Phase II RAINSPOT: a Multicentric Open Label Trial of Zolbetuximab-Paclitaxel-Ramucirumab in Second Line Setting for CLDN18.2 Positive Gastro-esophageal Adenocarcinoma

This study examines whether adding the drug Zolbetuximab to an existing treatment (Paclitaxel and Ramucirumab) can improve patients' survival. The goal is to see if this combination works better for patients whose tumours contain a specific protein (CLDN18.2). The results will be compared to past patient data from those who only received the standard treatment.
Zolbetuximab (Vyloy) is a cancer medicine that is used to treat adults with gastric or gastro-esophageal junction adenocarcinoma (a type of cancer of the stomach or the transition between the stomach and esophagus). Zolbetuximab will be administered via an intravenous infusion in combination with Paclitaxel and Ramucirumab (Cyramza) (two other cancer drugs that are the standard treatment for this condition). Treatment will take place at regular intervals in the hospital. In addition to treatment,patients will undergo a tumour biopsy. While the biopsy procedure may cause some discomfort or pain, it will only be performed if medically justifiable. Patients participation in the study will continue as long as they receive treatment and the disease does not worsen. The overall duration of the study, for all patients, will span several years.

开始日期2025-10-01

申办/合作机构-

NCT06901531

/ Recruiting临床3期

A Phase 3, Double-blind, Randomized Study of Zolbetuximab in Combination With Pembrolizumab and Chemotherapy (CAPOX or mFOLFOX6) in First-line Treatment of Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma in Participants Whose Tumors Are HER2-negative, Claudin (CLDN) 18.2-positive and Programmed Death-ligand 1 (PD-L1)-Positive

Zolbetuximab is being studied in people with cancer in and around the stomach or where the food pipe (esophagus) joins the stomach, called gastroesophageal junction (GEJ) cancer. Zolbetuximab with chemotherapy may be used to treat stomach and GEJ cancer when the cancer cells do not have a protein called HER2 (human epidermal growth factor receptor 2) on their surface (HER2-negative) but do have a protein called Claudin 18.2 (Claudin 18.2-positive). Zolbetuximab is thought to work by attaching to the Claudin 18.2 protein in their tumor, which switches on the body's immune system to attack the tumor. Certain stomach and GEJ cancers may be treated with immunotherapy, which helps the body's immune system fight cancer. This study will give more information about how well zolbetuximab works when given with an immunotherapy medicine called pembrolizumab and chemotherapy. In this study, adults with stomach cancer or GEJ cancer will either be given zolbetuximab with pembrolizumab and chemotherapy or a placebo with pembrolizumab and chemotherapy. A placebo looks like zolbetuximab but doesn't have any medicine in it.
The main aim of the study is to check how long people with stomach cancer and GEJ cancer live after treatment with zolbetuximab with pembrolizumab and chemotherapy compared to placebo with pembrolizumab and chemotherapy.
Adults with locally advanced unresectable or metastatic stomach cancer or GEJ cancer can take part. Locally advanced means the cancer has spread to nearby tissue. Unresectable means the cancer cannot be removed by surgery. Metastatic means the cancer has spread to other parts of the body. A tumor sample (biopsy) of their cancer will have the Claudin 18.2 protein, PD-L1 protein, and be HER2-negative. They may have been previously treated with certain standard therapies. People cannot take part if they need to take medicines to suppress their immune system, have blockages or bleeding in their gut, have specific uncontrollable cancers such as symptomatic or untreated cancers in the nervous system, or have a specific heart condition, or infections.
The study treatments are either zolbetuximab with pembrolizumab and chemotherapy, or placebo with pembrolizumab and chemotherapy. People who take part will receive just 1 of the study treatments by chance. The people in the study and the study doctors will not know who takes which of the study treatments. Study treatment will be given in 6-week (42-day) cycles. The study treatment is mainly given to people slowly through a tube into a vein. This is called an infusion. People will receive study treatment as follows: Zolbetuximab or placebo: 1 infusion every 2 or 3 weeks (2 or 3 infusions in a cycle) together with: Chemotherapy (1 of the following types of chemotherapy): 1. CAPOX (capecitabine and oxaliplatin): 1 infusion of oxaliplatin every 3 weeks (2 infusions in a cycle). People will also take 1 tablet of capecitabine twice a day for 2 weeks (14 days) at the start of each cycle (Day 1) and again in the middle of each cycle (Day 22). After 8 study treatments people will receive capecitabine only. 2. Modified FOLFOX6 or mFOLFOX6 (5-fluorouracil, folinic acid and oxaliplatin): 1 infusion every 2 weeks (3 infusions in a cycle). After 12 study treatments people will receive folinic acid and fluorouracil only, instead of mFOLFOX6. Pembrolizumab: 1 infusion every 3 or 6 weeks (1 or 2 infusions in a cycle). People can be in the study and will receive study treatment until their cancer worsens, they cannot tolerate the study treatment, or they need to start another cancer treatment. People may receive pembrolizumab for up to 2 years. People will visit the clinic on certain days to receive their study treatment and have health checks. The study doctors will check if people had any medical problems from taking zolbetuximab or the other study treatments. On some visits they will have scans to check for any changes in their cancer. People will have the option of giving a tumor sample if they stop treatment because their cancer has worsened. People will visit the clinic after they stop their study treatment. People will be asked about any medical problems and will have a health check. People will continue to have scans every 9 or 12 weeks to check for any changes in their cancer. They will have telephone health checks every 3 months. The number of visits and checks done at each visit will depend on the health of each person and whether they completed their study treatment or not.

开始日期2025-05-22

申办/合作机构

Astellas Pharma Global Development, Inc.

NCT06881017

/ Not yet recruiting临床2期IIT

Establishment of Precision Targeted Therapy Strategies for Advanced Gastric Cancer Based on Novel Molecular Subtyping: an Umbrella Phase II Exploratory Clinical Study

This study is a prospective, umbrella-design, Phase II clinical trial. Eligible participants with advanced or metastatic gastric cancer who are treatment-naïve for advanced-stage systemic therapy will undergo biomarker profiling (HER2, CLDN18.2, and PD-L1) via next-generation sequencing (NGS) or immunohistochemistry (IHC). Participants will be stratified into distinct molecular subtypes and assigned subtype-specific therapeutic regimens. The primary objectives are to assess treatment efficacy (e.g., objective response rate) and safety profiles across molecularly defined cohorts.

