What Is zolbetuximab?
zolbetuximab is an FDA-approved medication for the treatment of advanced stomach or gastroesophageal junction (GEJ) cancer in adults. It is also approved by the European Union European Medicines Agency and South Korea Pharmaceuticals and Medical Devices Agency for the same condition. zolbetuximab is an investigational product that works as a chimeric monoclonal antibody. It is thought to target and attach to the Claudin 18.2 protein, which is often found in tumor cells of people with gastric or GEJ cancer. By attaching to this protein, zolbetuximab may help to fight the cancer.
Beyond its approved use, zolbetuximab is currently being studied in clinical trials for a range of related conditions. These include metastatic gastroesophageal junction adenocarcinoma, gastric cancer, locally advanced unresectable gastroesophageal junction adenocarcinoma or cancer, locally advanced unresectable gastric adenocarcinoma or cancer, and metastatic gastric adenocarcinoma or cancer. It is also being investigated for CLDN18.2-positive adenocarcinoma of the gastroesophageal junction and HER2-positive gastric cancer, as well as metastatic pancreatic adenocarcinoma. These studies aim to further understand its effectiveness and safety in treating these cancers.
Uses and Conditions Under Study
zolbetuximab is primarily studied for cancers that occur in or around the stomach, including gastric cancer and gastroesophageal junction (GEJ) cancer. These cancers often involve a protein called Claudin 18.2 in their tumors, which zolbetuximab is designed to target.
- Gastric and Gastroesophageal Junction Cancers: This category includes various forms of cancer affecting the stomach and the area where the esophagus joins the stomach. zolbetuximab is being investigated for metastatic gastroesophageal junction adenocarcinoma (5 trials), gastric cancer (5 trials), and locally advanced unresectable gastroesophageal junction adenocarcinoma or cancer (4 trials). It is also studied for locally advanced unresectable gastric adenocarcinoma or cancer (4 trials), metastatic gastric adenocarcinoma or cancer (4 trials), and gastro-esophageal junction (GEJ) cancer (2 trials). Further studies include CLDN18.2-positive adenocarcinoma of the gastroesophageal junction (2 trials), gastroesophageal junction adenocarcinoma (1 trial), and HER2-positive gastric cancer (1 trial). These trials explore zolbetuximab's potential in different stages and types of these challenging cancers.
- Metastatic Pancreatic Adenocarcinoma: zolbetuximab is also being investigated for metastatic pancreatic adenocarcinoma (2 trials). This condition involves cancer that has spread from the pancreas to other parts of the body.
Overall, zolbetuximab has been studied in a total of 16 trials involving 5,290 participants across all conditions. The first trial began on June 28, 2012, with the latest trial starting on February 24, 2026.
Dosing
zolbetuximab is administered intravenously (IV), meaning it is given directly into a vein. It is supplied as a sterile lyophilized powder preparation, which is then reconstituted for IV infusion. The administration typically occurs on Day 1 of a treatment cycle.
Various dosing regimens have been studied in clinical trials:
- One common regimen involves an initial loading dose of 800 mg/m² on Cycle 1 Day 1, followed by subsequent doses of 600 mg/m². These subsequent doses are typically administered every three weeks.
- Another regimen involves IV infusion every two weeks or every three weeks, depending on the specific study protocol.
- Some trials have also investigated zolbetuximab at a dose of 1000 mg/m² in combination with other therapies.
zolbetuximab has been studied in combination with various other treatments, including docetaxel, oxaliplatin, S-1, pembrolizumab, mFOLFIRINOX, nab-paclitaxel, gemcitabine, CAPOX, mFOLFOX6, nivolumab, and FLOT. These combinations aim to enhance the therapeutic effect for conditions such as gastric and gastroesophageal junction cancers. Dosage forms studied are often referred to as "Arm A," "Arm B," or specific cohorts, reflecting different treatment groups within a trial.
