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-

NCT06396091

/ Recruiting临床1期

A Phase 1 Open-label Study to Assess the Safety and Tolerability of Zolbetuximab (IMAB362) in Combination With Chemotherapy (mFOLFIRINOX) in Participants With CLDN18.2 Positive Metastatic Pancreatic Adenocarcinoma

Pancreatic cancer is difficult to diagnose early. By the time people have been diagnosed, the cancer has usually spread to other parts of the body (metastatic). The standard treatment is chemotherapy, but other treatments are needed to improve outcomes in people with pancreatic cancer.
In this study, zolbetuximab will be given together with chemotherapy to people with pancreatic cancer. Zolbetuximab attaches to a protein called CLDN18.2 found at high levels on the surface of the cancer tumor. This switches on the immune system to attack the tumor.
Adults 18 years or older with metastatic pancreatic cancer who have not previously had chemotherapy can take part in the study.
There are 2 main aims of this study:
* To check the safety of zolbetuximab, when given with chemotherapy in people with metastatic pancreatic cancer
* To check if people could cope with (tolerate) any medical problems during the study This is an open-label study. This means people in the study and the study doctors will know that people will receive zolbetuximab with chemotherapy. Different small groups will receive lower to higher doses of zolbetuximab with chemotherapy.
Zolbetuximab and chemotherapy will be given through a vein. This is called an infusion. People will receive zolbetuximab on the first day they receive chemotherapy. This will happen every 14 days in a 28-day cycle.
People will receive zolbetuximab and chemotherapy in the study clinic and at home. Also, doctors will check for any medical problems. People will also have a health check including blood tests. On some visits they will also have scans to check for any changes in their cancer.
People will visit the study clinic about 7 days after they stop treatment. They will be asked about any medical problems and will have a health check including blood tests.
After this, people will have several more visits to the study clinic for health checks. The number of visits and checks done at each visit will depend on the health of each person and whether they complete their treatment or not.

开始日期2025-09-24

申办/合作机构

Astellas Pharma Global Development, Inc.

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.

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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127

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.

2025-12-12·Deutsches Arzteblatt International

Gastric Carcinoma: Diagnosis, Staging, and Treatment.

Review

作者: Moehler, Markus ; Nothacker, Monika ; Huber, Yvonne ; Langer, Thomas ; Unverzagt, Susanne ; Lynen Jansen, Petra

BACKGROUND:

Gastric carcinoma ranks tenth in incidence among all cancers in men and women in Germany. 5565 women and 9027 men received a diagnosis of gastric carcinoma in Germany in 2022.

METHODS:

The German clinical practice guideline was comprehensively revised with the interdisciplinary participation of German specialty societies under the leadership of the German Society for Gastroenterology, Digestive and Metabolic Disorders, according to the methodological specifications of the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF).

RESULTS:

The new recommendations promote preventive measures in the presence of risk factors such as hereditary diseases or infection with Helicobacter pylori. Combinations of chemotherapy with immunotherapy, such as nivolumab, pembrolizumab, and tislelizumab, prolong median overall survival compared to chemotherapy alone (e.g., nivolumab plus chemotherapy, 14.4 vs. 11.1 months, HR 0.71) and markedly prolong 5-year survival to 16%. In patients with high claudin18.2 expression, the antibody zolbetuximab, combined with chemotherapy, prolongs median survival to 16.4 vs. 13.4 months (HR 0.77). For patients in good general health, further chemotherapy or biomarker-defined approved second-line (trastuzumab deruxtecan, pembolizumab) or third-line treatment (e.g., trifluridine tipirazole) and advanced molecular-pathological diagnostic testing should be offered at centers for personalized oncology in case of treatment failure. The biomarkers HER2, PD-L1, MSI, and claudin18.2 enable new targeted therapies in palliative situations with long-term improvement in outcome.

CONCLUSION:

The diagnostic evaluation of gastric carcinoma should include high-resolution video endoscopy, and its treatment should be stage-adapted and interdisciplinary. Monoclonal antibodies and immune checkpoint inhibitors are increasingly being used for palliative treatment. The new modifications to the clinical practice guideline will promote the use of uniform strategies for perioperative and palliative treatment and supportive measures.

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.

