Zolbetuximab plus chemotherapy versus immune checkpoint inhibitor regimens by programmed death-ligand 1 combined positive score in locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma: a Bayesian network meta-analysis

BACKGROUND: In this network meta-analysis (NMA), efficacy of first-line (1L) zolbetuximab and immune checkpoint inhibitors (ICIs) was compared across programmed death-ligand 1 [PD-(L)1] combined positive score (CPS) levels in patients with locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma in global trials. MATERIALS AND METHODS: Studies evaluating zolbetuximab or ICIs plus chemotherapy as 1L treatments among adults with LA unresectable or mG/GEJ adenocarcinoma were included. A Bayesian fixed-effects NMA compared overall survival (OS) and progression-free survival (PFS) across treatments in PD-(L)1 CPS subgroups (CPS ≥1 to <5; ≥5 to <10; or ≥10). Because PD-(L)1 CPS is a biologically and clinically validated treatment effect modifier for ICIs, CPS-specific hazard ratios were used for ICIs but not zolbetuximab, which targets claudin 18 isoform 2 (CLDN18.2). Sensitivity analyses of PD-(L)1 CPS ≥10 leveraged patients with optimal zolbetuximab exposure-those who did not experience nausea/vomiting leading to inadequate dose exposure or discontinuation. RESULTS: Five regimens (zolbetuximab, pembrolizumab, tislelizumab, or nivolumab plus chemotherapy, and chemotherapy alone) were included. In PD-(L)1 CPS ≥1 to <5, zolbetuximab showed similar or numerically favorable OS and PFS versus ICIs. In PD-(L)1 CPS ≥5 to <10, zolbetuximab had numerically favorable OS and PFS versus ICIs. In PD-(L)1 CPS ≥10, ICIs had numerically favorable OS and PFS versus zolbetuximab. However, in sensitivity analyses, among patients with optimal zolbetuximab exposure, zolbetuximab showed similar OS and PFS to ICIs. CONCLUSIONS: These findings support a biomarker-informed treatment approach in human epidermal growth factor receptor 2 (HER2)-negative, CLDN18.2-positive advanced gastric/GEJ adenocarcinoma. In PD-(L)1 CPS ≥1 to <10, zolbetuximab plus chemotherapy demonstrated consistent efficacy and may represent a relevant option beyond PD-(L)1-driven selection. In CPS ≥10, zolbetuximab remained clinically meaningful, with efficacy comparable to select ICI-based regimens when exposure is optimized. Results should be interpreted cautiously given these are indirect comparisons and warrant confirmation in prospective studies.