The Food and Drug Administration (FDA) has approved Zolbetuximab (Vyloy) as a first-line treatment for patients with advanced HER2* negative Esophageal Cancer found at the junction of the stomach and the esophagus (GE Junction) whose cancer overexpresses a protein called Claudin 18.2. It’s estimated that 35 percent of adenocarcinoma tumors found at the junction of the esophagus and stomach overexpress claudin 18.2.

Two clinical trials relied upon by the FDA showed that the addition of Vyloy to chemotherapy reduced the risk of death by 25% compared to chemotherapy alone in this patient population.

Vyloy is a targeted monoclonal antibody developed by Astellas and it is the only therapy currently available that targets Claudin 18.2. It is reported that Vyloy will be available to order through specialty distributors in about 6-12 business days.

Claudin 18.2 is a cell surface protein found in the stomach lining that provides the primary route of communication among cells and the external environment and is thus key to tumor growth. Zolbetuximab binds claudin 18.2 and triggers immune responses that kill the cancer cells.

The FDA decision also includes the approval of a companion diagnostic test VENTANA® CLDN18 RxDx Assay, which will identify patients who are eligible for Vyloy based on their claudin 18.2 expression.

The Research
The FDA approval of Vyloy was based on two large, international phase 3 clinical trials that found the combination of zolbetuximab and chemotherapy resulted in a significant improvement in overall survival and progression-free survival when compared to chemotherapy alone.

The SPOTLIGHT study evaluated VYLOY plus mFOLFOX6 (a combination chemotherapy regimen that includes oxaliplatin, leucovorin, and fluorouracil) compared to placebo plus mFOLFOX6. The GLOW study evaluated VYLOY plus CAPOX (a combination chemotherapy regimen that includes capecitabine and oxaliplatin) compared to placebo plus CAPOX.

Both studies found the most common adverse reactions to Vyloy were nausea, vomiting and decreased appetite.

      Dr. Samuel J. Klempner, gastrointestinal oncologist at Massachusetts General Hospital in Boston
 shares his viewpoint on the new FDA approval.   (Thanks to OncLive by the Oncology Specialty Group.)

New Therapies are Urgently Needed
Patients with advanced Esophageal Cancer have few treatment options and very poor prognoses. Less than six percent of patients with this diagnosis survive five years.

Three years ago, the FDA approved checkpoint inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) combined with chemotherapy for these patients. Earlier this year, the FDA approved tislelizumab (Tevimbra), another checkpoint inhibitor, combined with chemotherapy for patients with advanced Esophageal Squamous Cell Carcinoma (ESCC) who have had prior systemic chemotherapy that did not include a PD-L1 inhibitor.  Last month, an FDA advisory panel recommended that the FDA restrict access to these therapies to patients whose cancer expresses PD-L1* at a level at or above a combined positive score of 1. (See our coverage of those hearings.) An estimated 40% of patients with GE Junction Adenocarcinoma are PD-L1 positive.

In 2021, the FDA also approved Enhertu (trastuzumab deruxtecan), a HER2-directed antibody drug conjugate (ADC) for patients with HER2 positive advanced GE Junction Adenocarcinoma who had already been treated with an anti-HER2 regimen. About 20 percent of GE Junction cancer patients are HER2 positive.

Eleven years earlier, the FDA approved the first targeted therapy for Esophageal Cancer patients: Herceptin (trastuzumab) plus chemotherapy for HER2 positive patients with advanced GE Junction Adenocarcinoma. Herceptin had been approved for breast cancer patients twelve years earlier.

Another Treatment Update
BeiGene announced that tislelizumab (Tevimbra) is now available in the U.S. for patients with advanced Esophageal Squamous Cell Carcinoma who have had prior systemic chemotherapy that did not include a PD-L1 inhibitor. The company says that the majority of eligible patients will have access to TEVIMBRA immediately through their insurance plans.

The FDA is currently reviewing applications for first-line treatment of both advanced ESCC and advanced GE Junction Adenocarcinoma with Tevimbra.

According to BeiGene, Tislelizumab is a uniquely designed humanized immunoglobulin G4 (IgG4) anti-programmed cell death protein 1 (PD-1) monoclonal antibody with high affinity and binding specificity against PD-1. It is designed to minimize binding to Fc-gamma (Fcγ) receptors on macrophages, helping the body’s immune cells detect and fight tumors.

More to Come?
Another trial is currently underway (ILUSTRO trial NCT03505320) that studies the combination of Vyloy and Opdivo with chemotherapy as a first-line treatment for HER2 negative patients with advanced GE Junction Adenocarcinoma.

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*HER2 – Human Epidermal Growth Factor 2 – a protein that promotes the growth of cancer cells

* PD-L1 – Programmed death ligand 1 – a protein that regulates the body’s immune response