378

项与佐妥昔单抗相关的新闻（医药）

2025-10-20

·Biotech前瞻

晚期胃癌一线竞争激烈丨FGFR单抗、CLDN18.2单抗，纷纷联合免疫+化疗

点击蓝字关注我们本期看点晚期胃癌治疗领域近年来取得了显著进展，尤其是针对CLDN18.2这一新兴靶点的治疗策略。既往胃癌的治疗靶点和创新药物选择相对匮乏，随着Her2、CLDN18.2、FGFR等靶点药物的相继成功以及PD-1/L1抑制剂的临床应用，对于多靶点共表达胃癌患者的治疗决策正在成为临床治疗的挑战问题。当缺乏选择时决策相对简单，而选择过多时则难以确定最优方案。目前在研的一众CLDN18.2正在联合免疫检查点抑制剂和化疗的标准方案，在胃癌一线中低表达人群中进行三期布局，并在初期研究中展现了令人鼓舞的疗效，为患者提供了新的希望。此外，评估贝玛妥珠单抗联合化疗及纳武利尤单抗的III期FORTITUDE-102研究已完成患者入组，数据预计将在2025年底或2026年初公布。由此可见，靶向+免疫+化疗正在冲击晚期胃癌一线的竞争格局。本文将深入探讨这一联合治疗模式的理论基础、机制协同性及临床前景。本期内容 01 CLDN18.2的生物学特性与靶点价值 02 协同作用的机制基础 03 临床证据与试验进展 04 总结与展望【01 CLDN18.2的生物学特性与靶点价值】 Claudin18.2（CLDN18.2）是紧密连接蛋白家族（Claudin family）的重要成员，属于跨膜蛋白，主要分布于正常胃黏膜上皮细胞的紧密连接结构中。在健康状态下，CLDN18.2的表达高度受限，其胞外结构域通常“隐藏”在紧密连接复合体中，不易被循环中的抗体识别。然而在肿瘤发生过程中，胃上皮细胞极性丧失、细胞间连接结构被破坏，CLDN18.2蛋白的表位逐渐暴露于细胞表面，从而为特异性单克隆抗体提供了结合靶点。图1.Claudin18.2的结构，功能和表达（文献：Claudin 18.2 as a novel therapeutic target. Nat Rev Clin Oncol. 2024 Mar 19）大量研究表明，CLDN18.2在多种消化系统恶性肿瘤中存在异常激活和过度表达。在胃腺癌及胃食管结合部腺癌患者中，表达率(即≥75%肿瘤细胞呈现中度(2+)至强(3+)的膜染色)高达38%，并且常与弥漫型或低分化亚型相关。此外，在胰腺癌、食管癌，甚至部分胆道癌和卵巢癌中，也可检测到CLDN18.2的异常表达。这种表达谱既体现了其作为肿瘤相关抗原的特征，又具有较好的肿瘤特异性，为靶向治疗提供了理论基础。图2. 随着胃肿瘤的发展，CLDN18.2可能会更容易暴露（截图来源：https://www.vyloyhcp.com/cldn182-and-testing）正是由于这种“肿瘤中暴露、正常组织中受限”的独特表达模式，CLDN18.2被认为是理想的治疗靶点。与其他广泛分布的分子相比，CLDN18.2靶向治疗有望在最大程度杀伤肿瘤细胞的同时，降低对正常组织的非特异性损伤。图3. CLDN18.2靶向疗法汇总（文献：Claudin 18.2 as a novel therapeutic target. Nat Rev Clin Oncol. 2024 Mar 19）目前，围绕该靶点的药物研发主要集中在单克隆抗体（如zolbetuximab已获批上市）以及双特异性抗体和ADC、CAR-T方向，并已在临床研究中展现出积极的抗肿瘤信号。首款CLDN18.2单抗上市表现 2024年12 月 31 日，NMPA 官网显示，安斯泰来申报的CLDN18.2 单抗-佐妥昔单抗在国内获批上市，适应症为联合含氟尿嘧啶类和铂类药物化疗用于 CLDN18.2 阳性、HER2阴性的局部晚期不可切除或转移性胃或胃食管交界处（GEJ）腺癌患者的一线治疗。 