Editor's Note: According to the latest data released by the National Cancer Center, over 350,000 new cases of gastric cancer are diagnosed annually in China, making it the fifth most common malignancy. Gastric cancer also ranks third in cancer-related mortality, with more than 260,000 deaths each year. Due to the limited implementation of early screening programs, nearly half of gastric cancer patients in China are diagnosed at advanced stages, resulting in poor prognoses. In recent years, the development and approval of new anti-cancer drugs have brought fresh opportunities for patients with advanced gastric cancer. However, compared to other cancers like lung and breast cancer, progress in precision therapy for advanced gastric cancer has been more challenging. There is an urgent need to identify “high-specificity, broad-coverage” therapeutic targets and develop innovative strategies to break through treatment barriers and improve patient outcomes.
To share insights into advances in precision therapy for gastric cancer and raise public awareness about cancer prevention and control, Oncology Frontier invited Dr. Ting Deng from Tianjin Medical University Cancer Institute and Hospital to discuss the current state of precision therapy for gastric cancer and the latest research progress.
Oncology Frontier: What are the main treatment approaches for advanced gastric cancer, and what challenges are faced during treatment?
Dr. Ting Deng: Despite advances in the overall treatment strategies for advanced gastric cancer, clinical outcomes still fall short of fully meeting the needs of patients. The mainstays of treatment remain chemotherapy, targeted therapy, and immunotherapy.
Traditional chemotherapy continues to be the cornerstone of treatment for advanced gastric cancer. However, its efficacy is limited, with the median survival typically ranging from 10 to 11 months. The concept of personalized and precision therapy has gained traction in recent years. Combining targeted therapies with chemotherapy has shown promising results, extending survival for patients. For example, since the breakthrough achievements of the ToGA trial in 2010, HER2 has become a classic target in gastric cancer treatment. However, only about 12% of gastric cancer patients are HER2-positive, meaning the majority of patients with advanced gastric cancer still lack access to more precise and effective treatments.
Immunotherapy has marked a new era in gastric cancer treatment since 2017. Over the years, multiple Phase III clinical trials have demonstrated its therapeutic potential. While positive results have been observed in intention-to-treat populations, a more detailed analysis reveals significant limitations. Patients with a PD-L1 combined positive score (CPS) <5, particularly those with CPS <1, derive minimal benefit from immunotherapy. Real-world data indicate that more than 50% of patients have a PD-L1 CPS <5, suggesting that a considerable number of individuals are unlikely to benefit from current immunotherapy options. This underscores the need to explore more effective treatment strategies and develop novel drugs to benefit a broader range of gastric cancer patients.
Another critical consideration in the treatment of advanced gastric cancer is the patient’s overall quality of life. Beyond achieving therapeutic efficacy, it is essential to address side effects that impact patients’ well-being. Tumor-related and drug-induced gastrointestinal issues often interfere with patients’ nutrition and overall condition. We are exploring supportive care measures to mitigate these challenges and enhance patients’ quality of life. Substantial progress in supportive therapy has improved patients’ daily experiences, allowing them to maintain better health alongside extended survival.
Oncology Frontier: In your clinical work, what are the proportions of patients with different targets?
Dr. Ting Deng: In our practice, we routinely test all patients for HER2, CPS, dMMR, and Claudin 18.2. The proportion of patients with positive targets varies. HER2 positivity is approximately 10%, and the proportion of patients with dMMR/MSI-H is around 5%. Real-world data shows that about 50% of patients have CPS ≥5, which aligns with our previous observations of 40%–50%. Claudin 18.2 expression presents a more optimistic scenario: approximately 20%–30% of patients have ≥75% of tumor cells with staining intensities of 2+ or 3+, while 50%–60% of patients have ≥40% of tumor cells with these staining intensities.
At this year’s ESMO Congress, a study explored the co-expression of FGFR2b, Claudin 18.2, HER2, dMMR, and CPS. The findings revealed that FGFR2 co-expressed with HER2 in about 15% of cases and overlapped to some extent with CPS ≥5, while co-expression with Claudin 18.2 was as high as 35%. Notably, dMMR patients did not express FGFR2b.
