SPOTLIGHT: zolbetuximab plus chemotherapy prolongs PFS and OS in CLDN18.2+ metastatic gastric cancer

Primary results from the Phase III SPOTLIGHT (NCT03504397) trial demonstrated a significant survival benefit for patients with Claudin18.2 (CLDN18.2)-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma with a combination of zolbetuximab and mFOLFOX6. 1

Gastric cancer is the fifth most diagnosed cancer worldwide.2 As symptoms of early-stage gastric cancer are rare and overlap with those of common stomach-related issues, gastric cancer is often advanced by the time of diagnosis. 3 The standard treatment for patients with HER2-negative, metastatic gastric/GEJ adenocarcinoma is chemotherapy with mFOLFOX6, however, with a 5-year survival rate of 6%, there remains a major unmet need in regard to effective targeted treatment options for this patient population.2, 4

Zolbetuximab is an investigational first-in-class IgG1 monoclonal antibody targeted against CLDN18.2, a transmembrane tight junction protein expressed on the surface of malignant gastric epithelial cells. 5, 6 Although typically submerged in gastric mucosal cells, oncogenesis of gastric epithelial tissue leads to the exposure of CLD18.2 epitopes on the cell surface, providing a highly selective target for precision therapy in various cancers, including gastric and GEJ. 7 The specific binding of zolbetuximab to CLDN18.2 initiates cell death via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). 5

The international, double-blind, placebo-controlled SPOTLIGHT trial enrolled patients with previously untreated locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma and CLDN18.2 positivity. Eligible patients must have had moderate-to-strong CLDN18 staining in at least 75% of tumor cells, have HER2-negative disease, and an ECOG performance status of 0 or 1.

Patients were randomly assigned 1:1 to receive zolbetuximab plus mFOLFOX6 (n=283) or placebo plus mFOLFOX6 (n=282). The primary endpoint was progression-free survival (PFS) and secondary endpoints include overall-survival (OS), objective response rate (ORR), duration of response (DOR) and tolerability and quality-of-life parameters.

Median PFS with zolbetuximab plus mFOLFOX6 was 10.6 months (95% CI, 8.90-12.48) versus 8.6 months (95% CI, 8.21-10.28) with placebo plus mFOLFOX6, equating to a 25% reduction in the risk of disease progression or death (HR, 0.751; 95% CI, 0.589-0.942; P = 0.0066). The median OS was 18.23 months (95% CI, 16.43-22.90) with zolbetuximab plus mFOLFOX6 versus 15.54 months (95% CI, 13.47-16.53) with placebo plus mFOLFOX6 (HR, 0.750; 95% CI, 0.601-0.936; P = .0053). At 12, 24, and 36 months, the OS rates in the zolbetuximab and placebo arms, respectively, were 68% vs 60%, 39% vs 28%, and 21% vs 9%, respectively.

The most commonly reported treatment-related adverse events in the zolbetuximab plus mFOLFOX6 group were nausea (81.0% vs 60.8% in zolbetuximab vs placebo arms), vomiting (64.5% vs 34.5%), and decreased appetite (47.0% vs 33.5%). The rates of serious adverse events were similar in both treatment groups (44.8% zolbetuximab plus mFOLFOX6 vs 43.5% placebo plus mFOLFOX6). 1, 8

The results of SPOTLIGHT were presented during the 2023 ASCO Gastrointestinal Cancers Symposium by Kohei Shitara, MD, of the National Cancer Center Hospital East, in Kashiwa, Japan.

The promising results of SPOTLIGHT establishes the potential of zolbetuximab in combination with mFOLFOX as a new standard first-line targeted treatment for HER2-negative, CLDN18.2-positive gastric/GEJ cancer, supporting the role of CLDN18.2 as a biomarker in gastric and GEJ cancer.

Written by Ellie Jackson


  1. Shitara K, Lordick F, Bang Y-J, et al. Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) withclaudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: primary results from phase 3 SPOTLIGHT study. J Clin Oncol. 2023;41(suppl; abstr LBA292). doi:10.1200/JCO.2023.41.3_suppl.LBA292
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