2025年7月30日，安斯泰来公布了2025Q1财报，作为近年来重点布局的创新产品，CLDN18.2单抗（佐妥昔单抗）的业绩表现成为业界关注的焦点：佐妥昔单抗（商品名：VYLOY）单季度销售额达到140亿日元（约合9681万美金），迅速成为公司排名第4畅销的药物。中国过去一个季度的销售额也达到了2282万美金。 CLDN18.2阳性人群定义但值得一提的是，佐妥昔单抗适应症的批准源自于两项关键III期研究（GLOW和SPOTLIGHT）数据。两项研究均采用免疫组化（IHC）检测筛选CLDN18.2阳性患者，定义标准为：≥75%肿瘤细胞呈中至强染色强度（IHC评分2+/3+）。国内外其他在研抗CLDN18.2单抗的最新进展和阳性表达率要求与佐妥昔单抗的有所不同，且在联合免疫检查点抑制剂进行三期布局，有望重新定义CLDN18.2单抗的竞争格局。 02 协同作用的机制基础 CLDN18.2靶向治疗（如Zolbetuximab）与免疫治疗、化疗的协同作用，源于它们通过不同机制攻击肿瘤细胞并调节肿瘤微环境。下面这个表格汇总了它们是如何联手发挥“1+1+1>3”效果的。其协同机制主要体现在以下几个方面：一、逆转免疫抑制，重塑肿瘤微环境（TME）： CLDN18.2靶向抗体（如Zolbetuximab）通过ADCC/CDC效应大量杀伤肿瘤细胞，不仅直接减少肿瘤负荷，其过程中募集的免疫细胞（如NK细胞）和释放的细胞因子（如IFN-γ）有助于改善肿瘤局部的免疫状态。化疗药物在杀伤肿瘤细胞的同时，也可能减少或重塑免疫抑制性细胞（如Treg、MDSC）的比例和功能，从而减轻TME的免疫抑制环境，为免疫细胞发挥作用创造条件。 PD-1/PD-L1抑制剂则直接解除T细胞受到的抑制信号，使其恢复杀伤活力。三者联合，能从去除抑制因素和提供激活信号两个方向同时用力，更有效地将不利于免疫攻击的“冷肿瘤”转化为免疫细胞浸润的“热肿瘤”。二、促进抗原释放与呈递，增强免疫识别：化疗和靶向治疗引起的肿瘤细胞死亡（包括免疫原性细胞死亡）会大量释放肿瘤抗原。这些抗原被抗原呈递细胞（APC）捕获并处理，进而激活和扩增能够识别肿瘤的特异性T细胞。三、创造协同增效的“机会窗口”：值得注意的是，研究显示CLDN18.2阳性与PD-L1高表达可能存在负相关关系。这意味着许多CLDN18.2高表达的患者，可能对单用免疫检查点抑制剂反应不佳。而CLDN18.2靶向治疗在杀伤肿瘤细胞和激活免疫反应的过程中，有潜力诱导肿瘤细胞上调PD-L1的表达。这就像是为免疫抑制剂“创造”了作用的靶点，从而打开了原本可能关闭的疗效大门，为PD-1/PD-L1抑制剂的成功介入提供了关键的“机会窗口”。值得关注的临床现象是：CLDN18.2高表达肿瘤往往伴随PD-L1低表达，天然属于“免疫冷”亚群，单用PD-1/PD-L1抑制剂疗效有限。然而，CLDN18.2靶向药物在启动ADCC/CDC、造成肿瘤细胞裂解的同时，会释放大量IFN-γ等炎性因子，有望诱导肿瘤上调PD-L1（相关机制需要更多数据的夯实）。这一“加热”过程恰好为免疫检查点抑制剂现场制造出可作用的靶点，把原本关闭的响应窗口重新打开，从而形成“先靶向治疗将冷肿瘤状态转变为热肿瘤状态，然后免疫治疗，进一步控制肿瘤进展”的序贯协同策略。四、针对特殊人群的精准协同：这种协同机制对于弥漫型胃癌或伴有腹膜转移的患者意义尤为重大。这类患者通常对传统化疗或免疫治疗反应欠佳，但其肿瘤往往高表达CLDN18.2。三联策略为他们提供了全新的精准治疗选择。【03 临床证据与试验进展】这种深刻的机制协同已得到临床研究的初步验证。