Zolbetuximab, a monoclonal antibody targeting claudin-18 isoform 2 (CLDN18.2), has shown efficacy in patients with CLDN18.2-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma. We report the results of the SPOTLIGHT trial, which investigated the efficacy and safety of first-line zolbetuximab plus mFOLFOX6 (modified folinic acid [or levofolinate], fluorouracil, and oxaliplatin regimen) versus placebo plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma. SPOTLIGHT is a global, randomised, placebo-controlled, double-blind, phase 3 trial that enrolled patients from 215 centres in 20 countries. Eligible patients were aged 18 years or older with CLDN18.2-positive (defined as ≥75% of tumour cells showing moderate-to-strong membranous CLDN18 staining), HER2-negative (based on local or central evaluation), previously untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma, with radiologically evaluable disease (measurable or non-measurable) according to Response Evaluation Criteria in Solid Tumors version 1.1; an Eastern Cooperative Oncology Group performance status score of 0 or 1; and adequate organ function. Patients were randomly assigned (1:1) via interactive response technology and stratified according to region, number of organs with metastases, and previous gastrectomy. Patients received zolbetuximab (800 mg/m loading dose followed by 600 mg/m every 3 weeks) plus mFOLFOX6 (every 2 weeks) or placebo plus mFOLFOX6. The primary endpoint was progression-free survival assessed by independent review committee in all randomly assigned patients. Safety was assessed in all treated patients. The study is registered with , , and is closed to new participants. Between June 21, 2018, and April 1, 2022, 565 patients were randomly assigned to receive either zolbetuximab plus mFOLFOX6 (283 patients; the zolbetuximab group) or placebo plus mFOLFOX6 (282 patients; the placebo group). At least one dose of treatment was administered to 279 (99%) of 283 patients in the zolbetuximab group and 278 (99%) of 282 patients in the placebo group. In the zolbetuximab group, 176 (62%) patients were male and 107 (38%) were female. In the placebo group, 175 (62%) patients were male and 107 (38%) were female. The median follow-up duration for progression-free survival was 12·94 months in the zolbetuximab group versus 12·65 months in the placebo group. Zolbetuximab treatment showed a significant reduction in the risk of disease progression or death compared with placebo (hazard ratio [HR] 0·75, 95% CI 0·60–0·94; p=0·0066). The median progression-free survival was 10·61 months (95% CI 8·90–12·48) in the zolbetuximab group versus 8·67 months (8·21–10·28) in the placebo group. Zolbetuximab treatment also showed a significant reduction in the risk of death versus placebo (HR 0·75, 95% CI 0·60–0·94; p=0·0053). Treatment-emergent grade 3 or worse adverse events occurred in 242 (87%) of 279 patients in the zolbetuximab group versus 216 (78%) of 278 patients in the placebo group. The most common all-grade adverse events with zolbetuximab plus chemotherapy were nausea, vomiting, and decreased appetite. Treatment-related deaths occurred in five (2%) patients in the zolbetuximab group versus four (1%) patients in the placebo group. No new safety signals were identified. Targeting CLDN18.2 with zolbetuximab significantly prolonged progression-free survival and overall survival when combined with mFOLFOX6 versus placebo plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Zolbetuximab plus mFOLFOX6 might represent a new first-line treatment in these patients. Astellas Pharma, Inc.

