Esophagus to Small Intestine
Lancet. 2023;401(10389):1655−68
Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced un-resectable or metastatic gastric or gastroesophageal junction adenocarcinoma (SPOTLIGHT): A multicenter, ran-domized, double-blind, phase 3 trial
Background: Zolbetuximab, a monoclonal antibody targeting claudin-18 isoform 2 (CLDN18.2), has shown efficacy in patients with CLDN18.2-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gas-troesophageal junction adenocarcinoma. The authors report the results of the SPOTLIGHT trial, which investigated the efficacy and safety of first-line zolbetuximab plus mFOLFOX6 (modified folinic acid [or levofolinate], fluorouracil, and oxaliplatin regimen) versus placebo plus mFOL-FOX6 in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction ade-nocarcinoma.
Methods: SPOTLIGHT is a global, randomized, placebo-controlled, double-blind, phase 3 trial that enrolled patients from 215 centers in 20 coun-tries. Eligible patients were aged 18 years or older with CLDN18.2-positive (defined as ≥ 75% of tumor cells showing moderate-to-strong mem-branous CLDN18 staining), HER2-negative (based on local or central evaluation), previously untreated, locally advanced unresectable or meta-static gastric or gastroesophageal junction adenocarcinoma, with radiologically evaluable disease (measurable or non-measurable) according to Response Evaluation Criteria in Solid Tumors version 1.1; an Eastern Cooperative Oncology Group performance status score of 0 or 1; and ade-quate organ function. Patients were randomly assigned (1:1) via interactive response technology and stratified according to region, number of organs with metastases, and previous gastrectomy. Patients received zolbetuximab (800 mg/m2 loading dose followed by 600 mg/m2 every 3 weeks) plus mFOLFOX6 (every 2 weeks) or placebo plus mFOLFOX6. The primary end point was progression-free survival (PFS) assessed by in-dependent review committee in all randomly assigned patients. Safety was assessed in all treated patients.
Findings: Between June 21, 2018, and April 1, 2022, 565 patients were randomly assigned to receive either zolbetuximab plus mFOLFOX6 (283 patients; the zolbetuximab group) or placebo plus mFOLFOX6 (282 patients; the placebo group). At least 1 dose of treatment was administered to 279 of 283 patients (99%) in the zolbetuximab group and 278 of 282 patients (99%) in the placebo group. In the zolbetuximab group, 176 patients (62%) were male and 107 (38%) were female. In the placebo group, 175 patients (62%) were male and 107 (38%) were female. The median follow-up duration for PFS was 12.94 months in the zolbetuximab group versus 12.65 months in the placebo group. Zolbetuximab treatment showed a significant reduction in the risk of disease progression or death compared with placebo (hazard ratio [HR] = 0.75, 95% confi-dence interval [CI]: 0.60−0.94; p = 0.0066). The median PFS was 10.61 months (95% CI: 8.90−12.48) in the zolbetuximab group versus 8.67 months (95% CI: 8.21−10.28) in the placebo group. Zolbetuximab treatment also showed a significant reduction in the risk of death versus pla-cebo (HR = 0.75, 95% CI: 0.60−0.94; p = 0.0053). Treatment-emergent grade 3 or worse adverse events occurred in 242 of 279 patients (87%) in the zolbetuximab group versus 216 of 278 patients (78%) in the placebo group. The most common grade 3 or worse adverse events were nau-sea, vomiting, and decreased appetite. Treatment-related deaths occurred in 5 patients (2%) in the zolbetuximab group versus 4 patients (1%) in the placebo group. No new safety signals were identified.
Interpretation: Targeting claudin-18 isoform 2 (CLDN18.2) with zolbetuximab significantly prolonged progression-free survival and overall surviv-al when combined with mFOLFOX6 versus placebo plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, locally advanced unre-sectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Zolbetuximab plus mFOLFOX6 might represent a new first-line treatment in these patients.