例如：根据2025年ASCO年会上公布的最新数据，TranStar102研究中Osemitamab (TST001) 联合纳武利尤单抗和CAPOX化疗一线治疗CLDN18.2中高表达晚期胃癌的疗效结果令人鼓舞。研究显示，在26例CLDN18.2中高表达（定义为≥40%的肿瘤细胞膜染色强度≥2+）患者中，确认的客观缓解率（cORR）达到68%，中位无进展生存期（mPFS）为16.6个月，中位总生存期（mOS）达到21.7个月，中位缓解持续时间（mDoR）为16.5个月。值得注意的是，这项研究还发现大多数CLDN18.2阳性患者（约80%）表现为PD-L1低表达（CPS<5），而Osemitamab三联疗法无论PD-L1表达水平如何，都能为CLDN18.2中高表达患者带来显著临床获益。在所有82例入组患者中，中位总生存期达到20.4个月，显示出该方案在这一人群中的广泛应用潜力。安全性方面，更新数据显示Osemitamab三联疗法的不良事件特征与既往报告一致，主要表现为可控的恶心、呕吐和低蛋白血症等，大多数为1-2级事件。这些数据为CLDN18.2中高表达的晚期胃癌患者提供了新的治疗选择，目前Osemitamab (TST001) 的III期临床试验正在启动中。下面汇总已经开展“CLDN18.2靶向治疗+免疫+化疗”三联方案的三期研究。创胜集团丨Osemitamab (TST001) 2023年7月获中国CDE与韩国MFDS批准，启动TranStar 301Ⅲ期全球多中心、随机、双盲、安慰剂对照试验。联合纳武利尤单抗（Opdivo）与CAPOX方案对比纳武利尤单抗联合化疗，在HER2阴性、CLDN18.2表达的局部晚期/转移性胃或胃食管交界腺癌一线治疗中展开疗效和安全性评估。伴随诊断：检测方法：本地实验室开发检测（LDT）或中央病理室IHC。阳性标准：≥1+膜染色强度，且至少10%肿瘤细胞呈现阳性（筛选出约55%患者）。奥赛康丨ASKB589 奥赛康的CLDN18.2单抗ASKB589于2024年启动全球多中心Ⅲ期注册试验，试验方案为ASKB589+CAPOX+替雷利珠单抗 vs 替雷利珠单抗+CAPOX 阳性标准：中高表达——IHC评分2+或3+，且≥40%肿瘤细胞阳性。明济生物丨FG-M108 正在开展Ⅲ期注册试验，评估FG-M108 + CAPOX vs CAPOX 在HER2阴性、CLDN18.2阳性、一线胃/GEJ腺癌患者中的疗效。纳入人群：CLDN18.2阳性（≥40% 的肿瘤细胞≥2+膜染色），PD-L1 CPS＜5 温馨提示：三款在研单抗均采用IHC评估CLDN18.2表达，但纳入的CLDN18.2阳性人群相较于佐妥昔单抗的≥75%肿瘤细胞呈中至强染色强度（IHC评分2+/3+）普遍较低，有望进一步拓展人群，且在联合PD-1单抗，符合当下胃癌一线免疫联合化疗的标准。更有甚者，开始尝试CLDN18.2ADC联合PD-L1：胃癌创新试验丨Her2单抗+Her2ADC+PD-1；CLDN18.2ADC联合PD-L1 基于如此竞争白热化态势，已经有企业放弃CLDN18.2单抗，尝试CAR-T和ADC产品。此外，佐妥昔单抗也不甘落后，一项III期临床研究（NCT06901531）正在探索佐妥昔单抗（Zolbetuximab）联合帕博利珠单抗（Pembrolizumab）及化疗（CAPOX或mFOLFOX6）的方案。该研究旨在评估此三联方案对比安慰剂联合帕博利珠单抗及化疗，一线治疗CLDN18.2阳性、HER2阴性晚期胃癌的疗效和安全性。 04 总结与展望总的来说，佐妥昔单抗联合免疫治疗和化疗的三联方案目前仍处于临床探索阶段，并非当前的标准治疗选择。患者是否适合参与此类研究，或选择何种治疗方案，务必由专业的肿瘤科医生根据患者的具体情况（如CLDN18.2表达水平、PD-L1表达状态、体力状况、既往治疗史等）综合判断。 ★

