Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial

Abstract

There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Claudin-18 isoform 2 (CLDN18.2) is expressed in normal gastric cells and maintained in malignant G/GEJ adenocarcinoma cells. GLOW (closed enrollment), a global, double-blind, phase 3 study, examined zolbetuximab, a monoclonal antibody that targets CLDN18.2, plus capecitabine and oxaliplatin (CAPOX) as first-line treatment for CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. Patients (n = 507) were randomized 1:1 (block sizes of two) to zolbetuximab plus CAPOX or placebo plus CAPOX. GLOW met the primary endpoint of progression-free survival (median, 8.21 months versus 6.80 months with zolbetuximab versus placebo; hazard ratio (HR) = 0.687; 95% confidence interval (CI), 0.544-0.866; P = 0.0007) and key secondary endpoint of overall survival (median, 14.39 months versus 12.16 months; HR = 0.771; 95% CI, 0.615-0.965; P = 0.0118). Grade ≥3 treatment-emergent adverse events were similar with zolbetuximab (72.8%) and placebo (69.9%). Zolbetuximab plus CAPOX represents a potential new first-line therapy for patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. ClinicalTrials.gov identifier: NCT03653507 .

Fig. 1. CONSORT diagram of GLOW study.

^a‘CLDN18.2-positive’ was defined as ≥75% of tumor cells with moderate-to-strong membranous CLDN18 staining as determined by central immunohistochemistry using the investigational VENTANA CLDN18 (43-14A) RxDx Assay. ^b‘Other’ represents patients whose tumors were CLDN18.2-positive but failed screening for other reasons, including laboratory findings, HER2 expression status, Eastern Cooperative Oncology Group (ECOG) performance status score, other exclusion criteria or withdrawal by patient. ^cIf patients discontinued from both zolbetuximab or placebo and CAPOX on the same day, all reasons for discontinuation were summarized; the sum of values for individual reasons for discontinuation is more than 212 for the zolbetuximab group and more than 213 for the placebo group. ^dOne patient randomized to the placebo plus CAPOX group received one dose of zolbetuximab as a protocol deviation and was moved to the zolbetuximab plus CAPOX group for the safety analysis set.

Fig. 2. PFS in the ITT population.

a, Kaplan–Meier PFS curves of all patients. b, Forest plots of PFS by subgroups.

Fig. 3. OS in the ITT population.

a, Kaplan–Meier OS curves of all patients. b, Forest plots of OS by subgroups.

Extended Data Fig. 1. PFS in the ITT population by investigator.

Kaplan-Meier curve of PFS in all patients. CAPOX, capecitabine plus oxaliplatin regimen; CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; mo., months; No., number; PFS, progression-free survival.

Extended Data Fig. 2. First occurrence of nausea and vomiting in the safety analysis set.

Events were counted if they did not occur in any previous onset interval. Individual data points are reported in Supplementary Tables 3 and 4. ^aThe onset day in the onset interval was defined as the date of onset minus the date of first dose plus 1. CAPOX, capecitabine plus oxaliplatin regimen.

Extended Data Fig. 3. All occurrence of nausea and vomiting in the safety analysis set.

Individual data points are reported in Supplementary Tables 5 and 6. ^aThe onset day in the onset interval was defined as the date of onset minus the date of first dose plus 1. CAPOX, capecitabine plus oxaliplatin regimen.