Gastric cancer is the fifth most common malignancy globally. For advanced gastric cancer, systemic treatments such as chemotherapy and targeted therapies are the primary treatment options. However, HER2-negative advanced gastric cancer patients have long lacked effective targeted drugs. Claudin 18.2 (CLDN18.2) is a tight junction protein, and nearly 40% of patients with HER2-negative gastric cancer exhibit high expression of CLDN18.2. Zolbetuximab, a monoclonal antibody targeting CLDN18.2, can mediate antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) effects in CLDN18.2-positive gastric cancer cells.

On September 16, 2024, the prestigious medical journal The New England Journal of Medicine (NEJM) published a correspondence article titled “Zolbetuximab in Gastric or Gastroesophageal Junction Adenocarcinoma,” summarizing the final survival outcomes and safety data from two global phase III clinical trials, SPOTLIGHT and GLOW. Dr. Ruihua Xu, Director of the Sun Yat-sen University Cancer Center, served as the global leading principal investigator (PI) for the GLOW trial and is the corresponding author of the article. The combined analysis demonstrated that zolbetuximab plus chemotherapy significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with advanced HER2-negative, CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma, providing a new first-line treatment option for this patient population.

Both SPOTLIGHT and GLOW are global, multicenter, randomized, double-blind, placebo-controlled phase III clinical trials. A total of 1,072 patients with CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma were enrolled. Patients were randomly assigned to receive zolbetuximab plus chemotherapy or placebo plus chemotherapy. The chemotherapy regimen in the SPOTLIGHT trial was mFOLFOX6, while CAPOX was used in the GLOW trial. The primary endpoint was progression-free survival (PFS), while key secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR), and safety.

The combined results showed that zolbetuximab plus chemotherapy significantly improved PFS compared to placebo plus chemotherapy. The median PFS for the treatment group was 9.2 months versus 8.2 months for the placebo group, representing a 29% reduction in the risk of disease progression (HR = 0.71; 95% CI, 0.61-0.83), meeting the primary endpoint. In terms of the key secondary endpoint, zolbetuximab plus chemotherapy significantly extended OS, with a median OS of 16.4 months in the treatment group compared to 13.7 months in the placebo group, reducing the risk of death by 23% (HR = 0.77; 95% CI, 0.67-0.89). The two-year survival rate in the treatment group was double that of the placebo group. The most common adverse events in the zolbetuximab-treated patients were nausea and vomiting, and no new safety signals were observed in this combined analysis.

The combined analysis of the SPOTLIGHT and GLOW studies demonstrated that zolbetuximab plus chemotherapy significantly prolonged both PFS and OS compared to placebo plus chemotherapy in patients with advanced HER2-negative, CLDN18.2-positive gastric cancer, without any new safety concerns. The GLOW study, led by Dr. Ruihua Xu, was an international, multicenter phase III clinical trial conducted at over 160 research centers across China, the United States, Europe, Japan, and other countries, with 75% of the study sites located outside of China. Professor Xu presented the results of the GLOW study at the ASCO Plenary Series in March 2023 and the ASCO Annual Meeting in June 2023. This combined analysis is set to reshape the global treatment landscape for advanced gastric cancer and establish a new treatment standard for patients with CLDN18.2-positive advanced gastric cancer. Based on the positive results of these two pivotal phase III clinical trials, zolbetuximab plus chemotherapy has already been approved by Japanese regulatory authorities for the treatment of unresectable or advanced CLDN18.2-positive gastric cancer patients. Applications for its approval are also under review in China, the United States, and Europe.

Corresponding Author: Dr. Ruihua Xu

Dr. Ruihua Xu is a member of the Chinese Academy of Medical Sciences, Director of the Sun Yat-sen University Cancer Center, and the hospital president. He also serves as the Director of the National Key Laboratory of Southern China Malignant Tumor Prevention and Treatment, and is a doctoral supervisor. He holds several prominent roles, including President of the Chinese Society of Clinical Oncology (CSCO), Vice President of the Chinese Anti-Cancer Association, and founding chair of the Targeted Therapy Committee of the Chinese Anti-Cancer Association. He has published over 200 high-impact papers as the corresponding author (some co-authored) in journals such as The New England Journal of Medicine, JAMA, BMJ, Cell, Nature Medicine, Nature Materials, Lancet Oncology, Cancer Cell, Annals of Oncology, and Journal of Clinical Oncology. His research has been included in 57 international guidelines, and he has been listed as a Highly Cited Researcher by Clarivate for three consecutive years and as one of China’s most highly cited scholars for seven consecutive years, with an H-index of 85.

As the lead researcher, Professor Xu has won two National Science and Technology Progress Awards (second class), six first-class provincial and ministerial awards, and various accolades, including the National Innovation Award, the Ho Leung Ho Lee Foundation Science and Technology Progress Award, and the Wu Jieping Medical Innovation Award. He has been recognized in several national talent programs, including the National Talent Engineering Program, and has been honored as a National Advanced Worker and a recipient of special government allowances.