临床3期临床结果临床成功临床失败

2025-10-16

·ioncology

Jeeyun Lee教授解析多组学技术如何重塑胃癌免疫微环境丨2025韩国国际胃癌周

点击蓝字关注我们编者按胃癌作为全球高发且难治性的恶性肿瘤之一，其治疗面临巨大挑战。近年来，随着对肿瘤微环境、免疫应答机制及分子分型的深入理解，基于生物标志物的精准医疗成为改善患者预后的关键方向。韩国成均馆大学医学院的Jeeyun Lee教授在韩国国际胃癌周（KINGCA WEEK 2025）上发表了最新研究成果，系统综述了多组学技术在解析胃癌异质性、预测免疫检查点抑制剂（ICB）疗效以及开发新型联合疗法方面的突破性进展，重点讨论了肿瘤突变负荷（TMB）、微卫星不稳定性（MSI）、Claudin18.2表达等关键生物标志物的临床价值，并分析了T细胞受体（TCR）克隆动态、空间转录组学和蛋白质组学如何揭示免疫逃逸机制。一、分子标志物的发展为胃癌靶向治疗带来新突破胃癌作为全球范围内高发的恶性肿瘤之一，其治疗一直面临巨大挑战。随着对胃癌分子机制的深入了解，以及生物技术的快速发展，胃癌治疗正逐步从传统的化疗向精准医疗转变。近年来，胃癌领域新药层出不穷，为晚期胃癌患者提供了多种治疗选择（图1）。图1. 胃癌常见分子标志物及治疗选择 HER2阳性胃癌的治疗取得了显著进展。ToGA试验奠定了曲妥珠单抗在HER2阳性胃癌一线治疗中的地位。近年来，新型HER2靶向药物如ENHERTU（T-DXd）的应用进一步提高了治疗效果。DESTINY-Gastric05试验显示，ENHERTU联合化疗和帕博利珠单抗相比曲妥珠单抗联合方案，在HER2阳性胃癌/胃食管交界癌（GC/GEJ）一线治疗中表现出更高的安全性和有效性。这一结果预示着HER2靶向治疗将进入一个新的阶段。FGFR2b过表达在胃癌中约占5%~10%，且多见于弥漫型胃癌。FIGHT试验表明，bemarituzumab联合FOLFOX化疗方案可显著延长FGFR2b过表达胃癌患者的生存期。这一发现为FGFR2b阳性胃癌患者提供了新的治疗选择。Claudin 18.2（CLDN18.2）作为胃癌的新兴靶点，近年来受到广泛关注。SPOTLIGHT和GLOW试验证实，Zolbetuximab联合XELOX化疗方案可显著改善CLDN18.2阳性胃癌患者的无进展生存期和总生存期。二、平台试验的优势与挑战自2014年起实施的双轨制试验体系包括常规赞助研究和深度探索性平台研究两部分。前者采用传统设计验证标准方案有效性，后者则允许动态调整入组标准以纳入难治性人群。例如，在伞式试验框架下，研究者根据实时生物标志物反馈将患者分配至不同治疗臂（如MEK抑制剂Selumetinib vs. PI3K抑制剂AZD5363），极大提高了试验效率。平台试验作为一种新型的临床试验模式，通过同一平台对多种治疗策略进行评估，显著提高了研究效率。VIKTORY伞式试验和SMC的平台试验均证实了生物标志物匹配的靶向治疗可显著延长胃癌患者的生存期。然而，平台试验的实施也面临诸多挑战，如患者入组标准、生物标志物检测标准化及数据分析复杂性等。三、多组学技术解析免疫微环境异质性，克服免疫耐药瓶颈多组学整合分析在胃癌预后预测和治疗响应评估中发挥着越来越重要的作用。通过整合基因组学、转录组学、蛋白质组学及空间转录组学数据，可实时理解非响应者与响应者的分子特征，为个体化治疗提供科学依据。