是在所有接受至少一剂指定治疗的患者中进行的。该试验已在 ClinicalTrials.gov 注册，NCT02711553，长期随访正在进行中。

 发现

2016 年 5 月 25 日至 2017 年 8 月 8 日期间，对 450 名患者进行了资格评估，其中 309 名患者 (69%) 入组并随机分配至雷莫芦单抗组 (n=106)、merestinib (n=102) 或合并安慰剂组 (n= 101）； 306 人接受了至少一剂研究治疗。数据截止时（2018 年 2 月 16 日）无进展生存期的中位随访时间为 10·9 个月（IQR 8·1–14·1）。雷莫芦单抗组的中位无进展生存期为 6·5 个月（80% CI 5·7–7·1），美瑞替尼组为 7·0 个月（6·2–7·1），而梅瑞替尼组为 6·6 个月(5·6–6·8) 在合并安慰剂组中（雷莫芦单抗与安慰剂风险比 1·12 [80% CI 0·90–1·40]，两侧分层 p=0·48；merestinib与安慰剂 0 ·92 [0·73–1·15]，两侧分层 p=0·64)。最常见的 3 级或更严重不良事件是中性粒细胞减少症（雷莫芦单抗组 104 名患者中有 51 名 [49%]；merestinib 组 102 名患者中有 48 名 [47%]；安慰剂组 100 名患者中有 33 名 [33%] ）、血小板减少症（36 例 [35%]、19 例 [19%] 和 17 例 [17%]）和贫血（28 例 [27%]、16 例 [16%] 和 19 例 [19%]）。雷莫芦单抗组有 53 名患者（51%）发生严重不良事件，merestinib 组有 56 名患者（55%）发生严重不良事件，安慰剂组有 48 名患者（48%）发生严重不良事件。雷莫芦单抗组 104 例患者中有 1 例 (1%) 发生治疗相关死亡（研究者认为相关）（心脏骤停），merestinib 组 102 例患者中有 2 例 (2%)（肺栓塞）[n=1]和败血症 [n=1]）。

 解释

在一线顺铂-吉西他滨中添加雷莫芦单抗或 Merestinib 耐受性良好，没有新的安全信号，但对于分子未选择的局部晚期或转移性胆道癌患者，两者都没有改善无进展生存期。这些靶向抑制剂的作用仍在研究中，强调需要进一步了解胆道恶性肿瘤和分子选择的贡献。

 资金

 礼来公司。