A First for Gastric and Gastroesophageal Junction Cancer: Claudin-Targeted Zolbetuximab Receives FDA Approval

On October 18, 2024, the United States Food and Drug Administration (FDA) approved Astellas Pharma's cytolytic antibody targeting claudin 18.2 (CLDN18.2), zolbetuximab-clzb (Vyloy), with fluoropyrimidine- and platinum-containing chemotherapy for adults with locally advanced unresectable or metastatic, human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction adenocarcinoma as first-line treatment. The therapy targets tumors found to be CLDN18.2-positive by an FDA-approved test.

The same day, the FDA also approved the VENTANA CLDN18 (43-14A) RxDx Assay diagnostic device, used to determine whether patients with gastric or gastroesophageal junction adenocarcinoma are eligible for zolbetuximab.

The Importance of Gastric Cancer

Gastric cancer is the fifth most frequently diagnosed cancer worldwide, and its incidence has increased in recent years. Often causing few symptoms early on, this cancer is frequently diagnosed only once advanced or metastatic (stage 4) . According to the United States National Cancer Institute, the 5-year survival rate in metastatic gastric cancer is only 7%. This highlights the growing, urgent need for first-line options in HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma.

A New Molecular Target in Gastric Cancer: Claudin 18.2 

For patients with gastric and gastroesophageal junction adenocarcinoma, targeted treatment options are very limited. Patients whose tumors express PD-L1 can receive immunotherapy , while those with HER2-positive tumors can receive trastuzumab or trastuzumab deruxtecan . However, patients with HER2-negative tumors may not fully fit either treatment category or may be unable to receive targeted therapy. These patients generally have levels of CLDN18.2, which is normally found in gastric mucosal cells and becomes more highly expressed as gastric cancer develops.

CLDN18.2 positivity is an important biomarker in gastric and gastroesophageal junction adenocarcinoma. Studies in the literature have identified approximately 30-50% as CLDN18.2-positive. This proportion supports the potential use of CLDN18.2 as a therapeutic target in these cancers.

How Does Zolbetuximab Work?

Zolbetuximab is an experimental monoclonal antibody developed against isoform 2 of Claudin-18 (CLDN18.2). It is being investigated for gastrointestinal and pancreatic cancers. In 2016, Astellas acquired Ganymed and obtained the rights to zolbetuximab. As of November 2021, the drug was in phase III trials for gastric cancer.

FDA Approval Through the GLOW and SPOTLIGHT Studies

Zolbetuximab's efficacy was evaluated in two major trials, SPOTLIGHT (NCT03504397) and GLOW (NCT03653507). Both were randomized (1:1), double-blind, multicenter studies in patients with CLDN18.2-positive, advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma. The primary efficacy endpoint, assessed by an Independent Review Committee using RECIST v1.1, was progression-free survival (PFS). Overall survival (OS) was an additional efficacy endpoint.

In SPOTLIGHT, 565 patients were randomized to zolbetuximab-clzb plus mFOLFOX6 chemotherapy or placebo plus mFOLFOX6. Median progression-free survival in the zolbetuximab-clzb/chemotherapy arm was 10.6 months (95% CI: 8.9, 12.5), compared with 8.7 months (95% CI: 8.2, 10.3) with placebo/chemotherapy (HR 0.75 [95% CI: 0.598, 0.942]; one-sided p-value = 0.0066). Overall survival was 18.2 months (95% CI: 16.4, 22.9) and 15.5 months (95% CI: 13.5, 16.5), respectively (HR 0.750 [95% CI: 0.601, 0.936]; one-sided p-value = 0.0053).

In GLOW, 507 patients were randomized to zolbetuximab-clzb plus CAPOX chemotherapy or placebo plus CAPOX. Median progression-free survival in the zolbetuximab-clzb/chemotherapy arm was 8.2 months (95% CI: 7.5, 8.8), compared with 6.8 months (95% CI: 6.1, 8.1) with placebo/chemotherapy (HR 0.687 [95% CI: 0.544, 0.866]; one-sided p-value = 0.0007). Overall survival 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]; one-sided p-value = 0.0118).

Adverse Effects

In SPOTLIGHT, the most common serious adverse effects (≥2%) included vomiting, nausea, neutropenia, febrile neutropenia, diarrhea, intestinal obstruction, fever, pneumonia, respiratory failure, pulmonary embolism, decreased appetite, and sepsis. In GLOW, the most common serious adverse effects (≥2%) were vomiting, nausea, decreased appetite, decreased platelet count, upper gastrointestinal bleeding, diarrhea, pneumonia, pulmonary embolism, and fever.

Zolbetuximab Dosage

The recommended zolbetuximab-clzb dosage with fluoropyrimidine- and platinum-containing chemotherapy is:

• Initial dose: 800 mg/m² intravenously,
• Subsequent doses: 600 mg/m² intravenously every 3 weeks or 400 mg/m² every 2 weeks.

This application was reviewed under the FDA's pilot program (Real-Time Oncology Review= RTOR) and received priority review, accelerated approval, and orphan drug status.