免疫检查点抑制剂（ICIs）在胃癌治疗中的应用日益广泛。KEYNOTE-059和ATTRACTION-2试验分别证实了帕博利珠单抗和纳武利尤单抗在PD-L1阳性或CPS≥5的胃癌患者中的有效性。然而，并非所有患者都能从ICIs治疗中获益，MSI-H/dMMR、EBV阳性及PD-L1阳性患者响应率较高，而MSS患者响应率较低。 M.Kwon等进行一项研究表明，高肿瘤突变负荷（TMB）与ICB疗效显著正相关（P=0.0018, r=-0.7133），尤其是微卫星高度不稳定（MSI-H）亚型患者表现出更强的免疫原性（图2）。一项纳入772例患者的回顾性分析显示，MSI-H肿瘤的平均非同义突变频率达每兆碱基5–10个，远超其他分子分型。这类肿瘤因累积大量新抗原而被CD8+ T细胞识别，同时CXCL13趋化因子招募B细胞形成三级淋巴结构，进一步增强抗肿瘤活性。图2. TMB与免疫治疗疗效呈正相关 M An等2024年在Cancer Discovery发表的一篇研究揭示了免疫治疗如何重塑胃癌患者的免疫微环境（图3）。通过对358,933个单细胞进行UMAP降维分析，研究者发现对帕博利珠单抗应答者的肿瘤浸润淋巴细胞中存在显著的克隆扩增现象，特别是CD8+CXCL13+双阳性T细胞亚群的比例增加。这些细胞具有更高的TCR多样性指数和相似性评分，提示其可能来源于共同祖先并针对共享抗原表位。进一步追踪TCR序列演变轨迹发现，免疫治疗有效患者的克隆群落呈现持续扩张趋势，而非应答者则表现为耗竭特征（如PD-1高表达、效应分子缺失）。图3. 免疫治疗重塑胃癌免疫微环境一项尚未公开发表的Ⅱ期研究评估了Ceralasertib（ATR抑制剂）联合Durvalumab在PD-L1阳性、IO耐药晚期胃癌中的疗效。初步数据显示，该组合在PD-L1阳性患者中表现出一定的抗肿瘤活性。其可能的机制包括ATR失活导致DNA损伤修复缺陷积累，进而增强基因组不稳定性并激活干扰素基因刺激因子（STING）通路，重塑肿瘤免疫原性。该研究为克服免疫耐药问题提供了新的思路。 SH Lim等进行一项研究发现化疗后部分CLDN18.2阴性患者可转为阳性，且与纤维化肿瘤微环境（TME）相关，这为CLDN18.2靶向治疗提供了新的视角。此外，他们团队进行的Ramucirumab联合帕博利珠单抗在难治性PD-L1阳性胃癌中的Ⅱ期试验也取得了积极结果，尽管免疫抑制性微环境仍是治疗抵抗的主要原因。研究者通过多组学整合分析发现，对抗血管生成靶向联合免疫治疗应答者的主要分子特征包括：PD-1表达增加、血管正常化、效应细胞浸润以及免疫细胞与血管之间的距离减少等（图4）。图4. 多组学技术靶向联合免疫治疗应答者主要分子特征四、未来展望胃癌治疗领域正经历着从传统化疗向精准医疗的深刻转变。靶向治疗、免疫治疗及新型疗法的不断涌现为胃癌患者提供了更多的治疗选择。然而，如何根据患者的分子特征选择最佳治疗方案仍是临床面临的主要挑战。未来，随着多组学技术的不断发展及平台试验模式的广泛应用，胃癌的精准治疗将取得更大突破。我们期待通过全球科研人员的共同努力，早日实现胃癌的个体化、精准化治疗。（来源：肿瘤瞭望消化时讯）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

