Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial.
Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial.
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DOI：
10.1016/s1470-2045(17)30566-1
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发表时间：
2017-11
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通讯作者：
Cunningham D
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作者：
Catenacci DVT;Tebbutt NC;Davidenko I;Murad AM;Al-Batran SE;Ilson DH;Tjulandin S;Gotovkin E;Karaszewska B;Bondarenko I;Tejani MA;Udrea AA;Tehfe M;De Vita F;Turkington C;Tang R;Ang A;Zhang Y;Hoang T;Sidhu R;Cunningham D
阿托木单抗是一种选择性靶向MET受体配体肝细胞生长因子（HGF）的全人源单克隆抗体。我们的目的是评估rilotumumab联合表阿霉素、顺铂和卡培他滨治疗晚期MET阳性胃腺癌或胃食管连接部腺癌患者的疗效、安全性和药代动力学，并评估潜在的生物标志物。这项多中心、随机、双盲、安慰剂对照、III期研究在27个国家的152个中心进行。我们招募了患有不可切除的局部晚期或转移性胃或胃食管交界处腺癌、东部肿瘤协作组（ECOG）体能状态评分为0或1、MET阳性肿瘤（≥25%的肿瘤细胞膜染色强度≥1+）和可评价疾病且既往未接受过全身治疗的成人（年龄≥18岁）。通过计算机语音应答系统将合格患者随机分配（1：1），以21天为一个周期接受静脉注射15 mg/kg rilotumumab或安慰剂联合开放标签化疗（静脉注射50 mg/m2表阿霉素;静脉注射60 mg/m2顺铂;口服卡培他滨625 mg/m2，每日两次），最多10个周期。化疗完成后，患者继续接受rilotumumab或安慰剂单药治疗，直至疾病进展、不耐受、撤回知情同意或研究终止。根据疾病程度和ECOG体力状态对随机化进行分层。患者和医生均对研究治疗分配设盲。主要终点是总生存率，通过意向治疗进行分析。我们报告最终分析。本研究注册于ClinicalTrials.gov，编号NCT 01697072。在2012年11月7日至2014年11月21日期间，609名患者被随机分配到rilotumumab + epiraldine，顺铂和卡培他滨（rilotumumab组; n=304）或安慰剂+epiraldine，顺铂和卡培他滨（安慰剂组; n=305）。在一个独立的数据监测委员会发现rilotumumab组的死亡人数高于安慰剂组后，研究治疗提前停止; rilotumumab组的所有患者随后停止了所有研究治疗。rilotumumab组患者的中位随访时间为7.7个月（IQR 3.6 - 12.0），安慰剂组患者为9.4个月（5.3 - 13.1）。rilotumumab组的中位总生存期为8.8个月（95%CI 7.7 - 10.2），而安慰剂组为10.7个月（9.6 - 12.4）（分层风险比1.34，95%CI 1.10 - 1.63; p= 0.003）。rilotumumab组和安慰剂组中最常见的3级或更严重的不良事件是中性粒细胞减少（298例患者中的86例[29%] vs 299例患者中的97例[32%]），贫血（37例[12%] vs 43例[14%]）和疲劳（30例[10%] vs 35例[12%]）。在rilotumumab和安慰剂组中，严重不良事件的频率相似（142 [48%] vs 149 [50%]）。与安慰剂组相比，rilotumumab组因不良事件导致的死亡人数更多（42 [14%] vs 31 [10%]）。在rilotumumab组中，298例患者中有33例（11%）因疾病进展而发生致命性不良事件，9例（3%）因疾病进展而发生致命性事件。在安慰剂组中，299例患者中有23例（8%）因疾病进展而发生致命性不良事件，8例（3%）因疾病进展而发生致命性事件。rilotumumab对MET通路的配体阻断抑制不能有效改善MET阳性胃腺癌或胃食管腺癌患者的临床结局。安进
Rilotumumab is a fully human monoclonal antibody that selectively targets the ligand of the MET receptor, hepatocyte growth factor (HGF). We aimed to assess the efficacy, safety, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine, and to assess potential biomarkers, in patients with advanced MET-positive gastric or gastro-oesophageal junction adenocarcinoma. This multicentre, randomised, double-blind, placebo-controlled, phase 3 study was done at 152 centres in 27 countries. We recruited adults (aged ≥18 years) with unresectable locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, MET-positive tumours (≥25% of tumour cells with membrane staining of ≥1+ staining intensity), and evaluable disease, who had not received previous systemic therapy. Eligible patients were randomly assigned (1:1) via a computerised voice response system to receive rilotumumab 15 mg/kg intravenously or placebo in combination with open-label chemotherapy (epirubicin 50 mg/m2 intravenously; cisplatin 60 mg/m2 intravenously; capecitabine 625 mg/m2 orally twice daily) in 21-day cycles for up to ten cycles. After completion of chemotherapy, patients continued to receive rilotumumab or placebo monotherapy until disease progression, intolerability, withdrawal of consent, or study termination. Randomisation was stratified by disease extent and ECOG performance status. Both patients and physicians were masked to study treatment assignment. The primary endpoint was overall survival, analysed by intention to treat. We report the final analysis. This study is registered with ClinicalTrials.gov, number NCT01697072. Between Nov 7, 2012, and Nov 21, 2014, 609 patients were randomly assigned to rilotumumab plus epirubicin, cisplatin, and capecitabine (rilotumumab group; n=304) or placebo plus epirubicin, cisplatin, and capecitabine (placebo group; n=305). Study treatment was stopped early after an independent data monitoring committee found a higher number of deaths in the rilotumumab group than in the placebo group; all patients in the rilotumumab group subsequently discontinued all study treatment. Median follow-up was 7·7 months (IQR 3·6–12·0) for patients in the rilotumumab group and 9·4 months (5·3–13·1) for patients in the placebo group. Median overall survival was 8·8 months (95% CI 7·7–10·2) in the rilotumumab group compared with 10·7 months (9·6–12·4) in the placebo group (stratified hazard ratio 1·34, 95% CI 1·10–1·63; p=0·003). The most common grade 3 or worse adverse events in the rilotumumab and placebo groups were neutropenia (86 [29%] of 298 patients vs 97 [32%] of 299 patients), anaemia (37 [12%] vs 43 [14%]), and fatigue (30 [10%] vs 35 [12%]). The frequency of serious adverse events was similar in the rilotumumab and placebo groups (142 [48%] vs 149 [50%]). More deaths due to adverse events occurred in the rilotumumab group than the placebo group (42 [14%] vs 31 [10%]). In the rilotumumab group, 33 (11%) of 298 patients had fatal adverse events due to disease progression, and nine (3%) had fatal events not due to disease progression. In the placebo group, 23 (8%) of 299 patients had fatal adverse events due to disease progression, and eight (3%) had fatal events not due to disease progression. Ligand-blocking inhibition of the MET pathway with rilotumumab is not effective in improving clinical outcomes in patients with MET-positive gastric or gastro-oesophageal adenocarcinoma. Amgen.