Side Effects
In clinical trials involving 3210 patients who received zolbetuximab or placebo, the most commonly reported side effects were gastrointestinal in nature. Patients taking zolbetuximab experienced:
- Nausea: 68.0% of patients on zolbetuximab experienced nausea, compared to 55.6% on placebo.
- Vomiting: 51.4% of patients on zolbetuximab experienced vomiting, compared to 32.3% on placebo.
- Decreased appetite: 40.9% of patients on zolbetuximab experienced decreased appetite, compared to 34.5% on placebo.
- Neutrophil count decreased: 30.5% of patients on zolbetuximab experienced a decreased neutrophil count, compared to 27.9% on placebo.
- Neutropenia: 28.0% of patients on zolbetuximab experienced neutropenia, compared to 24.3% on placebo.
Other common side effects occurred at similar rates in both the zolbetuximab and placebo groups:
- Diarrhea: 38.2% on zolbetuximab vs 39.5% on placebo.
- Anemia: 36.9% on zolbetuximab vs 37.0% on placebo.
- Peripheral sensory neuropathy: 33.3% on zolbetuximab vs 33.2% on placebo.
Clinical Trial Results
Clinical trials have evaluated zolbetuximab as a treatment for gastric cancer.
Study NCT03504397
This study compared zolbetuximab plus mFOLFOX6 chemotherapy to placebo plus mFOLFOX6 chemotherapy in adults with gastric cancer. A total of 278 patients received zolbetuximab, and 277 received placebo in this trial.
- Overall Survival (OS): Patients treated with zolbetuximab had a median overall survival of 18.23 months, compared to 15.57 months for those on placebo.
- Progression-Free Survival (PFS): The median time patients lived without their cancer getting worse was 11.04 months with zolbetuximab, compared to 8.94 months with placebo.
- Time to Confirmed Deterioration in Global Health Status: Patients on zolbetuximab experienced a delay in the worsening of their global health status, with a median time of 15.44 months, compared to 11.83 months for those on placebo. For physical functioning, the median time to deterioration was 9.89 months with zolbetuximab, compared to 12.32 months with placebo.
- Objective Response Rate (ORR): The percentage of patients whose tumors shrank or disappeared was 48.1% with zolbetuximab, which was similar to 47.5% with placebo.
- Anti-drug Antibodies (ADA): In this study, 17 out of 278 patients (6.1%) in the zolbetuximab group developed anti-drug antibodies.
Study NCT03653507 (GLOW)
This study investigated zolbetuximab plus CAPOX chemotherapy versus placebo plus CAPOX chemotherapy as a first-line treatment for patients with Claudin (CLDN) 18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. A total of 251 patients received zolbetuximab, and 244 received placebo in this trial.
- Overall Survival (OS): Patients treated with zolbetuximab had a median overall survival of 14.32 months, compared to 12.16 months for those on placebo.
- Progression-Free Survival (PFS): The median time patients lived without their cancer getting worse was 8.21 months with zolbetuximab, compared to 6.80 months with placebo.
- Time to Confirmed Deterioration in Global Health Status: Patients on zolbetuximab experienced a delay in the worsening of their global health status, with a median time of 9.40 months, compared to 7.49 months for those on placebo. For physical functioning, the median time to deterioration was 7.95 months with zolbetuximab, similar to 7.92 months with placebo.
- Objective Response Rate (ORR): The percentage of patients whose tumors shrank or disappeared was 42.5% with zolbetuximab, compared to 39.1% with placebo.
- Anti-drug Antibodies (ADA): In this study, 21 out of 251 patients (8.4%) in the zolbetuximab group developed anti-drug antibodies.
Currently Recruiting Trials
Zolbetuximab is currently being investigated in several clinical trials for various forms of gastric and gastroesophageal junction (GEJ) cancers. These studies aim to evaluate its efficacy and safety, often in combination with other established treatments, particularly for tumors expressing the Claudin18.2 (CLDN18.2) protein.