开始日期2025-05-01

申办/合作机构

中国医科大学

100 项与佐妥昔单抗相关的临床结果

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100 项与佐妥昔单抗相关的专利（医药）

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124

项与佐妥昔单抗相关的文献（医药）

2026-04-01·DEN open

Endoscopic Complete Response to Zolbetuximab for Advanced Gastric Cancer With Claudin 18.2 Positive: A Case Report

Article

作者: Kimura, Rika ; Yoshioka, Tsubasa ; Yamaba, Tomohiro ; Uchiyama, Gaku ; Sasaki, Akinori ; Tachibana, Ayu ; Okamoto, Risa

ABSTRACT:

Recently, zolbetuximab combined with chemotherapy has been approved as a first‐line treatment for advanced gastric cancer (GC). However, to date, no endoscopic images demonstrating endoscopic complete response (eCR) to zolbetuximab plus chemotherapy have been reported. Herein, we report the case of an 80‐year‐old man who presented with epigastric pain and loss of appetite and was diagnosed with undifferentiated GC and peritoneal metastasis. The patient received modified FOLFOX6 plus zolbetuximab because genetic testing revealed HER2‐negative and claudin 18.2‐positive. He experienced grade 2 nausea, which improved with the administration of antiemetic agents. Computed tomography performed at month 5 showed resolution of peritoneal dissemination. Endoscopic examination during the same period showed the disappearance of the primary gastric tumor with scarring. Biopsy of the scar area revealed only inflammatory cells; therefore, the primary lesion was defined as an eCR. To the best of our knowledge, this is the first report of eCR to zolbetuximab and chemotherapy in a patient with GC and claudin 18.2 positive. This case report suggested that chemotherapy combined with zolbetuximab may offer greater therapeutic benefit than chemotherapy combined with immune checkpoint inhibitors in patients with undifferentiated GC. Further analysis is expected to enable the identification of patients with claudin 18.2‐positive GC in whom zolbetuximab treatment is effective.

2025-12-01·CANCER CHEMOTHERAPY AND PHARMACOLOGY

Population pharmacokinetic analysis of fluorouracil and oxaliplatin in the absence or presence of zolbetuximab in locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma

Article

作者: Bonate, Peter L ; Yang, Jianning ; Yamada, Akihiro ; Poondru, Srinivasu ; Heo, Nakyo

PURPOSE:

Zolbetuximab, a monoclonal antibody targeting claudin 18.2 (CLDN18.2), is approved in combination with chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative, CLDN18.2-positive, unresectable, advanced or recurrent gastric cancer (in Japan) and in combination with fluoropyrimidine- and platinum-containing chemotherapy for first-line locally advanced unresectable or metastatic HER2-negative, CLDN18.2-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (in geographies including but not limited to the US, Europe, and China). Noncompartmental analysis (NCA) was previously used to evaluate the effect of zolbetuximab on pharmacokinetics (PK) of 5-fluorouracil (5-FU) and oxaliplatin; however, limitations of NCA confounded the results. This study utilized population pharmacokinetic (PopPK) analysis to address these limitations.

METHODS:

In Cohort 2 of the phase 2 ILUSTRO study (NCT03505320), patients with locally advanced unresectable or metastatic HER2-negative, CLDN18.2-positive G/GEJ adenocarcinoma received zolbetuximab with modified folinic acid, 5-FU, and oxaliplatin. PopPK models were developed to evaluate the impact of zolbetuximab on PK of 5-FU and oxaliplatin (including simultaneous analysis of free and total platinum).

RESULTS:

PK of 5-FU was adequately described by a 1-compartment model with zero-order input and first-order elimination. PK of free and total platinum was simultaneously described by a 3-compartment model with zero-order input, first-order elimination, and time-dependent free fraction. No impact of zolbetuximab on 5-FU PK or on systemic clearance or free fraction of oxaliplatin in plasma was observed. The effect of zolbetuximab on oxaliplatin distribution volume (12.3% decrease) was statistically significant but not considered clinically relevant.

CONCLUSION:

PopPK analysis suggests no effect of zolbetuximab on 5-FU or oxaliplatin PK.

2025-12-01·MODERN PATHOLOGY

Analytical and Clinical Performance of the VENTANA CLDN18 (43-14A) RxDx Assay in Gastric and Gastroesophageal Junction Adenocarcinoma Tissue Samples in SPOTLIGHT and GLOW

Article

作者: Guerruero, Abraham ; Kouzova, Margarita ; Moran, Sean ; Moran, Diarmuid ; Lawrence-Glaze, Rebecka ; Stratton, Steven P ; Pang, Lizhen ; Pugh, Judith ; Baldwin, Drew ; McDonald, Jannine

New therapies are needed to treat patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Zolbetuximab is a monoclonal antibody that targets the tight junction protein claudin 18 isoform 2 (CLDN18.2) in gastric or gastroesophageal junction (G/GEJ) adenocarcinoma cells. We describe the analytical and clinical performance of the VENTANA CLDN18 (43-14A) RxDx Assay (Roche Diagnostics Solutions) as a companion diagnostic immunohistochemistry assay for treatment with zolbetuximab. Analytical performance was assessed in commercially available G/GEJ adenocarcinoma samples. Clinical performance was assessed in the context of 2 phase 3 trials (SPOTLIGHT, NCT03504397; GLOW, NCT03653507) of first-line zolbetuximab plus chemotherapy in patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma, whose tumors were CLDN18.2 positive (≥75% of viable tumor cells demonstrating moderate-to-strong membrane CLDN18 staining). Staining acceptability rates were assessed in patients whose tumors were tested for CLDN18.2 status using the VENTANA CLDN18 (43-14A) RxDx Assay and who met enrollment eligibility criteria not related to CLDN18.2 status. Progression-free survival and overall survival were evaluated in the enrolled patients. Analytical performance: positive and negative percent agreement compared with immunohistochemistry reference scoring was 100% for between-antibody, between-detection kit, between-instrument, between-day, and within-run precision studies. Interlaboratory reproducibility exceeded 90% average positive and negative agreement between sites and 94% average positive and negative agreement between readers across 3 sites. Clinical performance: among 3783 patient tumor samples, staining acceptability rates exceeded 94%. Patients identified for eligibility using the VENTANA CLDN18 (43-14A) RxDx Assay demonstrated statistically significant improvement in progression-free survival and overall survival with zolbetuximab plus chemotherapy in both phase 3 trials. The VENTANA CLDN18 (43-14A) RxDx Assay demonstrated robust, reproducible analytical performance and clinical utility as a companion diagnostic for first-line zolbetuximab plus chemotherapy in patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma, whose tumors were CLDN18.2 positive.