2025-10-14

·EndPoints

FDA delays decision on Denali drug; Astellas’ Vyloy fails mid-stage pancreatic cancer trial

Plus, news about Spyre Therapeutics, Candel Therapeutics, Boehringer Ingelheim, Quantro Therapeutics, Clover, EVerZom and Apollomics: 🏛️ FDA pushes back decision on Denali Therapeutics’ Hunter syndrome treatment: The company is seeking accelerated approval of tividenofusp alfa for mucopolysaccharidosis type II. The PDUFA date is now April 5, three months later than expected. Denali’s stock price $DNLI was down about 4% on Tuesday morning, the day after it announced the delay. — Jaimy Lee 📉 Astellas’ Vyloy fails Phase 2 trial in pancreatic cancer: The Japanese drugmaker had been testing the drug in combination with gemcitabine and nab-paclitaxel in patients with metastatic pancreatic adenocarcinoma. The study did not meet the primary endpoint of overall survival. There will be “minor” impact to Astellas’ financial results, the company said. — Jaimy Lee 💰 Spyre Therapeutics’ $275M offering: The company is selling about 14.9 million shares at $18.50 apiece. — Jaimy Lee 💸 Candel Therapeutics inks $130M loan agreement: The five-year loan facility, which is being funded by Trinity Capital, consists of five tranches, including an initial $50 million tranche when the deal closes. The cash should support Candel as it eyes starting a Phase 3 trial of CAN-2409 in non-small cell lung cancer in the second quarter of 2026. Its share price $CADL dropped about 7% on Tuesday morning. — Ayisha Sharma 🫱🏼‍🫲🏽 Boehringer Ingelheim extends work with Quantro Therapeutics: The companies, which announced the up to €500 million (about $580 million) deal in 2022, have now extended the collaboration for two more years. They’re working on therapies that target cancer-associated transcription factors. Financial terms of the extension were not disclosed. — Jaimy Lee 🍀 Clover’s Phase 1 RSV data: The Shanghai-based biotech’s vaccine candidates, SCB-1022 and SCB-1033, produced an average six- to eight-fold increase in neutralizing antibodies against RSV in a trial of older adults in Australia. Both assets are combination vaccines designed to protect against multiple respiratory diseases. — Ayisha Sharma 💶 EVerZom raises €10M: The French biotech is developing exosome-based biotherapies for inflammatory diseases. It now plans to move its candidate into the clinic for Crohn’s perianal fistula next year. — Jaimy Lee 💼 Apollomics is no longer winding down: The biotech, which in August announced plans to discontinue work on its small molecule c-Met inhibitor, said it has since received funding to stay in business. Apollomics now has a new board and a new leadership team. Its main asset, APL-101, is currently in Phase 2. — Jaimy Lee

疫苗临床2期临床结果临床1期

100 项与佐妥昔单抗相关的药物交易

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外链

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

研发状态

批准上市

10 条最早获批的记录,

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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

未上市

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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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临床结果

适应症

分期

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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