中文翻译：

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Zolbetuximab 加 mFOLFOX6 治疗 CLDN18.2 阳性、HER2 阴性、未经治疗、局部晚期不可切除或转移性胃或胃食管交界腺癌患者 (SPOTLIGHT)：一项多中心、随机、双盲 3 期试验


Zolbetuximab 是一种靶向 Claudin-18 同工型 2 (CLDN18.2) 的单克隆抗体，已在 CLDN18.2 阳性、人表皮生长因子受体 2 (HER2) 阴性、局部晚期不可切除或转移性胃或胃肿瘤患者中显示出疗效。食管连接部腺癌。我们报告 SPOTLIGHT 试验的结果，该试验研究了一线佐贝妥昔单抗加 mFOLFOX6（改良亚叶酸 [或左亚叶酸]、氟尿嘧啶和奥沙利铂方案）与安慰剂加 mFOLFOX6 在 CLDN18.2 阳性患者中的疗效和安全性， HER2 阴性、局部晚期不可切除或转移性胃或胃食管交界腺癌。 SPOTLIGHT 是一项全球性、随机、安慰剂对照、双盲、3 期试验，招募了来自 20 个国家 215 个中心的患者。符合条件的患者年龄为 18 岁或以上，CLDN18.2 阳性（定义为 ≥75% 的肿瘤细胞显示中度至强膜性 CLDN18 染色）、HER2 阴性（基于局部或中心评估）、既往未经治疗、局部晚期不可切除或转移性胃或胃食管交界处腺癌，根据实体瘤反应评估标准 1.1 版，具有放射学可评估疾病（可测量或不可测量）；东部肿瘤合作组表现状态评分为 0 或 1；和足够的器官功能。通过交互式响应技术对患者进行随机分配（1:1），并根据区域、转移器官数量和既往胃切除术进行分层。患者接受 zolbetuximab（800 mg/m2 负荷剂量，随后每 3 周 600 mg/m2）加 mFOLFOX6（每 2 周）或安慰剂加 mFOLFOX6。 主要终点是由独立审查委员会对所有随机分配的患者进行评估的无进展生存期。对所有接受治疗的患者进行安全性评估。该研究已在 、 、 注册，并且不对新参与者开放。 2018年6月21日至2022年4月1日期间，565名患者被随机分配接受zolbetuximab加mFOLFOX6治疗（283名患者；zolbetuximab组）或安慰剂加mFOLFOX6治疗（282名患者；安慰剂组）。佐贝妥昔单抗组 283 名患者中的 279 名患者（99%）和安慰剂组 282 名患者中 278 名患者（99%）接受了至少一剂治疗。在佐贝妥昔单抗组中，176 名患者（62%）为男性，107 名患者（38%）为女性。在安慰剂组中，175 名患者（62%）为男性，107 名患者（38%）为女性。佐贝妥昔单抗组的中位无进展生存期随访时间为 12·94 个月，而安慰剂组为 12·65 个月。与安慰剂相比，佐贝妥昔单抗治疗显示疾病进展或死亡风险显着降低（风险比 [HR] 0·75，95% CI 0·60–0·94；p=0·0066）。佐贝妥昔单抗组的中位无进展生存期为 10·61 个月 (95% CI 8·90–12·48)，而安慰剂组为 8·67 个月 (8·21–10·28)。与安慰剂相比，佐贝妥昔单抗治疗还显示死亡风险显着降低（HR 0·75，95% CI 0·60–0·94；p=0·0053）。 zolbetuximab 组 279 名患者中有 242 名 (87%) 发生了治疗引起的 3 级或更严重不良事件，而安慰剂组 278 名患者中有 216 名 (78%) 发生了治疗引起的 3 级或更严重不良事件。佐贝妥昔单抗联合化疗最常见的所有级别不良事件是恶心、呕吐和食欲下降。 zolbetuximab 组中有 5 名患者 (2%) 发生治疗相关死亡，而安慰剂组有 4 名患者 (1%)。没有发现新的安全信号。对于 CLDN18.2 阳性、HER2 阴性、局部晚期不可切除或转移性胃或胃食管交界腺癌患者，用佐贝妥昔单抗 (zolbetuximab) 联合 mFOLFOX6 与安慰剂加 mFOLFOX6 相比，以 CLDN18.2 为靶点可显着延长无进展生存期和总生存期。 Zolbetuximab 加 mFOLFOX6 可能代表这些患者的新一线治疗。安斯泰来制药公司