Zolbetuximab Plus Chemotherapy Wins EU Approval for Advanced CLDN18.2+ Gastric/GEJ Cancer

The European Commission has approved frontline zolbetuximab plus chemotherapy for advanced, CLDN18.2-positive gastric and GEJ cancer.

The European Commission has approved zolbetuximab (Vyloy) plus fluoropyrimidine- and platinum-containing chemotherapy for the frontline treatment of adult patients with locally advanced, unresectable or metastatic, HER2-negative gastric and gastroesophageal junction (GEJ) cancer whose tumors are Claudin 18.2 (CLDN18.2) positive.1

Zolbetuximab is the first and only therapy approved in the European Union that targets CLDN18.2, a biomarker that was positively expressed in approximately 38% of patients with advanced gastric cancer across the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) clinical trials investigating the agent in this population. Data from SPOTLIGHT and GLOW supported the European Marketing Authorization of the agent in this indication.

In SPOTLIGHT, patients who received zolbetuximab plus mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) in the frontline setting (n = 283) achieved a median progression-free survival (PFS) of 10.61 months (95% CI, 8.90-12.48) vs 8.67 months (95% CI, 8.21-10.28) in patients who received first-line placebo plus mFOLFOX6 (n = 282; HR, 0.75; 95% CI, 0,60-0.94; P = .0053).2 The median overall survival (OS) was 18.23 months (95% CI, 16.43-22.90) in the zolbetuximab arm vs 15.54 months (95% CI, 13.47-16.53) in the placebo arm (HR, 0.75; 95% CI, 0,60-0.94; P = .0053).

In GLOW, patients who received frontline zolbetuximab plus CAPOX (capecitabine and oxaliplatin; n = 254) achieved a median PFS of 8.21 months vs 6.80 months among those who received placebo plus CAPOX (n = 253; HR, 0.687; 95% CI, 0.544-0.866; P = .0007).3 In these respective arms, the median OS was 14.39 months and 12.16 months (HR, 0.771; 95% CI, 0.615-0.965; P = .0118).

“Sadly, due to similar symptoms to more common stomach conditions, gastric and GEJ cancers are often diagnosed at the advanced or metastatic stage when treatment options have traditionally been relatively limited,” Zorana Maravic, chief executive officer of Digestive Cancers Europe, stated in a news release. “Ensuring timely diagnosis, followed by personalized treatment and care, will be essential to better survival and quality of life [QOL] for patients.”

SPOTLIGHT

The global, multicenter, double-blind, randomized SPOTLIGHT trial evaluated zolbetuximab plus mFOLFOX6 vs placebo plus mFOLFOX6 in the first-line setting for 565 patients with locally advanced, unresectable or metastatic, HER2-negative, CLDN18.2-positive gastric or GEJ adenocarcinoma.2 The primary end point was PFS. Secondary end points included OS, overall response rate (ORR), duration of response (DOR), safety and tolerability, and QOL parameters.

In the overall population, the ORR was 48% (95% CI, 42%-54%) in the zolbetuximab arm vs 48% (95% CI, 42%-54%) in the placebo arm. The median DOR was 9.00 months (95% CI, 6.87-10.25) with the zolbetuximab regimen vs 8.05 months (95% CI, 6.47-10.81) with the placebo regimen.

GLOW

The global, multicenter, double-blind, randomized GLOW trial evaluated zolbetuximab plus CAPOX vs placebo plus CAPOX in the first-line setting for 507 patients with locally advanced, unresectable or metastatic HER2-negative, CLDN18.2-positive gastric or GEJ adenocarcinoma.3 PFS served as the primary end point; key secondary end points included OS, ORR, DOR, safety and tolerability, and QOL parameters.

In the intention-to-treat population, the ORR was 42.5% (95% CI, 36.36%-48.85%) with zolbetuximab vs 40.3% (95% CI, 34.22%-46.64%) with placebo. The median DOR was 6.14 months (95% CI, 5.03-8.08) in the zolbetuximab arm vs 6.08 months (95% CI, 4.44-6.34) in the placebo arm.

Safety and Future Directions

In both SPOTLIGHT and GLOW, the incidence of serious treatment-emergent adverse effects (TEAEs) was similar between the zolbetuximab and control arms.1 The most common any-grade TEAEs reported in the zolbetuximab arms in both trials were vomiting, nausea, and decreased appetite.

“We are delighted to bring zolbetuximab, a first-in-class targeted treatment option, to patients in Europe where gastric and gastroesophageal cancers are the sixth leading cause of cancer-related death,” Moitreyee Chatterjee-Kishore, PhD, MBA, senior vice president and head of Immuno-Oncology Development at Astellas, added in the news release. “With zolbetuximab, we’re entering a new era in precision medicine for these advanced cancers, underpinning our ongoing commitment to pioneering scientific discovery that can advance patient outcomes.”

References

  1. Astellas receives approval from the European Commission for VYLOY (zolbetuximab) in combination with chemotherapy for advanced gastric and gastroesophageal junction cancer. News release. Astellas Pharma. September 20, 2024. Accessed September 20, 2024. https://newsroom.astellas.us/2024-09-20-Astellas-Receives-Approval-from-the-European-Commission-for-VYLOY-TM-zolbetuximab-in-Combination-with-Chemotherapy-for-Advanced-Gastric-and-Gastroesophageal-Junction-Cancer
  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. Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med. 2023;29(8):2133-2141. doi:10.1038/s41591-023-02465-7