Background

Paclitaxel plus ramucirumab is recommended as a second-line treatment regimen in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer. We aimed to assess whether switch maintenance or early second-line therapy with paclitaxel plus ramucirumab improved outcomes compared with continuation of oxaliplatin and fluoropyrimidine doublet chemotherapy as a first-line strategy.

Methods

ARMANI was a multicentre, open-label, randomised, phase 3 trial done in 31 hospitals in Italy. We enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and locally advanced unresectable or metastatic HER2-negative gastric or gastro-oesophageal junction cancer, who had disease control after 3 months of FOLFOX (leucovorin, fluorouracil, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin). Patients were randomly assigned (1:1) to either paclitaxel 80 mg/m² on days 1, 8, and 15 plus ramucirumab at 8 mg/kg on days 1 and 15 every 28 days intravenously (switch maintenance group) or continuation of oxaliplatin-based doublet chemotherapy (FOLFOX or CAPOX) for an additional 12 weeks, followed by fluoropyrimidine monotherapy maintenance (control group). Randomisation was stratified by previous gastrectomy (no vs yes), peritoneal carcinomatosis (yes vs no), and primary tumour location (gastro-oesophageal junction vs gastric). Treatment group allocation was done using a web-based system with a minimisation algorithm implementing a random component. The primary endpoint was progression-free survival, analysed on an intention-to-treat basis. The safety population included patients who received at least one dose of the study treatment. This study is registered with ClinicalTrials.gov, NCT02934464, and is complete.

Findings

Between Jan 1, 2017, and Oct 2, 2023, 280 patients were randomly assigned to receive paclitaxel plus ramucirumab (switch maintenance group; n=144) or to continue FOLFOX or CAPOX (control group; n=136). All patients were White. 180 (64%) of 280 patients were male and 100 (36%) were female. At a median follow-up of 43·7 months (IQR 24·0–57·9), 253 (90%) of 280 patients had a progression-free survival event: 131 (91%) of 144 patients in the switch maintenance group and 122 (90%) of 136 patients in the control group. Median progression-free survival was 6·6 months (95% CI 5·9–7·8) in the switch maintenance group and 3·5 months (2·8–4·2) in the control group (HR 0·61, 95% CI 0·48–0·79; p=0·0002). The assumption of proportional hazards was violated; in an analysis of 24-month restricted mean survival time, restricted mean progression-free survival was 8·8 months (95% CI 7·7–9·9) in the switch maintenance group and 6·1 months (5·0–7·2) in the control group (p=0·0010). The most frequent grade 3–4 treatment-related adverse events were neutropenia (37 [26%] patients in the switch maintenance group vs 13 [10%] patients in the control group), peripheral neuropathy (eight [6%] vs nine [7%]) and arterial hypertension (nine [6%] vs none). Serious adverse events occurred in 28 (20%) of 141 patients in the experimental group and 15 (11%) of 135 patients in the control group; these events were treatment-related in two (1%) patients in the switch maintenance group (pulmonary embolism) and two (1%) patients in the control group (mucositis and anaemia). No treatment-related deaths occurred.

Interpretation

Paclitaxel and ramucirumab switch maintenance could be a potential treatment strategy in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer who are not eligible for immunotherapy or targeted agents.

Funding

Partly funded by Eli Lilly.

中文翻译：

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雷莫芦单抗联合紫杉醇作为晚期 HER2 阴性胃癌或胃食管结合部癌 （ARMANI） 患者一线奥沙利铂化疗的转换维持与继续治疗：一项随机、开放标签、多中心、3 期试验

 背景

紫杉醇加雷莫芦单抗被推荐作为晚期 HER2 阴性胃癌或胃食管结合部癌患者的二线治疗方案。我们旨在评估与继续奥沙利铂和氟嘧啶双药化疗作为一线策略相比，紫杉醇加雷莫芦单抗的转换维持或早期二线治疗是否改善了结局。

 方法

ARMANI 是一项多中心、开放标签、随机、3 期试验，在意大利的 31 家医院进行。我们招募了 18 岁或以上、东部肿瘤合作组体能状态为 0 或 1 且局部晚期不可切除或转移性 HER2 阴性胃癌或胃食管交界处癌的患者，这些患者在 FOLFOX （亚叶酸、氟尿嘧啶和奥沙利铂） 或 CAPOX （卡培他滨和奥沙利铂） 治疗 3 个月后疾病得到控制。患者被随机分配 （1：1） 第 1 天、第 8 天和第 15 天紫杉醇 80 mg/m² 加第 1 天和第 15 天 8 mg/kg 雷莫芦单抗静脉注射 （转换维持组） 或继续以奥沙利铂为基础的双药化疗 （FOLFOX 或 CAPOX） 再持续 12 周，然后氟嘧啶单药维持治疗 （对照组）。随机分组按既往胃切除术 （no vs yes）、腹膜癌病 （yes vs no） 和原发性肿瘤位置 （gastro-oesophageal junction vs gastric） 进行分层。治疗组分配是使用基于 Web 的系统完成的，该系统具有实现随机成分的最小化算法。主要终点是无进展生存期，在意向性治疗的基础上进行分析。安全人群包括至少接受一剂研究治疗的患者。这项研究已在 ClinicalTrials.gov、NCT02934464 注册并且已完成。

 发现

在 2017 年 1 月 1 日至 2023 年 10 月 2 日期间，280 例患者被随机分配接受紫杉醇联合雷莫芦单抗治疗（转换维持组;n=144）或继续接受 FOLFOX 或 CAPOX（对照组;n=136）。所有患者均为白人。280 例患者中有 180 例 （64%） 为男性，100 例 （36%） 为女性。在中位随访 43·7 个月 （IQR 24·0–57·9） 时，280 例患者中有 253 例 （90%） 发生无进展生存期事件：转换维持组 144 例患者中有 131 例 （91%），对照组 136 例患者中有 122 例 （90%）。转换维持组的中位无进展生存期为 6·6 个月 （95% CI 5·9–7·8），对照组为 3·5 个月 （2·8–4·2） （HR 0·61,95% CI 0·48–0·79;p=0·0002）。违反了比例风险的假设;在对 24 个月限制性平均生存时间的分析中，转换维持组的限制性平均无进展生存期为 8·8 个月 （95% CI 7·7-9·9），对照组为 6·1 个月 （5·0-7·2） （p=0·0·0010）。最常见的 3-4 级治疗相关不良事件是中性粒细胞减少症（转换维持组 37 名 [26%] 患者，对照组 13 名 [10%] 患者）、周围神经病变（8 名 [6%] 对 9 名 [7%]）和动脉高血压（9 名 [6%] 患者，无）。试验组 141 例患者中有 28 例 （20%） 发生严重不良事件，对照组 135 例患者中有 15 例 （11%） 发生严重不良事件;这些事件在 SWITCH 维持组的 2 例 （1%） 患者 （肺栓塞） 和对照组的 2 例 （1%） 患者 （粘膜炎和贫血） 中与治疗相关。未发生与治疗相关的死亡。

 解释

紫杉醇和雷莫芦单抗转换维持治疗可能是一种潜在的治疗策略，用于不适合免疫治疗或靶向药物治疗的晚期 HER2 阴性胃癌或胃食管结合部癌患者。

 资金

部分由 Eli Lilly 资助。