Claudin-18.2 targeting by zolbetuximab: results of SPOTLIGHT in perspective

Advances in biomarker-based targeted treatments have been slow for patients with stage IV gastro-oesophageal adenocarcinoma, with median overall survival for patients with human epidermal growth factor receptor 2 (HER2)-negative disease not exceeding a year. 1 Ter Veer E Haj Mohammad N van Valkenhoef G et al. The efficacy and safety of first-line chemotherapy in advanced esophagogastric cancer: a network meta-analysis. J Natl Cancer Inst. 2016; 108djw166 Crossref PubMed Scopus (84) Google Scholar Studies on the efficacy of combining chemotherapy with programmed death 1 (PD-1) inhibitors have changed the standard of care for these patients. 2 Lordick F Carneiro F Cascinu S et al. Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022; 33: 1005-1020 Summary Full Text Full Text PDF PubMed Scopus (112) Google Scholar In The Lancet, Kohei Shitara and colleagues 3 Shitara K Lordick F Bang Y-J 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; (published online April 14.)https://doi.org/10.1016/S0140-6736(23)00620-7 Summary Full Text Full Text PDF PubMed Scopus (15) Google Scholar report the results of the phase 3 SPOTLIGHT trial, which investigated the effect of claudin-18 isoform 2 (CLDN18.2) targeting, using the monoclonal antibody zolbetuximab plus mFOLFOX6 (modified folinic acid [or levofolinate], fluorouracil, and oxaliplatin regimen) in patients from 215 centres in 20 countries with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma. CLDN18.2 is a tight junction protein that is specifically expressed in around 40% of HER2-negative adenocarcinomas of the upper gastrointestinal tract and has little expression elsewhere in the body, making it an attractive therapeutic target. 283 patients (median age 62·0 years, IQR 51·0–69·0; 176 [62%] men and 107 [38%] women; 88 [31%] from Asia and 195 [69%] from non-Asian regions) were randomly assigned to zolbetuximab (800 mg/m2 loading dose followed by 600 mg/m2 every 3 weeks) plus mFOLFOX6 (every 2 weeks). 282 patients (median age 60·0 years, 50·0–69·0; 175 (62%) men and 107 [38%] women; 89 [32%] from Asia and 193 [68%] from non-Asian regions) were randomly assigned to placebo. The primary endpoint was progression-free survival by independent review committee in all randomly assigned patients. The median progression-free survival was 10·61 months (95% CI 8·90–12·48) in the zolbetuximab group versus 8·67 months (8·21–10·28) in the placebo group (hazard ratio [HR] 0·75, 95% CI 0·60–0·94; p=0·0066). The median overall survival was 18·23 months (95% CI 16·43–22·90) in the zolbetuximab group versus 15·54 months (13·47–16·53) in the placebo group (HR 0·75, 95% CI 0·60–0·93; p=0·0053). Treatment-emergent grade 3 or worse adverse events occurred in 242 (87%) of 279 patients in the zolbetuximab group versus 216 (78%) of 278 patients in the placebo group. Treatment-related deaths occurred in five (2%) patients in the zolbetuximab group versus four (1%) patients in the placebo group. 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 trialTargeting CLDN18.2 with zolbetuximab significantly prolonged progression-free survival and overall survival when combined with mFOLFOX6 versus placebo plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Zolbetuximab plus mFOLFOX6 might represent a new first-line treatment in these patients. Full-Text PDF