Introduction
The U.S. Food and Drug Administration (FDA) has recently approved a breakthrough treatment, zolbetuximab-clzb (Vyloy, Astellas Pharma US, Inc.), for the first-line treatment of adults with locally advanced, unresectable, or metastatic gastric and gastroesophageal junction (GEJ) adenocarcinoma. Targeting a specific biomarker—claudin 18.2 (CLDN18.2)—this therapy, combined with chemotherapy, offers a promising new option for patients with HER2-negative tumors expressing CLDN18.2.
Current Regulatory Status
Zolbetuximab-clzb received FDA approval alongside the VENTANA CLDN18 (43-14A) RxDx Assay, a companion diagnostic by Ventana Medical Systems (Roche Diagnostics). This assay is essential to identify patients eligible for this treatment. The approval process leveraged the FDA’s Real-Time Oncology Review (RTOR) pilot, facilitating streamlined data submission, and included priority review, fast track, and orphan drug designation, underscoring the urgency and promise of this therapy.
Drug and Mechanism of Action
Zolbetuximab-clzb is a CLDN18.2-directed cytolytic antibody that, when combined with fluoropyrimidine- and platinum-based chemotherapy, targets the CLDN18.2 protein found in certain gastric and GEJ adenocarcinomas. This innovative approach allows the immune system to better recognize and attack cancer cells expressing CLDN18.2, thus halting tumor progression in this challenging-to-treat population.
Clinical Trials and Efficacy Data
The efficacy of zolbetuximab-clzb was confirmed in two pivotal, double-blind, multicenter clinical trials: SPOTLIGHT (NCT03504397) and GLOW (NCT03653507). Both trials evaluated patients with advanced, unresectable, or metastatic HER2-negative gastric or GEJ adenocarcinoma positive for CLDN18.2. Key measures included progression-free survival (PFS) and overall survival (OS), assessed by an independent review committee using RECIST v1.1 criteria.
In the SPOTLIGHT trial, 565 patients received either zolbetuximab-clzb with mFOLFOX6 chemotherapy or a placebo with the same chemotherapy. Results showed that patients on zolbetuximab-clzb had a median PFS of 10.6 months versus 8.7 months in the placebo group, with a median OS of 18.2 months compared to 15.5 months in the control group. The GLOW trial, with 507 participants, showed similar results; patients treated with zolbetuximab-clzb and CAPOX chemotherapy achieved a median PFS of 8.2 months compared to 6.8 months in the placebo group, and a median OS of 14.4 months compared to 12.2 months in the control group.
Safety Profile
Common serious adverse reactions (≥2%) reported across both trials included vomiting, nausea, neutropenia, diarrhea, pneumonia, and respiratory complications. These side effects reflect the known challenges of chemotherapy-based regimens and emphasize the need for thorough patient monitoring.
Dosage and Administration
For administration, the initial dose of zolbetuximab-clzb is 800 mg/m² intravenously, followed by maintenance doses of either 600 mg/m² every three weeks or 400 mg/m² every two weeks, in combination with fluoropyrimidine- and platinum-containing chemotherapy.
Conclusion
The FDA’s approval of zolbetuximab-clzb, in combination with chemotherapy, represents a significant advancement in the treatment of advanced gastric and GEJ adenocarcinoma. This targeted approach not only improves survival outcomes but also offers hope to a subset of patients who previously had limited options. The future of oncology may increasingly depend on such biomarker-driven therapies that enable personalized treatment strategies.
Dr. Vinoth Khandelwal, Ph.D.
Disclaimer
The editors take care to share authentic information. In case of any discrepancies please write to newsletter@medness.org
The sponsors do not have any influence on the nature or kind of the news/analysis reported in MedNess. The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of MedNess. Examples of analysis performed within this article are only examples. They should not be utilized in real-world analytic products as they are based only on very limited and dated open-source information. Assumptions made within the analysis are not reflective of the position of anyone volunteering or working for MedNess. This blog is strictly for news and information. It does not provide medical advice, diagnosis or treatment nor investment suggestions. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
MedNess is a part of STEMPeers® which is a 501(c)(3) organization registered in PA as PhD Career Support Group. The organization helps create a growing network of STEM scientists that is involved in peer-to-peer mentoring and support.