One significant study, NCT07431281, sponsored by AstraZeneca, is a Phase 3 trial enrolling up to 2,130 participants. This study is evaluating sonesitatug vedotin in combination with capecitabine, with or without rilvegostomig, for first-line CLDN18.2-positive, HER2-negative gastric, GEJ, or esophageal adenocarcinoma.
The Phase 2 RAINSPOT trial, NCT06962137, sponsored by Universitaire Ziekenhuizen KU Leuven, is recruiting 100 participants. It investigates whether adding zolbetuximab to a standard treatment of paclitaxel and ramucirumab can improve survival for patients with CLDN18.2-positive gastro-esophageal cancer.
Astellas Pharma Global Development, Inc. is sponsoring a Phase 3 study, NCT06901531, targeting 500 adults. This trial explores zolbetuximab in combination with pembrolizumab and chemotherapy for locally advanced unresectable or metastatic gastric and GEJ adenocarcinoma, specifically when cancer cells do not have a certain protein.
Another study, NCT06732856, from Asan Medical Center, is a Phase 1b/2 trial with an enrollment target of 57 patients. It is assessing neoadjuvant zolbetuximab combined with docetaxel, oxaliplatin, and S-1 chemotherapy for patients with locally advanced gastric cancer, focusing on the Claudin 18.2 target.
In South Korea, Astellas Pharma Korea, Inc. is conducting NCT06902545, an observational study for 377 people with locally advanced unresectable or metastatic gastric or GEJ cancer, focusing on the safety of VYLOY (zolbetuximab).
Finally, Shanghai Zhongshan Hospital is sponsoring NCT06468280, a Phase 2 study with 84 participants. This trial investigates synergistic effects of PD-1 antibody and chemotherapy or targeted therapy, followed by surgery-centric local treatment, for patients with limited-metastatic gastric or gastroesophageal adenocarcinoma.
Where to Participate
Clinical trials for zolbetuximab are currently recruiting participants across a wide geographic area, offering opportunities for patients in many regions. These studies are active at 26 sites, spanning 78 cities and 33 states.
The cities with the most active recruiting sites include:
- New York, New York (4 sites)
- Atlanta, Georgia (3 sites)
- The Bronx, New York (3 sites)
- Detroit, Michigan (2 sites)
- New Haven, Connecticut (2 sites)
- Boston, Massachusetts (2 sites)
- Portland, Oregon (2 sites)
- Omaha, Nebraska (2 sites)
- Dallas, Texas (2 sites)
- Indianapolis, Indiana (2 sites)
Eligibility for these trials generally includes individuals aged 18 to 79 years, with participation open to all genders. Healthy volunteers are not being recruited for these specific studies, and participation is not open to children.
Development Timeline
The journey of zolbetuximab in clinical development began on June 28, 2012, with the latest trial projected to conclude on February 24, 2026. Over this period, a total of 16 clinical trials have been initiated, involving approximately 5,290 participants.
Astellas Pharma Global Development, Inc. has been the primary driver of zolbetuximab's development, sponsoring 8 of these trials. Other organizations, including AstraZeneca, Universitaire Ziekenhuizen KU Leuven, and Asan Medical Center, have also contributed to its study.
Initially, zolbetuximab was explored for conditions such as IBS-C and hyperphosphatemia. However, its development pipeline significantly expanded to focus on various forms of cancer, particularly those affecting the stomach and gastroesophageal junction. The conditions studied now include locally advanced unresectable or metastatic gastric and gastroesophageal junction adenocarcinoma, with a strong emphasis on tumors that are CLDN18.2-positive.
The drug's progression through clinical phases reflects this evolving focus, with trials conducted across Phase 1, Phase 1/2, Phase 2, and Phase 3 stages, as well as some with unspecified or N/A phases. This broad range of studies underscores the ongoing effort to understand zolbetuximab's potential in treating these challenging cancers.