370

项与佐妥昔单抗相关的新闻（医药）

2025-10-01

·医药速览

双抗Givastomig的设计巧思：低毒高效的条件性激活肿瘤免疫

Claudin 18.2作为一种在实体瘤中得到验证的靶点，推动了下一代疗法的发展。将Claudin 18.2与条件性4-1BB激活联系起来的双特异性抗体为增强T细胞功能提供了一种新方法。通过将共刺激限制在肿瘤微环境中，旨在提高疗效，同时限制全身毒性。 01. Givastomig的分子设计 Givastomig是一种首创的Fc沉默的claudin 18.2（CLDN18.2）×4-1BB双特异性抗体。其IgG1骨架融合了两个scFv，同时，Fc段经过沉默突变改造以防止Fc介导的激活，丧失了与FcγR的结合能力。这种设计使Givastomig既不依赖ADCC/CDC发挥作用，规避了FcγR介导的免疫细胞在肝脏聚集导致的肝损伤，又降低了传统4-1BB激动剂的肝损伤风险。 02. Givastomig的作用机制 CLDN18.2是一种主要存在于胃黏膜中的紧密连接蛋白，它在胃癌和其他胃肠道癌症的恶性细胞表面异常暴露，使其成为癌症治疗的一个非常有吸引力的靶点。 4-1BB是TNF受体超家族的共刺激受体，短暂表达于活化的T细胞、B细胞和NK细胞上，在增强抗肿瘤免疫中发挥核心作用。 Givastomig靶向CLDN18.2阳性肿瘤细胞（如胃癌、食管癌等），特异性识别并杀伤肿瘤细胞。同时，靶向4-1BB以激活T细胞和自然杀伤细胞（NK细胞），增强抗肿瘤免疫应答。在双重结合后，该分子仅在CLDN18.2表达的肿瘤细胞存在时促进4-1BB的条件性聚集和激活。这导致T细胞增殖、细胞因子分泌（例如IFN-γ、IL-2）以及通过释放穿孔素和颗粒酶发挥细胞毒性功能。 03. Givastomig的I期临床结果 Givastomig的安全性特征良好，大多数TRAEs仅限于低级别恶心、疲劳、贫血和短暂性转氨酶升高。仅在21%的患者中报告了3级TRAEs，没有剂量限制性毒性，推荐的2期剂量被确定为12 mg/kg。在73名可评估的患者中，ORR为18%，DCR为37%。值得注意的是，在广泛的CLDN18.2表达水平范围内观察到了临床反应，从低至11%到100%，表明治疗效果可能超出传统定义的高表达亚组，并可能扩大患者资格。鉴于其临床活性和良好的耐受性，givastomig目前正在试验的第2部分中与nivolumab和mFOLFOX6联合评估，作为转移性胃/GEJ的一线治疗。最近公布的初步结果显示，在扩展队列中，ORR为83%，并且在所有PD-L1表达水平和CLDN18.2亚组中都观察到了反应。治疗相关的3级及以上不良事件发生在24%的患者中。 04. 其他治疗方式的临床结果（1）单克隆抗体zolbetuximab——一种首创的针对CLDN18.2的单克隆抗体该mAb与CLDN18.2结合，其完整的Fc区域与NK细胞上的FcγR结合，导致ADCC并释放穿孔素和颗粒酶，诱导CLDN18.2表达的肿瘤细胞凋亡。同时，Fc与C1q结合激活经典补体途径，通过膜攻击复合体（MAC）的形成导致补体依赖性细胞毒性（CDC）和随后的肿瘤细胞溶解。当添加到铂类-氟嘧啶化疗中时，能改善CLDN18.2阳性、晚期、未经治疗的胃或胃食管交界腺癌患者的总生存期，但是72.8-87%接受zolbetuximab治疗的患者会出现3级治疗相关不良事件。此外，这些研究只包括高CLDN18.2表达（定义为>75%的细胞通过IHC染色为2+或3+）的患者，约占胃或胃食管交界（GEJ）肿瘤患者的38%。（2）T细胞接合剂IBI389——一种CLDN18.2xCD3 bsAbs 该bsAb与肿瘤细胞上的CLDN18.2和T细胞上的CD3结合，物理上连接两者，导致T细胞激活，独立于MHC-肽复合物。激活的T细胞释放促炎细胞因子和含有穿孔素和颗粒酶的细胞毒性颗粒，触发凋亡。这种免疫突触的形成允许选择性地杀死表达CLDN18.2的肿瘤细胞，同时保留低表达或不表达的正常组织。在胃/GEJ癌症患者中的1期研究的初步结果显示，在CLDN18.2表达阳性且免疫组化（IHC）评分为2+或3+的患者中，客观缓解率（ORR）达到了30.8%，疾病控制率（DCR）达到了70%，这些患者的CLDN18.2表达水平超过10%。（3）针对CLDN18.2的CAR-T细胞疗法经过工程改造以表达针对CLDN18.2的CAR的T细胞识别并结合表达该抗原的肿瘤细胞，独立于MHC呈递。这触发了穿孔素和颗粒酶的释放，诱导凋亡。激活的CAR-T细胞还分泌促炎细胞因子。在一项针对CLDN18.2的CAR T细胞疗法的随机对照试验在经过大量预处理的胃/GEJ患者中，satri-ce CAR-T细胞疗法与医生选择的治疗相比，显著改善了无进展生存期（PFS）（中位PFS 3.25个月 vs 1.77个月；HR 0.37），并提供了具有临床意义的总生存期益处（中位总生存期7.92个月 vs 5.49个月；HR 0.69）。结语随着对Claudin 18.2（CLDN18.2）在胃肠道肿瘤中作用的深入理解，针对这一靶点的创新疗法不断涌现，为晚期胃癌和胃食管连接部癌（GEJ）患者带来了新的希望。Givastomig作为一种首创的Fc沉默CLDN18.2×4-1BB双特异性抗体，在临床试验中展现出良好的安全性和初步疗效，为肿瘤微环境中的免疫激活提供了新的策略。此外，satri-cel等CAR-T细胞疗法在随机对照试验中显著改善了患者的无进展生存期和总生存期，进一步证明了CLDN18.2靶向治疗的潜力。参考资料来源：https://doi.org/10.1158/1078-0432.CCR-25-2554 我们已经建立了医药交流群，群里有各大著名企业和重点高校的研究人员。大家可以一起讨论医药热点，分享经验，共同进步。想加入的话，扫码或添加小编微信（VX：chirouzhenxiang666），拉您进群！推文用于传递知识，如因版权等有疑问，请于本文刊发30日内联系医药速览。原创内容未经授权，禁止转载至其他平台。 ©2021 医药速览保留所有权利往期链接 “小小疫苗”养成记 | 医药公司管线盘点人人学懂免疫学| 人人学懂免疫学（语音版）综述文章解读 | 文献略读 | 医学科普|医药前沿笔记 PROTAC技术| 抗体药物| 抗体药物偶联-ADC 核酸疫苗 | CAR技术| 化学生物学温馨提示医药速览公众号目前已经有近12个交流群（好学，有趣且奔波于医药圈人才聚集于此）。进群请扫描上方二维码，备注“姓名/昵称-企业/高校-具体研究领域/专业”，此群仅为科研交流群，非诚勿扰。简单操作即可星标⭐️医药速览，第一时间收到我们的推送 ①点击标题下方“医药速览” ②至右上角“...” ③点击“设为星标

