Regulatory Decision Summary for Vyloy

The purpose of this New Drug Submission was to seek market authorization for Vyloy (zolbetuximab), a claudin (CLDN) 18.2-directed monoclonal antibody, in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumours are CLDN 18.2 positive.

After evaluation of the submitted data package, Health Canada authorized Vyloy, in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adult patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumours are CLDN 18.2 positive as determined by a validated test.

Authorization was based on the results of the SPOTLIGHT and GLOW studies, two phase 3, randomized, double-blind, placebo-controlled trials investigating zolbetuximab, in combination with fluoropyrimidine- and platinum- containing chemotherapy, in adult patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2) negative gastric or GEJ cancer whose tumours were Claudin 18.2 positive. In both trials the primary efficacy endpoint was Progression Free Survival (PFS), and the key secondary endpoint was Overall Survival (OS).

In SPOTLIGHT, 565 patients were randomized (1:1) to receive zolbetuximab in combination with 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) chemotherapy or placebo plus mFOLFOX6 chemotherapy. Zolbetuximab was administered intravenously as a single loading dose of 800 mg/m² followed by subsequent doses of 600 mg/m² every 3 weeks. The study demonstrated statistically significant and clinically meaningful improvements in PFS and OS in patients who received zolbetuximab plus mFOLFOX6 compared with placebo plus mFOLFOX6. The median PFS was 10.6 months in the zolbetuximab treatment arm compared to 8.7 months in the placebo treatment arm and the hazard ratio was 0.75. The median OS was 18.2 months in the zolbetuximab treatment arm and 15.5 months in the placebo treatment arm and the hazard ratio was 0.75.

In GLOW, 507 patients were randomized (1:1) to receive zolbetuximab in combination with oxaliplatin and capecitabine (CAPOX) chemotherapy or placebo plus CAPOX chemotherapy. Zolbetuximab was administered intravenously as a single loading dose of 800 mg/m² followed by subsequent doses of 600 mg/m² every 3 weeks. The study demonstrated statistically significant and clinically meaningful improvements in PFS and OS in patients who received zolbetuximab plus CAPOX compared with placebo plus CAPOX. The median PFS was 8.2 months in the zolbetuximab treatment arm compared to 6.9 months in the placebo treatment arm and the hazard ratio was 0.69. The median OS was 14.4 months in the zolbetuximab treatment arm and 12.2 months in the placebo treatment arm and the hazard ratio was 0.77.

Important-identified risks associated with zolbetuximab include nausea, vomiting, hypersensitivity and infusion-related reactions. The most common treatment emergent adverse events (AEs) (≥ 20%) were nausea, vomiting, anemia, neutropenia, diarrhea, constipation, abdominal pain, fatigue, asthenia, weight decreased, peripheral sensory neuropathy, decreased appetite, aspartate aminotransferase increased and edema peripheral. Treatment-emergent AEs resulting in interruption of zolbetuximab infusion occurred in 65.3% of patients and treatment emergent AEs resulting in permanent discontinuation of zolbetuximab occurred in 19.9% of patients. The most common adverse reactions resulting in treatment interruption or discontinuation were nausea and vomiting. The safety findings and risk mitigation measures are described in the Vyloy Product Monograph.

Overall, the benefit-risk profile of zolbetuximab, in combination with fluoropyrimidine- and platinum- containing chemotherapy, is considered favourable in the target patient population when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

The recommended dosing regimen of zolbetuximab with fluoropyrimidine- and platinum-containing chemotherapy is a single loading dose of 800 mg/m² intravenously followed by 600 mg/m² every 3 weeks or 400 mg/m² every 2 weeks.

An updated Risk Management Plan (RMP) for Vyloy was reviewed by Health Canada and considered acceptable.

The chemistry and manufacturing information submitted for Vyloy has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable.

For further details about Vyloy, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.