On October 18, 2024, the Food and Drug Administration sanctioned zolbetuximab-clzb (Vyloy, Astellas Pharma US, Inc.), a claudin 18.2 (CLDN18.2)-targeted cytolytic antibody, in conjunction with fluoropyrimidine- and platinum-based chemotherapy, for the initial treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma exhibiting CLDN18.2 positivity, as verified by an FDA-approved assay.
Today, the FDA authorized the VENTANA CLDN18 (43-14A) RxDx Assay (Ventana Medical Systems, Inc./Roche Diagnostics) as a companion diagnostic tool to identify patients with gastric or gastroesophageal junction adenocarcinoma who may qualify for therapy with zolbetuximab.
Efficacy and Safety
The efficacy was assessed in the SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials. Both trials were randomized (1:1), double-blind, and multicenter, enrolling patients with CLDN18.2 positive advanced unresectable or metastatic HER2-negative stomach or gastroesophageal junction cancer. The primary effectiveness endpoint in both studies was progression-free survival (PFS), evaluated according to RECIST v1.1 by an independent review committee. Overall survival (OS) constituted an additional efficacy outcome metric.
In the SPOTLIGHT trial, 565 patients were randomized to receive either zolbetuximab-clzb in conjunction with mFOLFOX6 chemotherapy or a placebo alongside mFOLFOX6 chemotherapy. The median progression-free survival (PFS) was 10.6 months (95% CI: 8.9, 12.5) in the zolbetuximab-clzb/chemotherapy group and 8.7 months (95% CI: 8.2, 10.3) in the placebo/chemotherapy group (hazard ratio [HR] 0.751 [95% CI: 0.598, 0.942]; 1-sided p-value=0.0066). The median overall survival (OS) was 18.2 months (95% CI: 16.4, 22.9) and 15.5 months (95% CI: 13.5, 16.5), respectively, with a hazard ratio (HR) of 0.750 (95% CI: 0.601, 0.936) and a one-sided p-value of 0.0053.
In GLOW, 507 patients were randomized to receive either zolbetuximab-clzb in conjunction with CAPOX chemotherapy or a placebo alongside CAPOX chemotherapy. The median progression-free survival (PFS) was 8.2 months (95% CI: 7.5, 8.8) in the zolbetuximab-clzb/chemotherapy group and 6.8 months (95% CI: 6.1, 8.1) in the placebo/chemotherapy group (hazard ratio [HR] 0.687 [95% CI: 0.544, 0.866]; 1-sided p-value=0.0007). The median overall survival (OS) was 14.4 months (95% CI: 12.3, 16.5) and 12.2 months (95% CI: 10.3, 13.7), respectively (HR 0.771 [95% CI: 0.615, 0.965]; 1-sided p-value=0.0118).
The predominant severe adverse effects in SPOTLIGHT (≥2%) included vomiting, nausea, neutropenia, febrile neutropenia, diarrhea, intestinal obstruction, pyrexia, pneumonia, respiratory failure, pulmonary embolism, diminished appetite, and sepsis. The predominant severe side events in GLOW (≥2%) included vomiting, nausea, reduced appetite, diminished platelet count, upper gastrointestinal bleeding, diarrhea, pneumonia, pulmonary embolism, and fever.
The advised dosage of zolbetuximab-clzb in conjunction with fluoropyrimidine- and platinum-based chemotherapy is:
Initial dose: 800 mg/m² intravenously. Subsequent doses: 600 mg/m² intravenously every 3 weeks, or 400 mg/m² intravenously every 2 weeks.
Dr. Nishant Mittal is a highly accomplished researcher with over 13 years of experience in the fields of cardiovascular biology and cancer research. His career is marked by significant contributions to stem cell biology, developmental biology, and innovative research techniques.
Research Highlights
Dr. Mittal's research has focused on several key areas:
1) Cardiovascular Development and Regeneration: He studied coronary vessel development and regeneration using zebrafish models1.
2) Cancer Biology: At Dartmouth College, he developed zebrafish models for studying tumor heterogeneity and clonal evolution in pancreatic cancer.
3) Developmental Biology: His doctoral work at Keio University involved identifying and characterizing medaka fish mutants with cardiovascular defects.
4) Stem Cell Research: He investigated the effects of folic acid on mouse embryonic stem cells and worked on cryopreservation techniques for hematopoietic stem cells.
Publications and Presentations
Dr. Mittal has authored several peer-reviewed publications in reputable journals such as Scientific Reports, Cardiovascular Research, and Disease Models & Mechanisms1. He has also presented his research at numerous international conferences, including the Stanford-Weill Cornell Cardiovascular Research Symposium and the Weinstein Cardiovascular Development Conference.
In summary, Dr. Nishant Mittal is a dedicated and accomplished researcher with a strong track record in cardiovascular and cancer biology, demonstrating expertise in various model systems and a commitment to advancing scientific knowledge through innovative research approaches.