免疫疗法临床1期临床2期细胞疗法

2025-09-30

·BioDialectics

天境生物CLDN18.2/4-1BB双抗Givastomig条件性激活肿瘤免疫

在胃癌及胃肠道肿瘤治疗领域，Claudin18.2（CLDN18.2）已成为验证性靶点，首款单抗药物Zolbetuximab虽确立新治疗标准，但仍面临毒性高、获益人群有限（仅38%高表达患者）的困境。近期研究聚焦首款Fc沉默型CLDN18.2×4-1BB双特异性抗体Givastomig的I期临床数据，其通过“肿瘤靶向的4-1BB条件性激活”机制，在降低全身毒性的同时，突破CLDN18.2表达水平限制，为胃肠道肿瘤患者带来更安全、更广谱的治疗选择。一：Givastomig的“肿瘤靶向性4-1BB激活”设计 4-1BB（CD137）是TNF受体超家族共刺激分子，激活后可显著增强T细胞增殖、细胞因子分泌及细胞毒性，但传统4-1BB激动剂（如Urelumab）因全身激活导致严重肝毒性，临床应用受限。Givastomig通过创新设计解决这一难题。 Givastomig为四价双抗（IgG骨架融合两个scFv），同时结合肿瘤细胞表面的CLDN18.2与免疫细胞表面的4-1BB：仅当双抗同时结合CLDN18.2⁺肿瘤细胞与4-1BB⁺免疫细胞时，才会诱导4-1BB交联激活，避免外周组织（如肝脏）的4-1BB非特异性激活。CLDN18.2结合域实现肿瘤靶向，4-1BB结合域提供共刺激信号，促进T细胞增殖、IFN-γ/IL-2分泌及颗粒酶B介导的肿瘤杀伤。 Givastomig的Fc段经过突变改造，丧失与FcγR的结合能力：统单抗（如Zolbetuximab）通过Fc段介导ADCC/CDC杀伤正常CLDN18.2⁺胃黏膜细胞，导致胃肠道毒性。而Fc沉默设计使Givastomig不依赖ADCC/CDC，仅通过免疫调控发挥作用。规避FcγR介导的免疫细胞在肝脏聚集，降低传统4-1BB激动剂的肝损伤风险。二：GivastomigI期临床的“安全性与疗效突破” I期研究纳入75例晚期实体瘤患者（约50%为胃癌/GEJ癌），探索0.1-18mg/kg剂量范围，结果显示仅21%患者出现3级TRAEs，无剂量限制性毒性，常见不良反应为轻度恶心、疲劳、贫血及短暂转氨酶升高，无严重胃肠道毒性或肝毒性。推荐II期剂量（RP2D）为12mg/kg，此剂量下患者耐受性良好，无需预防性使用止吐药，解决Zolbetuximab的毒性痛点。在73例可评估患者中，Givastomig展现广谱抗肿瘤活性：ORR 18%：8例患者达到PR，DCR 37%，且患者均为经多线治疗失败的难治性人群。疗效覆盖CLDN18.2低表达（11%阳性）至高表达（100%阳性）患者，除胃癌/GEJ癌外，在头颈部鳞状细胞癌中也观察到临床缓解，提示CLDN18.2靶向疗法的潜在广谱应用价值。与当前主流CLDN18.2靶向疗法相比，Givastomig在机制、安全性、获益人群上展现显著差异化：类型药物机制 3级TRAEs发生率 CLDN18.2表达要求优势人群单抗 Zolbetuximab ADCC/CDC 72.8%-87% IHC2+/3+且≥75%阳性高表达、免疫浸润型肿瘤 CD3双抗 IBI389 CD3激活 58.3% IHC2+/3+且≥10%阳性免疫浸润型肿瘤 4-1BB双抗 Givastomig CLDN18.2靶向4-1BB激活 21% 11%-100%阳性各表达水平、多瘤种 CAR-T Satri-cel 工程化T细胞直接杀伤未明确（需细胞输注） IHC阳性难治性、高表达肿瘤总结思考 Givastomig的I期数据证实，“肿瘤靶向的共刺激激活”可在降低毒性的同时，突破靶点表达水平限制，使更多患者（包括低表达人群）获益。其联合免疫检查点抑制剂（如nivolumab）的高缓解率，提示“免疫调控双抗+ICIs”可能成为CLDN18.2阳性肿瘤的新治疗范式。随着II期联合治疗研究的推进，Givastomig有望成为CLDN18.2阳性胃肠道肿瘤的“基石疗法”，推动精准免疫治疗向“更安全、更广谱”方向发展。 Rewiring antitumor immunity: targeting CLDN18.2 with conditional 4-1BB activation. Clin Cancer Res. 2025 Sep 29. doi: 10.1158/1078-0432.CCR-25-2554.

