Zolbetuximab-clzb (Vyloy)

Number: 1071

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses zolbetuximab-clzb (Vyloy) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of zolbetuximab-clzb (Vyloy) is required of all Aetna participating providers and members in applicable plan designs. For precertification of zolbetuximab-clzb (Vyloy), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification. 

1. Criteria for Initial Approval

   Esophageal, Gastric, and Gastroesophageal Junction Adenocarcinoma

   Aetna considers zolbetuximab-clzb (Vyloy) medically necessary for CLDN18.2-positive, HER2-negative esophageal, gastric, or gastroesophageal junction (GEJ) adenocarcinoma when the member has unresectable, recurrent, or metastatic disease or is not a surgical candidate as first-line treatment, in combination with fluoropyrimidine- and platinum-containing chemotherapy.

   Aetna considers all other indications as experimental, investigational, or unproven.

2. Continuation of Therapy

   Aetna considers continuation of zolbetuximab-clzb (Vyloy) therapy medically necessary in members requesting reauthorization for an indication outlined in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Zolbetuximab-clzb is supplied as Vyloy 100 mg lyophilized powder in a single-dose vial for injection for intravenous use.

• Administer Vyloy as an intravenous infusion only. Do not administer Vyloy as an intravenous push or bolus.
• The recommended first dose of Vyloy is 800 mg/m² followed by 600 mg/m² every 3 weeks or 400 mg/m² every 2 weeks.

Source: Astellas Pharma US, 2025

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
96413 - 96415	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
J1326	Injection, zolbetuximab-clzb, 2 mg
Other HCPCS codes related to the CPB:
Nedaplatin – No specific code
J8522	Capecitabine, oral, 50 mg
J9045	Injection, carboplatin, 50 mg
J9060	Injection, cisplatin, powder or solution, 10 mg
J9263	Injection, oxaliplatin, 0.5 mg
ICD-10 codes covered if selection criteria are met:
C15.3 – C15.9	Malignant neoplasm of lower third, overlapping sites of esophagus and unspecified [CLDN18.2-positive, HER2-negative]
C16.0 - C16.9	Malignant neoplasm of stomach [CLDN18.2-positive, HER2-negative]

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Vyloy is indicated in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are claudin (CLDN) 18.2 positive as determined by an FDA-approved test.

Compendial Uses

• Esophageal and esophagogastric junction cancers
• Gastric cancer

Zolbetuximab-clzb is available as Vyloy (Astellas Pharma US, Inc.) is a chimeric (mouse/human) antibody composed of variable regions derived from mouse anti-human claudin-18 isoform 2 monoclonal antibody and constant regions derived from human IgG1. Being a claudin 18.2 (CLDN18.2)-directed cytolytic antibody, Vyloy depletes CLDN18.2-positive cells via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In CLDN18.2-expressing mouse tumor models, Vyloy in combination with chemotherapy had increased antitumor activity compared to Vyloy or chemotherapy alone (Astella Pharma US, 2024). 

According to the prescribing information, Vyloy carries the following warnings and precautions and adverse reactions:

• Warnings and precautions

  • Hypersensitivity reactions including serious anaphylaxis reactions and serious and fatal infusion-related reactions have occurred. Monitor patients during and for at least 2 hours after infusion with Vyloy. Interrupt, slow the rate of infusion or permanently discontinue Vyloy based on severity and type of reaction. Premedicate with antihistamines for subsequent infusions after a hypersensitivity reaction.
  • Severe nausea and vomiting: Premedicate patients with antiemetics prior to each infusion. Interrupt or permanently discontinue Vyloy based on the severity of the nausea and/or vomiting. Manage patients during and after infusion with antiemetics or fluid replacement.
    
    

• Adverse reactions

  • The most common adverse reactions (≥15%) for Vyloy in combination with mFOLFOX6 or CAPOX were nausea, vomiting, fatigue, decreased appetite, diarrhea, peripheral sensory neuropathy, abdominal pain, constipation, decreased weight, hypersensitivity reactions, and pyrexia.
  • The most common laboratory abnormalities (≥15%) for Vyloy in combination with mFOLFOX6 or CAPOX were decreased neutrophil count, decreased leucocyte count, decreased albumin, increased creatinine, decreased hemoglobin, increased glucose, decreased lymphocyte count, increased aspartate aminotransferase, decreased platelets, increased alkaline phosphatase, increased alanine aminotransferase, decreased glucose, decreased sodium, increased phosphate, decreased potassium, and decreased magnesium.

On October 18, 2024, the U.S. Food and Drug Administration (FDA) approved zolbetuximab-clzb (Vyloy), a claudin 18.2 (CLDN18.2)-directed cytolytic antibody, with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2(HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, as determined by an FDA-approved test. The FDA approval was based on supporting data from the SPOTLIGHT and GLOW studies (FDA, 2024).

In the SPOTLIGHT study, a double-blind, randomized, multicenter phase 3 trial, Shitara et al. (2024) evaluated the efficacy of zolbetuximab-clzb (Vyloy) in combination with modified folinic acid [or levofolinate], fluorouracil, and oxaliplatin regimen (mFOLFOX6) for the treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors were CLDN18.2 positive.

