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 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
- 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
- Morgan E, Arnold M, Camargo MC, et al. The current and future incidence and mortality of gastric cancer in 185 countries, 2020–40: A population-based modelling study. eClinicalMedicine. 2022;47:101404.
- Stomach cancer: Causes, symptoms, diagnosis & treatment. Cleveland Clinic. Available from: https://my.clevelandclinic.org/health/diseases/15812-stomach-cancer
- Stomach (gastric) cancer survival rates [Internet]. Stomach (Gastric) Cancer Survival Rates. Available from: https://www.cancer.org/cancer/stomach-cancer/detection-diagnosis-staging/survival-rates.html
- Zhang J, Dong R, Shen L. Evaluation and reflection on Claudin 18.2 targeting therapy in Advanced gastric cancer. Chinese Journal of Cancer Research. 2020;32(2):263–70.
- Sahin U, Koslowski M, Dhaene K, Usener D, Brandenburg G, Seitz G, et al. Claudin-18 splice variant 2 is a Pan-Cancer target suitable for therapeutic antibody development. Clinical Cancer Research. 2008;14(23):7624–34.
- Cao W, Xing H, Li Y, Tian W, Song Y, Jiang Z, et al. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. Biomarker Research. 2022;10(1).
- Mauro G. Zolbetuximab and mfolfox6 survival in CLDN18.2+ advanced gastric/gej adenocarcinoma. Targeted Oncology. Targeted Oncology; 2023. Available from: https://www.targetedonc.com/view/zolbetuximab-and-mfolfox6-extends-survival-in-cldn18-2-advanced-gastric-gej-adenocarcinoma