The Future of Zolbetuximab in Upper GI Cancers
Key Points
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Treatment with zolbetuximab, a monoclonal antibody against claudin 18.2 (CLDN18.2), improved survival outcomes for patients with upper gastrointestinal (GI) cancers.
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Zolbetuximab-based combinations evaluated to date are limited by toxicity and modest improvements in overall response rate (ORR). However, novel triplet regimens may offer a more favorable risk-benefit balance.
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Anti–CLDN18.2 therapies continue to show promise in upper GI cancers, and CLDN18.2 may be the first viable target for chimeric antigen receptor (CAR) T-cell therapies in solid tumors.
Zolbetuximab Data from ASCO GI 2026
Shruti Patel, MD, of Stanford Medicine, met with Timothy Brown, MD, MSCE, of University of Texas Southwestern Medical Center, at the 2026 American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI) to discuss current and upcoming data for zolbetuximab, a monoclonal antibody against CLDN18.2, in upper GI cancers.
Previously, the phase 3 SPOTLIGHT and GLOW clinical trials reported that first-line treatment with zolbetuximab plus chemotherapy improved survival outcomes for patients with CLDN18.2–positive metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. While zolbetuximab improved survival, it has only shown small benefits in ORR, and the overall benefit may not outweigh the potential toxicities, said Dr. Brown.
At ASCO GI 2026, the presentation from the phase 2 ILUSTRO trial on zolbetuximab plus chemotherapy and nivolumab in advanced gastric or GEJ cancer showed promising results, particularly in patients expressing both CLDN18.2 and PD-L1. Although positive, the phase 2 data alone are not enough for Dr. Brown to implement zolbetuximab in his practice. He suggested the phase 3 LUCERNA trial on zolbetuximab with pembrolizumab and chemotherapy may determine the future of zolbetuximab in upper GI cancers.
From a broader perspective, CLDN18.2 is proving to be an intriguing treatment target. It may represent the first viable target for CAR T-cell therapies in solid tumors, as was shown with satricabtagene autoleucel in gastric and GEJ cancer, said Dr. Brown.