免疫疗法临床结果临床2期临床1期

2025-09-25

·Biotech前瞻

一线佐妥昔单抗靶向治疗之后，CLDN18.2仍阳性的概率有多大

点击蓝字关注我们本期看点背景：佐妥昔单抗（Zolbetuximab）联合化疗已成为不可切除的晚期胃癌中，HER2阴性且CLDN18.2阳性（≥75%肿瘤细胞CLDN18.2膜染色IHC 2+或3+）患者的标准治疗方案。然而，佐妥昔单抗治疗后CLDN18.2表达的动态变化仍不清楚。材料与方法：采用免疫组化（IHC），对接受佐妥昔单抗联合化疗的CLDN18.2阳性晚期胃癌患者，在治疗前及治疗后获得的肿瘤样本进行回顾性评估。表达水平根据≥2+染色强度的阳性细胞比例判定，并设定多个阈值（75%、40%、25%）进行分析。结果：在65例接受佐妥昔单抗治疗的患者中，15例患者的肿瘤样本在基线和疾病进展时均可进行CLDN18.2状态评估。在疾病进展时，53.3%的病例转为CLDN18.2阴性。当采用40%和25%阈值时，仍分别有66.7%和73.3%的患者保持CLDN18.2阳性。结论：以≥75%为阈值时，佐妥昔单抗治疗后CLDN18.2表达水平下降，但在较低阈值下，表达往往能够保留。这支持了后续CLDN18.2靶向治疗的潜在可行性。本期内容 01 研究背景 02 研究方法 03 研究结果 04 总结与展望【01 研究背景】佐妥昔单抗（Zolbetuximab）是一种嵌合型单克隆抗体，能够特异性靶向紧密连接蛋白 Claudin-18.2（CLDN18.2），该蛋白在胃癌（GC）中高度表达。两项全球Ⅲ期临床试验（SPOTLIGHT 和 GLOW）分别证明：在HER2阴性、CLDN18.2阳性的晚期胃癌或胃食管结合部癌（GEJC）患者中，佐妥昔单抗联合化疗能显著改善无进展生存期（PFS）和总生存期（OS），从而确立了其在这一人群中的一线标准治疗地位。上述的两项三期研究的CLDN18.2阳性的定义为：≥75%肿瘤细胞呈2+或3+染色强度。在佐妥昔单抗取得成功之后，针对CLDN18.2的多模式治疗策略正在不断探索，包括新一代单克隆抗体、双特异性抗体、抗体偶联药物（ADC）、以及CAR-T细胞疗法等，主要应用于二线及后线治疗。早期临床试验显示，即使在较低的CLDN18.2表达水平下，这些新型疗法也展现出可观的抗肿瘤活性，提示CLDN18.2靶向治疗的潜在适用范围或将进一步扩大。文献截图然而，关于在一线佐妥昔单抗治疗后，CLDN18.2表达的时间动态变化的数据仍然有限。本研究旨在评估CLDN18.2阳性晚期胃癌/GEJC患者在接受一线佐妥昔单抗联合化疗后的表达变化情况。 02 研究方法研究设计与患者选择本观察性研究在日本的国立癌症研究中心东医院开展。入组患者需符合以下条件：病理学确诊为CLDN18.2阳性（即≥75%的肿瘤细胞呈2+或3+染色强度）的胃或胃食管结合部（GEJ）腺癌；为不可切除的晚期或复发性疾病；在2025年3月31日之前至少接受过1个周期的佐妥昔单抗一线化疗；可获得治疗前及治疗后的原发肿瘤组织标本；并已提供治疗和生物标志物分析的书面知情同意（UMIN000019129）。治疗剂量与给药方案与关键性研究一致。本研究已获本机构伦理委员会（国立癌症研究中心东医院认证审查委员会）批准（批准编号：2017-120，批准日期：2017年9月26日）。所有研究程序均遵循相关机构与国家的人体实验伦理标准，并符合1964年《赫尔辛基宣言》及其后续修订版本。评估方法为每位患者收集临床病理学特征。利用免疫组化方法检测原发肿瘤中的 CLDN18.2 表达（抗体：Clone 43-14A，Roche Ventana）。根据染色强度将CLDN18.2表达分为弱（1+）、中等（2+）、强（3+），并计算CLDN18.2阳性肿瘤细胞的比例。参照既往CLDN18.2靶向治疗临床试验的标准，以25%、40%和75%作为阈值评估阳性比例。治疗后再次活检的时间与指征由各主治医师自行决定。统计学分析CLDN18.2表达水平从基线到疾病进展的变化，采用Sankey图进行可视化分析，基于两种阳性判定标准（≥2+染色强度和≥1+染色强度）。所有统计学分析均使用 R 4.4.1 软件(R Foundation for Statistical Computing,Vienna, Austria)完成。【03 研究结果】患者特征共有65例连续患者接受了一线含佐妥昔单抗的化疗方案；其中29例发生疾病进展，20例在进展时获得了活检标本。5例患者未检测到肿瘤细胞；其余15例患者的疾病进展标本可用于评估CLDN18.2表达状态。在这15例具有治疗前及疾病进展时配对肿瘤样本的患者中，年龄中位数为68岁（范围37–82岁）；大多数为胃原发肿瘤（93.3%）且为弥漫型组织学（86.7%）。所有患者均为HER2阴性，且具有错配修复功能正常（pMMR）。在PD-L1检测方面，按综合阳性评分（CPS）计算，93.0%的患者CPS ≥1，其中33.3%的患者CPS ≥5（表1）。佐妥昔单抗联合治疗后CLDN18.2表达的变化通过Sankey图（图1A和1B）展示了CLDN18.2表达从基线到疾病进展时的动态变化。图1. 佐妥昔单抗治疗后CLDN18.2表达从基线到疾病进展的变化。(A) CLDN18.2表达水平为≥2+染色强度。(B) CLDN18.2表达水平为≥1+染色强度。 Sankey图展示了肿瘤细胞中具有中-强（2+/3+）CLDN18.2染色强度的比例，从基线（左图）到疾病进展（右图）的变化。不同颜色代表不同表达水平：蓝色表示≥75%，绿色表示≥40%至<75%，棕色表示≥25%至<40%，红色表示<25%。流线宽度反映了患者在表达水平变化中所占的比例。图中数值表示CLDN18.2阳性肿瘤细胞的百分比。