NCT03504397 (SPOTLIGHT \| SPOTLIGHT study, CTgov)	临床3期	-	565	folinic acid+zolbetuximab+oxaliplatin+fluorouracil	鹽遞鏇壓積壓繭壓鹽淵(夢願網齋餘鑰膚廠積繭) = 網蓋壓襯蓋夢糧夢鹽醖鏇構製壓鏇遞鹹鹽繭網 (選廠醖製遞夢蓋壓願遞, 網襯製膚範壓範鹹蓋顧 ~ 鏇簾廠齋選鬱積襯獵鹽) 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)	廠窪襯壓艱艱遞鹽艱膚(餘範觸願齋顧廠醖鑰範) = 範範鑰艱糧築顧願醖襯蓋願積淵製襯觸窪鑰憲 (築夢積遞範製淵襯選選, 鏇積憲淵憲製齋鹹衊遞 ~ 願鑰簾網繭構願範壓糧) 更多	-	2025-01-27
				Placebo (CAPOX+ Placebo)	廠窪襯壓艱艱遞鹽艱膚(餘範觸願齋顧廠醖鑰範) = 獵膚夢憲範憲積網淵獵蓋願積淵製襯觸窪鑰憲 (築夢積遞範製淵襯選選, 憲憲齋願鏇築顧餘廠糧 ~ 顧艱選獵齋鹽鬱顧衊衊) 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	選範膚憲鬱網願構構顧(遞簾鏇願淵窪淵鏇構廠) = 壓鑰衊繭製鑰網膚餘網艱遞衊廠醖遞顧遞糧壓 (淵顧淵窪繭繭艱襯糧繭, 6.1 ~ 9.1) 更多	积极	2024-09-28
				安慰剂联合CAPOX	選範膚憲鬱網願構構顧(遞簾鏇願淵窪淵鏇構廠) = 醖鹹網夢構鹹獵衊繭蓋艱遞衊廠醖遞顧遞糧壓 (淵顧淵窪繭繭艱襯糧繭, 5.0 ~ 8.0) 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	築構築積範範鏇繭憲製(襯壓蓋鹽艱繭製顧鏇鬱) = 憲鏇鏇鏇遞顧衊範壓壓鹽糧構廠淵鏇窪夢窪構 (艱選憲鹹壓築構鹽糧鏇, 6.7 ~ 16.7) 更多	积极	2024-09-28
				安慰剂+mFOLFOX6	築構築積範範鏇繭憲製(襯壓蓋鹽艱繭製顧鏇鬱) = 獵壓鹹襯簾製鹹艱築鹹鹽糧構廠淵鏇窪夢窪構 (艱選憲鹹壓築構鹽糧鏇, 6.0 ~ 8.4) 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	餘築獵鹽襯齋衊鏇鹹齋(鹽構蓋鬱築廠顧蓋齋衊) = 構顧選範鬱觸鬱製鏇膚網夢繭遞製膚鹽襯衊蓋 (膚鬱鑰積繭襯遞鹽繭蓋, 8.4 ~ 10.4) 更多	积极	2024-09-16
				Placebo + chemotherapy	餘築獵鹽襯齋衊鏇鹹齋(鹽構蓋鬱築廠顧蓋齋衊) = 窪齋淵遞積製網廠顧蓋網夢繭遞製膚鹽襯衊蓋 (膚鬱鑰積繭襯遞鹽繭蓋, 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	夢壓願鏇築網簾獵遞壓(壓鑰構築鬱壓鬱遞膚遞) = 製憲築衊衊網顧網膚糧衊範簾構窪齋積願齋膚 (餘艱淵獵鏇觸蓋鑰壓鑰 ) 更多	积极	2024-05-24
				Placebo + mFOLFOX6	夢壓願鏇築網簾獵遞壓(壓鑰構築鬱壓鬱遞膚遞) = 簾鹽範蓋鹹淵觸壓艱襯衊範簾構窪齋積願齋膚 (餘艱淵獵鏇觸蓋鑰壓鑰 ) 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	蓋夢願鹽襯獵鹹網糧憲(糧襯鏇築願願艱憲鏇顧) = 淵齋齋憲觸顧夢憲窪壓憲壓淵遞簾鏇積糧獵襯 (網願膚夢鹹淵衊選淵鏇 ) 更多	积极	2024-05-24
				Placebo plus chemotherapy	蓋夢願鹽襯獵鹹網糧憲(糧襯鏇築願願艱憲鏇顧) = 積網鹹淵積繭選選鏇繭憲壓淵遞簾鏇積糧獵襯 (網願膚夢鹹淵衊選淵鏇 ) 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	鬱網遞構鏇鹽繭積築選(簾憲鬱淵鹹壓餘衊範網) = 醖夢憲願鏇築鹽壓餘遞遞衊繭築膚構齋積鹽餘 (構壓選壓鏇獵壓鏇衊觸 ) 更多	积极	2024-01-18
				Zolbetuximab + CAPOX	鬱網遞構鏇鹽繭積築選(簾憲鬱淵鹹壓餘衊範網) = 壓鏇範網構膚鹹製襯獵遞衊繭築膚構齋積鹽餘 (構壓選壓鏇獵壓鏇衊觸 ) 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))	遞齋夢醖鏇壓膚繭膚顧(餘鹽齋糧淵憲積鏇簾鹽) = 構範淵窪鏇廠鹹襯淵膚襯願憲觸遞艱糧淵簾衊 (壓糧觸願糧網顧襯衊衊, 96) 更多	积极	2024-01-18
				Zolbetuximab (Steady State (600 mg/m2 Q3W))	遞齋夢醖鏇壓膚繭膚顧(餘鹽齋糧淵憲積鏇簾鹽) = 夢簾獵壓壓夢餘構網構襯願憲觸遞艱糧淵簾衊 (壓糧觸願糧網顧襯衊衊, 91) 更多
GLOW study (ESMO_ASIA2023 \| ESMO2023)	临床3期	CLDN18.2阳性胃食管交界处腺癌一线 CLDN18.2+ \| HER2−	507	Zolbetuximab + CAPOX	鏇夢蓋醖鏇構鏇構製獵(遞醖齋簾遞夢構夢獵選) = 繭齋顧鬱憲蓋範網積衊艱範範窪鬱鑰鏇壓願鬱 (構餘膚夢繭願構蓋繭鹽 ) 更多	积极	2023-12-03
				Placebo + CAPOX	鏇夢蓋醖鏇構鏇構製獵(遞醖齋簾遞夢構夢獵選) = 糧蓋範膚廠憲遞網製衊艱範範窪鬱鑰鏇壓願鬱 (構餘膚夢繭願構蓋繭鹽 ) 更多