Dr Klempner on the FDA Approval of Zolbetuximab for CLDN18.2+, HER2– Gastric or GEJ Adenocarcinoma

Samuel J. Klempner, MD, gastrointestinal oncologist, Massachusetts General Hospital, discusses the clinical implications of the FDA approval of zolbetuximab-clzb (Vyloy) for the first-line treatment of adult patients with Claudin 18.2 (CLDN18.2)–positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

On October 18, 2024, the FDA approved zolbetuximab in combination with fluoropyrimidine- and platinum-containing chemotherapy for patients with gastric or GEJ adenocarcinoma whose tumors express CLDN18.2, a novel biomarker in gastroesophageal cancers.

This approval was supported by data from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials, which demonstrated that zolbetuximab significantly improved progression-free survival and overall survival in patients with CLDN18.2-positive gastric and GEJ adenocarcinoma.

Zolbetuximab works by targeting CLDN18.2, leading to tumor cell destruction through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. According to Klempner, this mechanism, combined with chemotherapy, has shown synergistic effects, making zolbetuximab plus chemotherapy an effective first-line treatment option for patients with CLDN18.2-positive disease.

Findings from the SPOTLIGHT trial demonstrated that at a median follow-up of 12.94 months for the zolbetuximab group (n = 283) and 12.65 months for the placebo group (n = 282), zolbetuximab plus mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) elicited a median progression-free survival (PFS) of 10.6 months (95% CI, 8.9-12.5) compared with 8.7 months (95% CI, 8.2-10.3) for placebo plus mFOLFOX6 (HR, 0.751; 95% CI, 0.598-0.942; 1-sided P = .0066). An overall survival (OS) benefit was also observed in the zolbetuximab group (HR, 0.750; 95% CI, 0.601-0.936; P = .0053).

Additionally, the GLOW trial met its primary end point, showing that zolbetuximab plus CAPOX (capecitabine plus oxaliplatin) reduced the risk of progression or death by 31.3% compared with placebo plus CAPOX (HR, 0.687; 95% CI, 0.544-0.866; 1-sided P = .0007). Patients treated in the experimental arm (n = 254) achieved a median PFS of 8.2 months (95% CI, 7.5-8.8) compared with 6.8 months (95% CI, 6.1-8.1) for those given placebo plus CAPOX (n = 253). The respective 12- and 24-month PFS rates were 35% and 14% in the zolbetuximab arm, compared with 19% and 7%, respectively, in the placebo arm.

The median OS was 14.4 months (95% CI, 12.3-16.5) for the experimental arm vs 12.2 months (95% CI, 10.3-13.7) for the control arm (HR, 0.771; 95% CI, 0.615-0.965; 1-sided P = .0118)

Klempner concludes that this approval marks a significant milestone, introducing a new biomarker and targeted therapy for a patient population that has seen limited treatment advancements in recent years. The introduction of CLDN18.2 as a target offers oncologists a valuable tool for personalizing treatment, which may lead to better patient outcomes. He emphasizes the importance of integrating CLDN18.2 testing into diagnostic protocols to identify candidates for zolbetuximab, further underscoring the growing role of biomarker-driven therapies in the management of gastric and GEJ cancers.