Novel Targeted Therapy Combination May Be an Effective First-Line Option for Gastric or Gastroesophageal Junction Adenocarcinoma

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Researchers have found that the novel targeted therapy zolbetuximab in combination with a standard chemotherapy may extend survival in patients with advanced gastric or gastroesophageal junction adenocarcinoma and overexpression of the claudin-18 isoform 2 protein (CLDN18.2), according to a novel study published by Shah et al in Nature Medicine.


Gastric cancer is the fifth most diagnosed cancer type globally, and its incidence has increased significantly over the last few decades. Patients with gastric cancer or gastroesophageal junction adenocarcinoma typically have few symptoms in early disease stages. Therefore, most cases go undiagnosed until the cancer has advanced or become metastatic. According to the National Cancer Institute, the 5-year survival rate for patients with metastatic disease is about 7%.

There are few targeted treatments available for patients with gastric cancer and gastroesophageal junction adenocarcinoma. Whereas patients with tumors expressing the PD-L1 protein can be treated with immunotherapy, and patients with HER2-positive tumors can be treated with trastuzumab, those who have HER2-negative tumors may not fit into either treatment category or receive targeted therapies. However, these patients tend to have higher levels of CLDN18.2—which is normally found in gastric mucosa cells and becomes more exposed as gastric cancer develops.

Zolbetuximab is an intravenous monoclonal antibody that is capable of binding to CLDN18.2, killing the dividing cancer cells directly, and inducing an immune response.

“Currently, standard chemotherapy regimens are the only treatment options for many patients with HER2-negative and low PD-L1 gastric [cancer] and gastroesophageal [junction adenocarcinoma], and survival is about 12 months,” explained lead study author Manish Shah, MD, the Bartlett Family Professor of Gastrointestinal Oncology and Director of the Gastrointestinal Oncology Program in the Division of Hematology and Medical Oncology at Weill Cornell Medicine as well as Chief of the Solid Tumor Oncology Service and Co-Director of the Center for Advanced Digestive Care at the NewYork-Presbyterian/Weill Cornell Medical Center. “A new treatment for these patients would address a significant unmet need to extend survival,” he stressed.

Study Methods and Results

In the new international phase III GLOW trial, the researchers randomly assigned 507 patients with previously untreated HER2-negative locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma expressing CLDN18.2 to receive either zolbetuximab in combination with capecitabine plus oxaliplatin chemotherapy (CAPOX) or placebo plus CAPOX. The study was conducted between November 2018 and February 2022 at 166 sites across 18 countries.

The researchers discovered that zolbetuximab plus CAPOX significantly increased progression-free survival compared with placebo plus CAPOX. Specifically, zolbetuximab plus CAPOX lowered the risk of disease progression or mortality by 31%. The median progression-free survival was 8.2 months for patients in the zolbetuximab group compared with 6.8 months for those in the placebo group. Further, compared with placebo, the addition of zolbetuximab was found to double the likelihood of progression-free disease after 2 years of follow-up (14% vs 7%).

The novel drug combination also lengthened the overall survival and reduced the risk of mortality by 23% compared with placebo plus CAPOX. The patients who received zolbetuximab plus CAPOX demonstrated a median overall survival of 14.4 months vs 12.2 months among those who received placebo plus CAPOX. Long-term survival similarly increased to 29% in the zolbetuximab group vs 17% in the placebo group.

The researchers reported that there were both groups experienced similar treatment-related adverse events—including nausea, vomiting, and decreased appetite.

“These side effects were as expected,” noted Dr. Shah. “It was good to see [that] zolbetuximab did not add significant toxicity,” he emphasized.

In a separate study, the international phase III SPOTLIGHT trial—recently published by Shitara et al in The Lancet—researchers described strong survival outcomes for patients who received zolbetuximab in combination with a different chemotherapy regimen consisting of modified folinic acid or levofolinate, fluorouracil, and oxaliplatin (mFOLFOX).


Since the publication of the results from the GLOW and SPOTLIGHT trials, the U.S. Food and Drug Administration has granted priority review to the zolbetuximab’s manufacturer’s biologic license application and set January 12, 2024, as the target decision date.

If approved, zolbetuximab may be the first targeted therapy in the United States for patients with previously untreated HER2-negative, CLDN18.2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma.

“We now have evidence from two large trials showing that the addition of zolbetuximab provides a meaningful survival benefit for patients with CLDN 18.2-positive gastric cancers,” Dr. Shah highlighted. “If zolbetuximab is approved, patients will be able to decide with their physicians whether zolbetuximab plus CAPOX or mFOLFOX is the right regimen for them,” he concluded.

Disclosure: The research in this study was sponsored by Astellas Pharma. For full disclosures of the study authors, visit and

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.