采用桑基图（图1A、图1B）可视化呈现从基线到疾病进展期CLDN18.2表达的变化情况。在15例患者中，7例（46.7%）维持≥75%肿瘤细胞染色强度≥2+的CLDN18.2表达状态。采用40%阈值时，10例患者（66.7%）维持CLDN18.2表达；采用25%阈值时，11例患者（73.3%）维持CLDN18.2表达（图1A）。在≥75%肿瘤细胞染色强度≥1+的标准下，15例患者中有8例（53.3%）仍保持该表达状态。采用40%和25%临界值时，均有11例患者（73.3%）维持该表达状态（图1B）。从基线到疾病进展期，染色强度≥2+和≥1+的CLDN18.2阳性肿瘤细胞比例中位变化值分别为-25%（范围-100%至20%）和-20%（范围-97%至20%）。佐妥昔单抗治疗过程中CLDN18.2表达动态变化的代表性病例本文呈现了两例代表性病例，用以说明在佐妥昔单抗联合治疗过程中CLDN18.2表达的变化。病例1：一名72岁女性患者，胃癌合并淋巴结和腹膜转移。基线胃镜显示从胃体上部至幽门部位有环形Ⅳ型肿瘤，活检证实为低分化腺癌伴印戒细胞成分，CLDN18.2阳性表达（肿瘤细胞中3+占90%，2+占10%）。治疗9个月后行胃镜检查，原发病灶无明显影像学变化，但CLDN18.2表达下降（3+占10%，2+占30%，1+占10%，阴性占50%）。在12个月疾病进展时，胃镜显示原发病灶范围较基线更为广泛，此时CLDN18.2表达有所恢复（3+占50%，2+占20%，1+占10%）（图2A）。病例2：一名76岁男性患者，胃食管结合部弥漫型腺癌，伴肝转移和胸膜播散。基线时，CLDN18.2表达为肿瘤细胞中3+占95%，2+占5%。治疗5个月后胃镜复查，原发病灶无明显变化，CLDN18.2表达大体保持（3+占80%，2+占10%）。但在7个月疾病进展时，CLDN18.2表达显著下降，仅有3+占5%，2+占5%（图2B）。这两例病例展示了佐妥昔单抗治疗过程中CLDN18.2表达的动态变化。病例1表现为表达短暂下降后在进展时部分恢复，而病例2则表现为持续维持后在进展时急剧下降。在这两例中，CLDN18.2表达的时间性变化并未与佐妥昔单抗联合治疗的临床反应直接相关。仍需进一步研究来阐明CLDN18.2动态变化的临床意义。 04 讨论与总结讨论据我们所知，这是首个报道接受佐妥昔单抗联合化疗患者在基线至疾病进展期间CLDN18.2表达动态变化的研究。在疾病进展时，仍有46.7%的患者保持CLDN18.2阳性（≥2+、且≥75%肿瘤细胞）。既往研究也报道过，在未使用CLDN18.2靶向药物的化疗后，约40%–60%的患者出现CLDN18.2表达下降，但这些研究样本量普遍较小。肿瘤内异质性是评估小活检样本时的主要局限。近期研究显示，CLDN18.2在原发病灶内也存在异质性表达。因此，仍需进一步探索：CLDN18.2靶向治疗是否更易导致表达下降。在机制层面，CLDN18表达受 T/EBP/NKX2.1（TTF-1）介导的转录激活调控；然而，CLDN18启动子区域的甲基化会阻止TTF-1结合，从而降低其表达。一般而言，化疗引起的细胞毒性应激可导致DNA甲基化，这可能是化疗过程中CLDN18.2表达下降的潜在机制。一项临床前研究提示，转录因子的作用有限，说明可能还有其他机制调控CLDN18.2的表达。既往研究还显示：与原发病灶相比，肝脏、腹膜等转移灶中CLDN18.2表达更低；同时，从肿瘤表浅区域向浸润前沿，CLDN18.2表达也呈下降趋势。这些发现提示：上皮–间质转化（EMT）可能参与CLDN18.2表达的降低，这一过程具有可塑性和可逆性。在靶向治疗过程中，由于克隆选择导致靶蛋白表达下降，CLDN18.2表达减少可能是一种耐药机制，类似于抗HER2治疗中HER2的丢失。然而，考虑到其可逆性，CLDN18.2表达下降可能是暂时性的，其生物学意义可能不同于HER2等涉及信号转导的靶点。在本研究中，当采用40%和25%阈值时，分别有66.7%和73.3%的病例保持≥2+强度的CLDN18.2表达；若采用更宽松的标准（≥1+），则有73.3%的病例在两个阈值下均保持阳性。这表明：接受过化疗和佐妥昔单抗治疗的患者，仍可能具备进入新一代CLDN18.2靶向疗法的条件。目前多种新型疗法（如ADC、双特异性抗体、CAR-T细胞）已在临床试验中采用更低的阈值，并展现出令人鼓舞的抗肿瘤活性。本研究也存在若干局限性：可能存在选择偏倚，仅纳入了具有可评估的治疗前后配对样本的患者； CLDN18.2的检测基于有限的活检样本，可能无法全面反映肿瘤内异质性；研究仅包含佐妥昔单抗联合治疗单臂，缺乏单纯化疗对照，因此难以区分CLDN18.2下降究竟是由化疗、佐妥昔单抗，还是二者共同作用所致。解读本研究结果时应充分考虑这些局限性。结论在胃癌/胃食管结合部癌（GC/GEJC）患者中，接受佐妥昔单抗联合治疗后，仍有46.7%的患者在疾病进展时保持 CLDN18.2阳性（≥2+且≥75%肿瘤细胞）。当采用更低的阈值（40%和25%）时，阳性率分别上升至66.7%和73.3%。这些结果提示：最初被判定为CLDN18.2阳性的患者，在疾病进展后仍可能具备进入后续CLDN18.2靶向治疗的条件。未来需要进一步研究来验证这些发现，并探讨CLDN18.2动态变化作为后线CLDN18.2导向治疗预测性生物标志物的潜在价值。参考文献： Yamamoto, K. et al. Temporal dynamics of CLDN18.2 expression following zolbetuximab treatment in advanced gastric cancer. ESMO Gastrointestinal Oncology, Volume 9, 100206 ★

