The FDA has approved zolbetuximab (Vyloy) in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced, unresectable, or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN 18.2–positive. This approval marks a significant advancement in the treatment of gastric cancer, a disease with a 5-year overall survival rate of approximately 32%.
The approval was based on findings from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials. These trials demonstrated that adding zolbetuximab to standard chemotherapy regimens improved survival compared to chemotherapy alone. Cindy M. Pabon, MD, assistant professor at Sylvester Cancer Center, University of Miami, noted that the approval encourages further exploration of CLDN 18.2–targeted agents, highlighting the importance of identifying novel targets to improve outcomes in hard-to-treat tumors.
Mechanism of Action
Zolbetuximab targets CLDN 18.2, a protein involved in maintaining cell junctions in the stomach lining. In gastric cancer, abnormal expression of CLDN 18.2 can lead to uncontrolled cell growth. Zolbetuximab, a monoclonal antibody, binds to CLDN 18.2, triggering cancer cell death through various mechanisms. This targeted approach aims to block tumor growth more effectively than traditional chemotherapy alone.
Clinical Trial Data
The SPOTLIGHT and GLOW trials evaluated the efficacy of adding zolbetuximab to mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) chemotherapy. Results from both trials confirmed that the addition of zolbetuximab improved outcomes and provided a survival benefit compared to standard chemotherapy alone. The FDA approval now allows clinicians to offer this combination to patients with limited treatment options.
The Role of Biomarker Testing
Biomarker testing is crucial in shaping treatment strategies for gastric cancer. According to Dr. Pabon, molecular profiling should be conducted as soon as a patient is diagnosed with gastric cancer to determine the biomarker landscape. Knowing the CLDN 18.2 status, HER2 status, and combined positive score (CPS) helps guide treatment decisions. Emerging markers like CLDN 18.2 may lead to longer responses compared to what has been observed with CPS-positive patients. Dr. Pabon expressed hope that targeting specific overexpressed proteins or mutations, such as CLDN 18.2, will improve outcomes for these patients.
Implications for Precision Medicine
The approval of zolbetuximab represents a shift toward precision medicine in gastric cancer treatment. By targeting specific biomarkers like CLDN 18.2, clinicians can tailor treatment to the individual characteristics of a patient's tumor. This approach has the potential to improve outcomes and reduce the toxicity associated with traditional chemotherapy regimens. The development and approval of zolbetuximab revitalize efforts to target CLDN18.2 in gastric cancer, opening new avenues for managing this challenging cancer.
