The FDA has approved zolbetuximab (Vyloy) in combination with platinum- and fluoropyrimidine-containing chemotherapy for the treatment of adult patients with previously untreated, locally advanced, unresectable or metastatic, HER2-negative, CLDN18.2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This approval marks a significant advancement in the treatment landscape for gastric cancer, addressing a critical unmet need for patients with PD-L1-low and HER2-negative tumors. The decision was supported by data from the phase 3 SPOTLIGHT and GLOW trials.
Clinical Trial Data Supporting Approval
The approval of zolbetuximab was primarily based on the results of two phase 3 clinical trials: SPOTLIGHT (NCT03504397) and GLOW (NCT03653507). These trials evaluated zolbetuximab in combination with mFOLFOX6 (leucovorin calcium, fluorouracil, and oxaliplatin) and CAPOX (capecitabine and oxaliplatin), respectively. Both studies demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone.
The SPOTLIGHT trial showed a median PFS of 11.0 months in the zolbetuximab arm compared to 8.9 months in the chemotherapy arm (HR, 0.73; P = .0024). The median OS was 18.2 months in the zolbetuximab arm versus 15.6 months in the chemotherapy arm (HR, 0.78; P = .0075).
Similarly, the GLOW trial reported a median OS of 14.39 months in the zolbetuximab arm compared to 12.16 months in the placebo arm (HR, 0.771; P = .0118). These results underscore the clinical benefit of adding zolbetuximab to standard chemotherapy regimens for patients with CLDN18.2-positive gastric or GEJ adenocarcinoma.
Mechanism of Action and Target Population
Zolbetuximab is a monoclonal antibody that targets CLDN18.2, a protein expressed in 50% to 80% of gastric cancers. This protein is a tight junction protein in the stomach mucosa that regulates epithelial barrier integrity. By binding to CLDN18.2 on the surface of cancer cells, zolbetuximab induces antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), leading to the destruction of cancer cells. Patients eligible for zolbetuximab treatment must have CLDN18.2-positive disease, defined as having immunohistochemistry 3+ expression of the protein in at least 25% of their tumor sample.
Expert Commentary
Dr. Yelena Y. Janjigian, chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, emphasized the importance of routine CLDN18.2 testing in the first-line setting. "Testing should be done routinely in the first-line setting, and using targeted agents in the first-line setting, even for this previously non-targetable population, is important," she stated. She also noted that for patients with PD-L1-low or -negative disease, zolbetuximab combined with chemotherapy has become the standard of care in the frontline treatment setting.
Dr. John Marshall, physician executive director of MedStar Washington DC Integrated Hematology-Oncology Division, highlighted the significance of this approval, stating, "In GI cancers, we have been longing for new targets. We have been longing for new therapies. Finally, we are getting one." He also noted that the biggest challenge will be incorporating CLDN18.2 testing into routine clinical practice.
Adverse Events
The most common adverse events associated with zolbetuximab in combination with chemotherapy include nausea, vomiting, and appetite loss. These gastrointestinal side effects are generally manageable with appropriate supportive care, including antiemetics and dose adjustments.
Future Directions
With the approval of zolbetuximab, future research will likely focus on exploring its use in combination with other therapies, such as immunotherapies and novel targeted agents. Ongoing trials will aim to expand its applicability beyond first-line treatments and potentially extend its use to other cancers expressing CLDN18.2. Further investigation into biomarker-driven strategies will also be crucial to optimize patient selection and treatment outcomes.
