Editor's Note:At the 2024 Chinese Congress of Holistic Integrative Oncology (CCHIO) held from November 14–17 in Xi’an, Dr. Yinying Wu from The First Affiliated Hospital Xi'an Jiao Tong University delivered a comprehensive lecture titled “Advances in CLDN18.2-Positive Gastric Cancer Research.” The presentation delved into the role of CLDN18.2 protein in gastric cancer, advancements in drug therapies, and preliminary explorations into drug and immunotherapy combinations.

Overview of CLDN18.2

CLDN18.2 is a crucial component of tight junction complexes and plays an important role in cellular function. It exhibits highly tissue-specific expression, being present in normal gastric mucosal cells and exposed in gastric cancer cells due to disrupted cell polarity. High CLDN18.2 expression correlates with pathological features and prognosis in gastric cancer. A 2022 study indicated that poorly differentiated gastric cancers showed significantly higher CLDN18.2 positivity than well-differentiated cases and that CLDN18.2 positivity was associated with more advanced cancer stages. Among the Chinese population, more than 30% of gastric cancers exhibit CLDN18.2 positivity (≥75% strong membrane staining in tumor cells), making it a viable therapeutic target. Studies have shown no significant correlation between HER2, MSI-H/dMMR, PD-L1 expression, and CLDN18.2 status. Both domestic and international guidelines now recommend CLDN18.2 testing before initiating treatment for gastric adenocarcinoma.

Advances in CLDN18.2-Targeting Therapies

Significant progress has been made in developing therapies targeting CLDN18.2, including monoclonal antibodies, antibody-drug conjugates (ADCs), and CAR-T cell therapies.

Monoclonal Antibodies

Zolbetuximab, a first-in-class chimeric IgG1 monoclonal antibody targeting CLDN18.2, has shown dual benefits in progression-free survival (PFS) and overall survival (OS) when combined with chemotherapy in CLDN18.2-positive, HER2-negative, unresectable locally advanced (LA) or metastatic gastric/gastroesophageal junction (G/GEJ) adenocarcinomas. The SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials demonstrated significant improvements in median PFS (9.2 months vs. 8.2 months, HR=0.71) with Zolbetuximab compared to placebo. Subgroup analyses showed superior PFS benefits in Chinese patients, with reduced risks of disease progression or death by 52% (SPOTLIGHT) and 39% (GLOW). These findings establish Zolbetuximab plus chemotherapy as the global first-line standard for CLDN18.2-positive gastric cancer.

FG-M108, another IgG1 monoclonal antibody targeting CLDN18.2 with enhanced ADCC activity, demonstrated promising safety and efficacy in combination with CAPOX for advanced G/GEJ adenocarcinomas in a Phase I/IIa trial.

Antibody-Drug Conjugates (ADCs)

SHR-A1904 is a novel ADC comprising a humanized IgG1 monoclonal antibody targeting CLDN18.2, a cleavable linker, and a topoisomerase I inhibitor payload. Early-phase trials (NCT04877717) demonstrated manageable safety and promising efficacy, with dose levels of 6.0 mg/kg and 8.0 mg/kg advancing to expansion phases. Other agents, such as RC118, have also shown encouraging anti-tumor activity and manageable safety profiles.

CAR-T Cell Therapy

CT-041 is a first-in-class autologous CAR-T therapy targeting CLDN18.2-positive solid tumors. A Phase I trial (n=59) demonstrated an objective response rate (ORR) of 54.9% and a disease control rate (DCR) of 96.1% in CLDN18.2-positive gastric/gastroesophageal cancer. Median PFS and OS were 5.8 and 9.0 months, respectively. CT-041 showed durable efficacy and favorable tolerability without significant long-term complications.

Preliminary Explorations in CLDN18.2 and Immunotherapy Combinations

T-cell exhaustion is a major mechanism of resistance to cellular therapies. Research suggests that CLDN18.2-positive tumors have higher CD8+ and CD4+ T-cell infiltration, potentially enhancing CAR-T cell activity. Targeting CLDN18.2 can promote T-cell infiltration and antigen presentation, complementing immune checkpoint inhibitors (ICIs). Early studies are exploring these combination strategies.

The Transtar102 study (NCT04495296) investigated Osemitamab (a CLDN18.2-targeting antibody) combined with CAPOX and Nivolumab in HER2-negative advanced G/GEJ cancer. Preliminary results indicated encouraging survival rates and durable anti-tumor activity, particularly in high or intermediate CLDN18.2-expressing tumors, regardless of PD-L1 CPS scores.

The ILUSTRO study assessed Zolbetuximab combined with Pembrolizumab for CLDN18.2-high advanced gastric cancer. Results showed acceptable toxicity and disease control rates, though further large-scale studies are needed to confirm efficacy.

Conclusion

CLDN18.2 is highly expressed in gastric cancer, particularly in diffuse-type and HER2-negative, PD-L1-low populations. It offers a promising therapeutic target, with monoclonal antibodies like Zolbetuximab demonstrating significant survival benefits in pivotal trials. Emerging ADCs and CAR-T therapies further expand the treatment landscape.

Future research into CLDN18.2-targeted and immunotherapy combinations could address resistance mechanisms and enhance therapeutic efficacy. Continued exploration and optimization of these strategies are expected to improve outcomes and quality of life for advanced gastric cancer patients.

Dr. Yinying Wu

Associate Chief Physician, MD

• Department of Oncology, First Affiliated Hospital of Xi’an Jiaotong University
• Member, CSCO Youth Expert Committee
• Member, CSCO Immunotherapy Expert Committee
• Member, CSCO Biliary Tumor Expert Committee
• Member, CSCO Colorectal Cancer Expert Committee
• Member, CSCO Neuroendocrine Tumor Expert Committee
• Clinical Trial Data Reviewer, National Medical Products Administration (NMPA)
• Member, Youth Committee of the Chinese Anti-Cancer Association Targeted Therapy Committee
• Chair, Youth Committee of Shaanxi Anti-Cancer Association Biological Therapy Committee
• Deputy Chair, Shaanxi Anti-Cancer Association Neuroendocrine Tumor Committee
• Deputy Chair, Shaanxi Anti-Cancer Association Anti-Cancer Drug Committee
• Deputy Chair, Shaanxi Anti-Cancer Association Comprehensive Therapy Committee