Zolbetuximab Accepted For Regulatory Review for Gastric/GEJ Cancer in Europe

“Patients with gastric cancer in Europe face extremely low 5-year survival rates regardless of their disease stage, and innovative therapies that extend survival are needed,” said Moitreyee Chatterjee-Kishore, PhD, MBA.

The European Medicines Agency (EMA) will review a marketing authorization application (MAA) for zolbetuximab (IMAB362), a Claudin 18.2 (CLDN18.2)­–targeting monoclonal antibody for the frontline treatment of patients with locally advanced unresectable or metastatic, HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to a press release from Astellas Pharma.¹

Findings from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials support the MAA.

The phase 3 SPOTLIGHT trial assessed zolbetuximabin combination with oxaliplatin, leucovorin, and fluorouracil (mFOLFOX6).² The zolbetuximab regimen yielded a significant reduction in the risk of progression or death over placebo (HR, 0.75; 95% CI, 0.60-0.94; P = .0066). Median progression-free survival (PFS) in the experimental arm was 10.61 months (95% CI, 8.90-12.48) compared with 8.67 months (95% CI, 8.21-10.28) in the placebo arm.

Additionally, the investigators behind thephase 3 GLOW trial assessed the zolbetuximab in combination with capecitabine and oxaliplatin (CAPOX).³ The zolbetuximab regimen produced a 12-month PFS rate of 35% vs 19% with placebo; the corresponding figures at 24 months were 14% vs 7%, respectively. Median PFS was 8.21 months (95% CI, 7.46-8.84) with zolbetuximab vs 6.80 months (95% CI, 6.14-8.08) with placebo (HR, 0.687; 95% CI, 0.544-0.866; P = .0007).

A recommendation regarding the MAA from the EMA Committee for Medicinal Products for Human Use (CMHP) is expected to take place in 2024.

“Patients with gastric cancer in Europe face extremely low 5-year survival rates regardless of their disease stage, and innovative therapies that extend survival are needed,” Moitreyee Chatterjee-Kishore, PhD, MBA, senior vice president and head of immune-oncology development at Astellas, said in the press release.¹

“The EMA's acceptance of the zolbetuximab MAA continues a cascade of regulatory milestones for Astellas that are aimed at bringing a new option to patients with advanced gastric and gastroesophageal junction cancer.”

Zolbetuximab binds to CLDN18.2, a transmembrane protein, on the surface of gastric epithelial cells. This is designed to induce cancer cell death by activating antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.

The double-blind, randomized SPOTLIGHT study included 565 patients across 215 locations in North America, Australia, Europe, South America, and Asia. In the first treatment cycle, the experimental regimen consisted of intravenous zolbetuximab at a dose of 800 mg/m² on day 1 and 600 mg/m² on day 22 followed by leucovorin at a dose of 400 mg/m², levofolinate at 200 mg/m², fluorouracil bolus at 200 mg/m² followed by a 2400 mg/m² infusion, and oxaliplatin at 85 mg/m², on days 1, 15, and 29.

The GLOW trial is a double-blind, randomized study with an enrollment of 507 patients across 166 locations distributed globally. Patients in the experimental arm received CAPOX in addition to intravenous zolbetuximab at a dose of 800 mg/m² on the first day of the first cycle, followed by 600 mg/m² on the first day of subsequent cycles once every 3 weeks. From cycle 9 onward, patients received zolbetuximab at 600 mg/m² once every 3 weeks plus capecitabine.

The primary end point of both trials is PFS. Secondary end points for both include overall survival, objective response rate, and duration of response.

The zolbetuximab has also received priority review from the FDA for those with CLDN18.2-positive, locally advanced, unresectable or metastatic, HER2-negative gastric or GEJ carcinoma.⁴

References

1. European Medicines Agency accepts Astellas' Marketing Authorization Application for zolbetuximab. News Release. Astellas Pharma Inc. July 13, 2023. Accessed July 14, 2023. https://bit.ly/43ljoLC
2. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2023;401(10389):1655-1668. doi:10.1016/S0140-6736(23)00620-7
3. Xu R, Shitara K, Ajani JA, et al. Zolbetuximab + CAPOX in 1L claudin-18.2+ (CLDN18.2+)/HER2− locally advanced (LA) or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: primary phase 3 results from GLOW. J Clin Oncol. 2023;41(suppl 36):405736. doi:10.1200/JCO.2023.41.36_suppl.405736
4. Astellas announces U.S. FDA grants priority review for zolbetuximab biologics license application. News release. Astellas Pharma Inc. July 6, 2023. Accessed July 14, 2023. https://shorturl.at/egzU1