Zolbetuximab-clzb Receives FDA Approval for Treatment of Advanced Gastric and GEJ Adenocarcinoma

Zolbetuximab-clzb (Vyloy; Astellas Pharma Inc) was granted FDA approval for the treatment of patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2-negative (HER2–) gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are claudin (CLDN) 18.2 positive. The decision is based on results from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03462719) trials which both met their primary end point of progression-free survival.^1,2

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According to the American Cancer Society, there will be approximately 27,000 new stomach cancer diagnosis in 2024. Gastric and gastroesophageal junction (GEJ) adenocarcinomas make up about 90% to 95% of all stomach cancers that develop from gland cells in the mucosa of the stomach. Patients with locally advanced, metastatic, or HER2– negative disease typically have worse outcomes.^3,4

Zolbetuximab-clzb is a cytolytic antibody that targets CLDN18.2, a novel therapeutic target in gastrointestinal malignancies, that affects nearly 38% of patients screened in the trials. CLDN18.2 positivity was defined as ≥75% of tumor cells showing moderate to strong membranous CLDN18 immunohistochemical staining, which was determined using the CLDN18 (43-14A) RxDx Assay (Ventana; Roche).^5,6

In the SPOTLIGHT trial, the researchers evaluated zolbetuximab-clzb in combination with oxaliplatin (Eloxatin; Sanofi-Aventus), leucovorin, and fluorouracil (Tolak; Hill Dermaceuticals Inc) (mFOLFOX6) compared with placebo and mFOLFOX6. The GLOW study investigated zolbetuximab-clzb plus capecitabine (Xeloda; Genetech) and oxaliplatin (CAPOX) compared with placebo and oxaliplatin. The trials had a primary end point of PFS and a secondary end point of overall survival, which were met in both. The most common treatment-emergent adverse events associated with zolbetuximab-clzb were nausea, vomiting, and decreased appetite.⁵

"While there have been advances in the first-line treatment of locally advanced unresectable and metastatic gastric and GEJ cancers in the last several years, there is still a tremendous unmet need among our patients,” said Samuel J. Klempner, MD, associate professor at Harvard Medical School, medical oncologist at Massachusetts General Hospital, Boston, in a press release. “The approval of [zolbetuximab-clzb], based on the pivotal Phase 3 SPOTLIGHT and GLOW trials, brings forward a novel biomarker and new therapy for patients whose tumors are CLDN18.2 positive, and for those on the frontlines of treatment decision-making."⁵

The FDA’s decision makes zolbetuximab-clzb the first and only CLDN18.2-targeted treatment for adults with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma.⁵

REFERENCES

1. A phase 3 efficacy, safety and tolerability study of zolbetuximab (experimental drug) plus mfolfox6 chemotherapy compared to placebo plus mfolfox6 as treatment for gastric and gastroesophageal junction (gej) cancer (spotlight). ClinicalTrials.gov Identifier: NCT03504397. Updated October 8, 2024. Accessed October 18, 2024. https://clinicaltrials.gov/study/NCT03504397

2. A study of the combination of ibrutinib plus venetoclax versus chlorambucil plus obinutuzumab for the first-line treatment of participants with chronic lymphocytic leukemia (cll)/​small lymphocytic lymphoma (sll) (glow). ClinicalTrials.gov Identifier: NCT03462719. Updated October 10, 2024. Accessed October 18, 2024. https://clinicaltrials.gov/study/NCT03462719

3. What is stomach cancer? American Cancer Society. January 22, 2021. Accessed October 18, 2024. https://www.cancer.org/cancer/types/stomach-cancer/about/what-is-stomach-cancer.html

4. Key statistics about stomach cancer. American Cancer Society. January 19, 2024. Accessed October 18, 2024. https://www.cancer.org/cancer/types/stomach-cancer/about/key-statistics.html

5. Claudin-18.2 emerges as a novel therapeutic target in gi malignancies. OncLive. May 24, 2023. Accessed October 18, 2024. https://www.onclive.com/view/claudin-18-2-emerges-as-a-novel-therapeutic-target-in-gi-malignancies

6. Astellas' vyloy™ (zolbetuximab-clzb) approved by u.s. fda for treatment of advanced gastric and gej cancer. Astellas. October 18, 2024. Accessed October 18, 2024. https://newsroom.astellas.us/2024-10-18-Astellas-VYLOY-TM-zolbetuximab-clzb-Approved-by-U-S-FDA-for-Treatment-of-Advanced-Gastric-and-GEJ-Cancer