Zolbetuximab plus chemotherapy versus immune checkpoint inhibitor plus chemotherapy as first-line treatment for HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma: an anchored indirect meta-analysis.

Authors

Zixuan Wan, Yingxia Lan, Yuemin Ma, Siyan Peng, Ping Chen, Honglin Zhu, Yanming Wang, Zhixin Yu, Yixin Zhou

Published in

Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. Oct 26, 2026. Epub Oct 26, 2026.

Abstract

Immune checkpoint inhibitor plus chemotherapy (ICI+Chemo) and Zolbetuximab plus chemotherapy (ZOL+Chemo) are first-line options for HER2-negative advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. Lacking head-to-head trials, the optimal choice for dually eligible patients remains uncertain.
We performed a PRISMA-guided systematic review comparing the efficacy and safety of ZOL+Chemo and ICI+Chemo via adjusted indirect analysis (Bucher method), using chemotherapy as common comparator. Subgroup analyses evaluated effect modification by Programmed Death-Ligand 1 (PD-L1) expression.
Eleven RCTs (n=8445) were included. Versus chemotherapy, ICI+Chemo improved OS (HR, 0.79; 95% CI, 0.75-0.83; P< .001), PFS (HR, 0.72; 95% CI, 0.66-0.78; P < .001), and ORR (RR, 1.24; 95% CI, 1.18-1.30; P < .001). ZOL+Chemo improved OS (HR, 0.74; 95% CI, 0.65-0.83; P < .001) and PFS (HR, 0.66; 95% CI, 0.57-0.76; P < .001), with no significant ORR increase (RR, 1.06; 95% CI, 0.94-1.21; P = .346). Indirect comparisons showed no significant differences in OS (HR, 0.93; 95% CI, 0.81-1.06; P = .267) or PFS (HR, 0.92; 95% CI, 0.78-1.08; P = .310) between the two regimes. ZOL+Chemo showed lower ORR (RR, 0.86; 95% CI, 0.75-0.98; P = .027). Subgroup analyses suggested improved OS with ZOL+Chemo in PD-L1-low subgroups (CPS <1: HR, 0.81; CPS <5: HR, 0.82; CPS <10: HR, 0.85) and improved PFS in CPS <1 (HR, 0.76), whereas ORR disadvantage was in PD-L1 CPS ≥5 and ≥10. Safety outcomes were comparable, with fewer serious adverse events (RR, 0.66; 95% CI, 0.57-0.77; P < .001) for ZOL+Chemo.
ZOL+Chemo and ICI+Chemo provided comparable survival outcomes, with clinical differences by PD-L1 strata, response dynamics, and safety, supporting patient-centered selection and need for biomarker-harmonized head-to-head trials.

PMID:
42932139
Bibliographic data and abstract were imported from PubMed on 27 Oct 2026.

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