细胞疗法临床结果抗体药物偶联物免疫疗法临床3期

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KEGG	Wiki	ATC	Drug Bank
-	佐妥昔单抗	-	DB15118

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适应症	国家/地区	公司	日期
晚期胃食管交界处腺癌	加拿大	Astellas Pharma Canada, Inc.	2025-01-09
CLDN18.2阳性胃食管交界处腺癌	英国	Astellas Pharma, Inc.	2024-08-14
CLDN18.2阳性胃腺癌	英国	Astellas Pharma, Inc.	2024-08-14
CLDN18.2阳性胃癌	日本	Astellas Pharma, Inc.	2024-03-26

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适应症	最高研发状态	国家/地区	公司	日期
局部晚期胃食管交界处腺癌	临床3期	美国	Astellas Pharma Global Development, Inc.	2018-11-28
局部晚期胃食管交界处腺癌	临床3期	中国	Astellas Pharma Global Development, Inc.	2018-11-28
局部晚期胃食管交界处腺癌	临床3期	日本	Astellas Pharma Global Development, Inc.	2018-11-28
局部晚期胃食管交界处腺癌	临床3期	阿根廷	Astellas Pharma Global Development, Inc.	2018-11-28
局部晚期胃食管交界处腺癌	临床3期	加拿大	Astellas Pharma Global Development, Inc.	2018-11-28
局部晚期胃食管交界处腺癌	临床3期	克罗地亚	Astellas Pharma Global Development, Inc.	2018-11-28
局部晚期胃食管交界处腺癌	临床3期	希腊	Astellas Pharma Global Development, Inc.	2018-11-28
局部晚期胃食管交界处腺癌	临床3期	爱尔兰	Astellas Pharma Global Development, Inc.	2018-11-28
局部晚期胃食管交界处腺癌	临床3期	马来西亚	Astellas Pharma Global Development, Inc.	2018-11-28
局部晚期胃食管交界处腺癌	临床3期	荷兰	Astellas Pharma Global Development, Inc.	2018-11-28