The VENTANA CLDN18 (43-14A) RxDx Assay was used to identify CLDN18.2 positivity (defined as ≥75% of tumor cells demonstrating moderate to strong membranous CLDN18 staining) determined by immunohistochemistry on gastric or GEJ tumor tissue specimens from all patients. The study excluded patients if they had a complete or partial gastric outlet syndrome, or history of central nervous system metastases (Astellas Pharma US, 2025).

In SPOTLIGHT, 565 patients were randomized 1:1 to receive Vyloy in combination with mFOLFOX6 chemotherapy (n=283) or placebo in combination with mFOLFOX6 chemotherapy (n=282). Vyloy was administered intravenously at an initial dose of 800 mg/m2 (Day 1 of cycle 1) followed by subsequent doses of 600 mg/m2 every 3 weeks in combination with up to 12 treatments (4 cycles) of mFOLFOX6 (oxaliplatin 85 mg/m2, folinic acid (leucovorin or local equivalent) 400 mg/m2, fluorouracil 400 mg/m2 given as a bolus and fluorouracil 2400 mg/m2 given as a continuous infusion) administered on Days 1, 15 and 29 of a 42-day cycle. After 12 treatments, patients were allowed to continue treatment with Vyloy, 5-fluorouracil and folinic acid (leucovorin or local equivalent) at the discretion of the investigator, until progression of disease or unacceptable toxicity. Tumor assessments were performed every 9 weeks up to and including Week 54, then every 12 weeks thereafter (Astellas Pharma US, 2025).

The primary efficacy outcome measure was progression-free survival (PFS), as assessed per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by an independent review committee (IRC). Secondary efficacy outcome measures included overall survival (OS), objective response rate (ORR) and duration of response (DOR) as assessed per RECIST v1.1 by IRC (Astellas Pharma US, 2025; FDA, 2024).

The median PFS was 10.6 months (95% Confidence Interval [CI]: 8.9, 12.5) in the Vylox with chemotherapy arm and 8.7 months (95% CI: 8.2, 10.3) in the placebo with chemotherapy arm (hazard ratio [HR] 0.751 [95% CI: 0.598, 0.942]; 1-sided p-value=0.0066). The median OS 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]; 1-sided p-value=0.0053). The ORR was 40.3% (95% CI: 34.5, 46.3) and 39.7% (95% CI: 34.0, 45.7), respectively. The median DOR was 10.3 months (95% CI: 8.3, 10.9; n = 114) and 10.5 months (95% CI: 7.7, 13.3; n = 112), respectively (Astellas Pharma US, 2025).

In the GLOW, a double-blind, randomized, multicenter, phase 3 trial, Shah et al. (2023) evaluated the efficacy of zolbetuximab-clzb (Vyloy) in combination with capecitabine and oxaliplatin (CAPOX) for the treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors were CLDN18.2 positive.

The VENTANA CLDN18 (43-14A) RxDx Assay was used to identify CLDN18.2 positivity (defined as ≥75% of tumor cells demonstrating moderate to strong membranous CLDN18 staining) determined by immunohistochemistry on gastric or GEJ tumor tissue specimens from all patients. The study excluded patients if they had a complete or partial gastric outlet syndrome, or history of central nervous system metastases (Astellas Pharma US, 2025).

In GLOW, 507 patients were randomized 1:1 to receive Vyloy in combination with CAPOX chemotherapy (n=254) or placebo in combination with CAPOX chemotherapy (n=253). Vyloy was administered intravenously at an initial dose of 800 mg/m2 (Day 1 of cycle 1) followed by a subsequent dose of 600 mg/m2 every 3 weeks in combination with up to 8 treatments (8 cycles) of CAPOX administered on Day 1 (oxaliplatin 130 mg/m2) and on Days 1 to 14 (capecitabine 1000 mg/m2) of a 21-day cycle. After 8  treatments of oxaliplatin, patients were allowed to continue treatment of Vyloy and capecitabine at the discretion of the investigator, until progression of disease or  unacceptable toxicity. Tumor assessments were performed every 9 weeks up to and including Week 54, then every 12 weeks thereafter (Astellas Pharma US, 2025).

The primary efficacy outcome measure was PFS as assessed per RECIST v1.1 by IRC. Secondary outcome measures included OS, ORR, and DOR as assessed per RECIST v1.1 by IRC (Astellas Pharma US, 2025; FDA, 2024).

The median PFS was 8.2 months (95% CI:7.5, 8.8) in the Vyloy with chemotherapy arm and 6.8 months (95% CI: 6.1, 8.1) in the placebo with chemotherapy arm (hazard ratio [HR] 0.687 [95% CI: 0.544, 0.866]; 1-sided p-value=0.0007). The median 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 ORR was 32.3% (95% CI: 26.6, 38.4) and 31.2% (95% CI: 25.6, 37.3), respectively. The median DOR was 8.3 months (95% CI: 6.3, 11.4) and 6.2 months (6.0, 7.6), respectively (Astellas Pharma US, 2025).

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References