Oncology Frontier: Claudin 18.2 is highly expressed in gastric and gastroesophageal junction adenocarcinomas, with an overall positivity rate ranging from 21% to 95%. Could this target be a breakthrough for gastric cancer therapies? What is the current progress in drug development for this target?
Dr. Ting Deng: Claudin 18.2 is indeed a highly expressed target in gastric cancer and gastroesophageal junction adenocarcinomas. Its overall positivity rate ranges from 21% to 95%. Quantitative analysis of Claudin 18.2 expression generally uses staining intensity and the percentage of positive cells, classified into four grades: 0 (no membrane reaction), 1+ (weak membrane reaction), 2+ (moderate membrane reaction), and 3+ (strong membrane reaction).
In the GLOW and SPOTLIGHT trials for Zolbetuximab, a Claudin 18.2-targeting monoclonal antibody, the inclusion criteria required ≥75% of tumor cells to exhibit staining intensities of 2+ or 3+, representing the strongly positive population. This subgroup accounts for more than 30% of gastric cancer patients, a relatively high positivity rate. Zolbetuximab achieved a significant milestone on December 31, 2024, when China’s National Medical Products Administration (NMPA) approved it for injection based on Phase III results from the SPOTLIGHT and GLOW trials. The drug is now authorized for first-line treatment, in combination with fluoropyrimidine- and platinum-based chemotherapy, for patients with HER2-negative, Claudin 18.2-positive, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Many other drugs now reference its positivity threshold for clinical trial inclusion criteria.
For patients with lower Claudin 18.2 expression, studies are exploring Claudin 18.2 ADCs, which have less stringent inclusion criteria, requiring only ≥40% of tumor cells with 2+ or 3+ staining intensity. Early results for these drugs have been encouraging.
Overall, Claudin 18.2-targeted therapies, like Zolbetuximab, have demonstrated advantages in first-line treatment in Phase III trials. In fact, a September 2024 publication in The New England Journal of Medicine summarized the SPOTLIGHT and GLOW trials, highlighting that Zolbetuximab combined with chemotherapy significantly extended PFS and OS in patients with HER2-negative, Claudin 18.2-positive advanced gastric or gastroesophageal junction adenocarcinoma, offering a new therapeutic option for this population. Additionally, Claudin 18.2 ADCs are now being evaluated in head-to-head Phase III trials for second- and third-line treatments in advanced gastric cancer.
Looking ahead, innovative drugs targeting Claudin 18.2, including bispecific antibodies, ADCs, and CAR-T therapies, are poised to further improve patient survival. For example, current studies focus on combining Zolbetuximab with immunotherapy, which may yield unexpected outcomes. The mechanisms of monoclonal antibodies and ADCs differ, suggesting that integrating these therapies across first- to third-line treatments could extend survival significantly.
The Claudin 18.2 development pipeline is highly competitive, encompassing a variety of drug types. In addition to multiple monoclonal antibody studies—some comparing combinations with chemotherapy or immunotherapy—research on bispecific antibodies and ADCs is rapidly advancing. Notably, Professor Lin Shen’s team has achieved significant progress in developing Claudin 18.2 CAR-T therapy. Should this CAR-T therapy succeed in gaining market approval, it would likely provide a highly effective option for late-line treatments. Over the next 2–4 years, more innovative drugs targeting Claudin 18.2 are expected to emerge, offering increasingly effective treatment solutions and marking this target as a promising breakthrough in gastric cancer therapy.
Ting Deng
Associate Chief Physician, Department of Gastrointestinal Oncology, Tianjin Medical University Cancer Institute and Hospital
Dr. Ting Deng serves as a master’s supervisor and holds various leadership roles in oncology-related professional committees, including the Chinese Anti-Cancer Association. She is also Chair of the Tianjin Anti-Cancer Association’s Tumor Nutrition and Supportive Therapy Committee and an active member of multiple national and regional oncology societies.