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ASCO2025	N/A	CLDN18.2阳性胃癌 CLDN18.2-positive	-	Zolbetuximab + Chemotherapy	鬱衊顧築網獵獵遞選膚(鹽壓鑰鏇積齋膚壓選襯) = 8% 窪齋廠願鑰齋醖衊鹹醖 (窪憲醖簾襯餘鹽網獵積 ) 更多	积极	2025-05-30
NCT03504397 (SPOTLIGHT \| SPOTLIGHT study, CTgov)	临床3期	-	565	folinic acid+zolbetuximab+oxaliplatin+fluorouracil	蓋製窪窪遞窪築獵遞觸(醖鬱顧廠觸餘願鏇衊襯) = 構窪鹹憲選醖艱醖顧願繭鏇顧觸齋顧襯膚積壓 (鑰糧鹹壓繭齋顧願選窪, 鹹衊膚齋願範鬱簾齋廠 ~ 繭獵鏇觸艱糧構膚蓋糧) 更多	-	2025-02-26
NCT03653507 (GLOW, CTgov)	临床3期	局部晚期胃食管交界处腺癌 \| 转移性胃食管结合部腺癌	507	CAPOX+Zolbetuximab (CAPOX+ Zolbetuximab)	艱積簾遞糧鏇鑰夢願壓(獵夢鬱糧壓遞構選齋鏇) = 觸齋鏇積衊顧範鹽範夢遞淵願網壓築製蓋構構 (餘選願壓築範鏇選襯選, 壓蓋築糧窪夢淵廠顧觸 ~ 鹹簾憲製蓋醖範簾願夢) 更多	-	2025-01-27
				Placebo (CAPOX+ Placebo)	艱積簾遞糧鏇鑰夢願壓(獵夢鬱糧壓遞構選齋鏇) = 構壓艱選憲範廠艱壓繭遞淵願網壓築製蓋構構 (餘選願壓築範鏇選襯選, 簾餘衊繭製鑰鑰鹽齋鏇 ~ 壓醖糧構選繭衊膚觸願) 更多
NCT03504397 (SPOTLIGHT, NEWS) 人工标引	临床3期	胃食管交界处腺癌一线 CLDN18.2 Positive \| HER2 Negative	61	佐妥昔单抗+mFOLFOX6	鏇鹹鏇簾蓋蓋獵艱觸蓋(蓋鏇簾構鹽艱襯窪製製) = 餘壓醖築繭範淵顧築願願憲網築製網艱膚窪襯 (構醖積醖繭糧醖夢製網, 6.7 ~ 16.7) 更多	积极	2024-09-28
				安慰剂+mFOLFOX6	鏇鹹鏇簾蓋蓋獵艱觸蓋(蓋鏇簾構鹽艱襯窪製製) = 衊顧夢醖築餘鑰憲窪選願憲網築製網艱膚窪襯 (構醖積醖繭糧醖夢製網, 6.0 ~ 8.4) 更多
NCT03653507 (GLOW, NEWS) 人工标引	临床3期	胃癌 \| 胃食管交界处腺癌一线 HER2 Negative \| CLDN18.2 Positive	145	佐妥昔单抗联合CAPOX	憲鹽構築醖窪獵繭淵網(襯窪衊餘窪網廠醖餘夢) = 淵獵鬱窪糧衊觸鹽壓膚糧窪鏇顧糧糧艱製壓淵 (選鏇鏇觸築繭願廠選壓, 6.1 ~ 9.1) 更多	积极	2024-09-28
				安慰剂联合CAPOX	憲鹽構築醖窪獵繭淵網(襯窪衊餘窪網廠醖餘夢) = 齋觸艱窪範鹹網餘簾鏇糧窪鏇顧糧糧艱製壓淵 (選鏇鏇觸築繭願廠選壓, 5.0 ~ 8.0) 更多
NCT03653507 \| NCT03504397 (SPOTLIGHT \| GLOW, ESMO2024)	临床3期	CLDN18.2阳性胃食管交界处腺癌一线 CLDN18.2+ \| HER2-	1,072	Zolbetuximab + chemotherapy	範鏇壓餘觸網憲憲壓鏇(廠夢鹽鑰襯鑰蓋獵壓積) = 網顧鬱遞築壓遞觸構膚簾觸願窪醖構構餘餘壓 (獵廠襯築糧淵鹹遞鑰鏇, 8.4 ~ 10.4) 更多	积极	2024-09-16
				Placebo + chemotherapy	範鏇壓餘觸網憲憲壓鏇(廠夢鹽鑰襯鑰蓋獵壓積) = 膚憲夢鹹衊鹽遞製觸簾簾觸願窪醖構構餘餘壓 (獵廠襯築糧淵鹹遞鑰鏇, 7.6 ~ 8.4) 更多
NCT03504397 (SPOTLIGHT, ASCO2024) 人工标引	临床3期	CLDN18.2阳性胃食管交界处腺癌 \| CLDN18.2阳性胃癌一线 HER2 Negative \| CLDN18.2 Positive	565	Zolbetuximab + mFOLFOX6	積觸築鏇廠膚顧艱製積(廠醖餘衊遞膚鏇遞構積) = 壓壓鹹選艱網鹽鹽築餘鹹廠襯淵觸齋網網醖繭 (襯齋蓋鬱襯衊觸淵艱範 ) 更多	积极	2024-05-24
				Placebo + mFOLFOX6	積觸築鏇廠膚顧艱製積(廠醖餘衊遞膚鏇遞構積) = 積齋襯顧醖選醖築壓蓋鹹廠襯淵觸齋網網醖繭 (襯齋蓋鬱襯衊觸淵艱範 ) 更多
NCT03653507 \| NCT03504397 (Pubmed \| Future Oncol)	临床3期	胃食管交界处癌 CLDN18.2-positive \| HER2-negative	-	Zolbetuximab plus chemotherapy	膚憲範鏇糧鹽鑰積網範(襯鑰簾積製繭鹽獵鹽遞) = 選構齋積築構構夢齋選積膚衊襯鬱範築齋蓋膚 (淵鏇範範遞構醖襯鏇窪 ) 更多	积极	2024-05-24
				Placebo plus chemotherapy	膚憲範鏇糧鹽鑰積網範(襯鑰簾積製繭鹽獵鹽遞) = 積糧夢醖築構壓鏇簾襯積膚衊襯鬱範築齋蓋膚 (淵鏇範範遞構醖襯鏇窪 ) 更多
NCT03653507 \| NCT03504397 (SPOTLIGHT, ASCO_GI2024) 人工标引	临床3期	胃腺癌 \| 胃食管交界处腺癌一线 HER2 Negative \| CLDN18.2 Positive	-	Zolbetuximab + mFOLFOX6	構餘淵鹹鏇艱膚膚鑰鹽(齋鏇鏇觸壓憲願選積夢) = 膚選鬱選鏇繭鏇觸鹽淵窪遞衊憲獵鹹選積顧遞 (糧簾簾糧齋遞蓋積積鑰 ) 更多	积极	2024-01-18
				Zolbetuximab + CAPOX	構餘淵鹹鏇艱膚膚鑰鹽(齋鏇鏇觸壓憲願選積夢) = 鹽鏇簾艱廠鏇齋獵遞範窪遞衊憲獵鹹選積顧遞 (糧簾簾糧齋遞蓋積積鑰 ) 更多
NCT04086758 \| NCT03653507 \| NCT00909025 \| NCT03504397 \| NCT03505320 \| NCT01630083 \| NCT01197885 \| NCT03528629 \| NCT01671774 (ASCO_GI2024) 人工标引	N/A	食管腺癌 \| CLDN18.2阳性胃食管交界处腺癌 \| CLDN18.2阳性胃腺癌一线 CLDN18.2 Positive	-	Zolbetuximab (First Dose (800 mg/m2))	糧夢齋顧淵餘遞廠繭鹹(構願鑰繭襯築選鏇繭鹹) = 製願遞網膚餘繭網齋願鹹顧齋襯夢蓋鏇鑰鏇壓 (簾範夢繭齋壓鬱膚積積, 96) 更多	积极	2024-01-18
				Zolbetuximab (Steady State (600 mg/m2 Q3W))	糧夢齋顧淵餘遞廠繭鹹(構願鑰繭襯築選鏇繭鹹) = 襯鹽範蓋憲願觸選築廠鹹顧齋襯夢蓋鏇鑰鏇壓 (簾範夢繭齋壓鬱膚積積, 91) 更多