Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa City, Japan.
Department of Medicine and University Cancer Center Leipzig, University of Leipzig Medical Center, Leipzig, Germany.
Lancet. 2023 May 20;401(10389):1655-1668. doi: 10.1016/S0140-6736(23)00620-7. Epub 2023 Apr 15.
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 ClinicalTrials.gov, NCT03504397, 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 grade 3 or worse adverse events 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.
靶向 Claudin-18 同种型 2（CLDN18.2）的单克隆抗体zolbetuximab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食管交界处腺癌患者中显示出疗效。我们报告了 SPOTLIGHT 试验的结果，该试验调查了一线zolbetuximab 联合 mFOLFOX6（改良亚叶酸钙[或左亚叶酸钙]、氟尿嘧啶和奥沙利铂方案）与安慰剂联合 mFOLFOX6 治疗 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处腺癌患者的疗效和安全性。
SPOTLIGHT 是一项全球性、随机、安慰剂对照、双盲、III 期临床试验，在 20 个国家的 215 个中心招募了患者。符合条件的患者年龄在 18 岁或以上，CLDN18.2 阳性（定义为≥75%的肿瘤细胞显示中等至强的膜 CLDN18 染色），HER2 阴性（基于局部或中心评估），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 有可测量或不可测量的疾病；东部合作肿瘤学组体能状态评分为 0 或 1；以及足够的器官功能。患者通过交互式响应技术以 1:1 的比例随机分配，并根据区域、转移器官的数量和先前的胃切除术进行分层。患者接受 zolbetuximab（800mg/m 负荷剂量，随后每 3 周 600mg/m）联合 mFOLFOX6（每 2 周）或安慰剂联合 mFOLFOX6。主要终点是独立审查委员会评估的所有随机分配患者的无进展生存期。所有接受治疗的患者均评估了安全性。该研究在 ClinicalTrials.gov 上注册，编号为 NCT03504397，目前已不再招募新的参与者。
2018 年 6 月 21 日至 2022 年 4 月 1 日，565 名患者被随机分配接受 zolbetuximab 联合 mFOLFOX6（283 名患者；zolbetuximab 组）或安慰剂联合 mFOLFOX6（282 名患者；安慰剂组）。在 zolbetuximab 组中，283 名患者中有 279 名（99%）至少接受了一次治疗，在安慰剂组中，282 名患者中有 278 名（99%）至少接受了一次治疗。在 zolbetuximab 组中，176 名（62%）患者为男性，107 名（38%）为女性。在安慰剂组中，175 名（62%）患者为男性，107 名（38%）为女性。无进展生存期的中位随访时间为 zolbetuximab 组 12.94 个月，安慰剂组 12.65 个月。与安慰剂相比，zolbetuximab 治疗显著降低了疾病进展或死亡的风险（风险比[HR]0.75，95%CI0.60-0.94；p=0.0066）。zolbetuximab 组的中位无进展生存期为 10.61 个月（95%CI8.90-12.48），安慰剂组为 8.67 个月（8.21-10.28）。与安慰剂相比，zolbetuximab 治疗也显著降低了死亡风险（HR0.75，95%CI0.60-0.94；p=0.0053）。在 zolbetuximab 组中，279 名患者中有 242 名（87%）发生了 3 级或更高级别的不良事件，安慰剂组中有 278 名患者中有 216 名（78%）发生了 3 级或更高级别的不良事件。最常见的 3 级或更高级别的不良事件是恶心、呕吐和食欲下降。在 zolbetuximab 组中有 5 名（2%）患者发生了治疗相关死亡，安慰剂组中有 4 名（1%）患者发生了治疗相关死亡。未发现新的安全信号。
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处腺癌患者中，zolbetuximab 联合 mFOLFOX6 治疗显著延长了无进展生存期和总生存期，与安慰剂联合 mFOLFOX6 相比。zolbetuximab 联合 mFOLFOX6 可能成为这些患者的新一线治疗方法。
Astellas Pharma，Inc.
