Gastric Adenocarcinoma

In the RATIONALE-305 trial, first-line tislelizumab + chemotherapy (CAPOX ([capecitabine + oxaliplatin] or 5-fluorouracil [5-FU] + cisplatin) significantly improved overall and progression-free survival (PFS) versus placebo + chemotherapy in unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric/gastroesophageal junction cancer (GC/GEJC). This exploratory analysis evaluated the comparative efficacy of tislelizumab + CAPOX versus tislelizumab + CAPOX or FOLFOX (5-FU, leucovorin, oxaliplatin) using a matching-adjusted indirect comparison (MAIC) approach...Although median PFS was numerically longer with the mixed chemotherapy backbone, these findings are exploratory in nature and warrant further investigation. ClinicalTrials.gov, RATIONALE-305 (NCT03777657); DisTinGuish (NCT04363801).

NOX4 emerges as a key regulator of the STAD inflammatory microenvironment and a robust prognostic biomarker. Its role in immune modulation and chemoresistance provides novel insights for developing precision therapeutic strategies in STAD.

Based on multi-omics integration, this study establishes PRGs signature as a robust prognostic biomarker for STAD, enabling risk stratification, molecular subtyping, and prediction of immunotherapy response while elucidating PRGs-mediated remodeling of the tumor-immune microenvironment. The online version contains supplementary material available at 10.1007/s10616-026-01014-7.

P3, N=600, Recruiting, NingBo Junyan Hongshi Biosciences Co., Ltd | Not yet recruiting --> Recruiting

P3, N=570, Not yet recruiting, Astellas Pharma Global Development, Inc.

P1, N=15, Active, not recruiting, Mayo Clinic | Trial completion date: Apr 2030 --> Jun 2029 | Recruiting --> Active, not recruiting

Zolbetuximab, a CLDN18.2-targeted monoclonal antibody, has been approved in combination with chemotherapy as a first-line treatment option for patients with HER2-negative and CLDN18.2-positive gastric adenocarcinoma...In conclusion, precision targeting of CLDN18.2 represents a promising approach in GC therapy, shifting from conventional chemotherapy to biomarker-guided strategies. Continued development of next-generation agents and rational combination therapies may enhance outcomes and expand benefit.

Low baseline CALLY was independently associated with shorter OS in this retrospective cohort. These findings support CALLY as a practical candidate prognostic biomarker, while external validation and time-to-event-based cut-off assessment are needed before clinical implementation.

In addition, a prognostic risk model derived from C3 subtype-associated genes (MUC16, RALA, and PCBD1) effectively stratified STAD patients and was associated with immune checkpoint expression and immune infiltration. Collectively, our findings identify an OLFM4-associated gastric cancer cell state with palmitoylation-related signatures and altered metabolic activities, highlighting its potential relevance to metabolic heterogeneity in gastric adenocarcinoma.

First-line disitamab vedotin with tislelizumab and S-1 demonstrated remarkable antitumor activity and a manageable safety profile in HER2-overexpressing advanced G/GEJ adenocarcinoma, warranting validation in randomized controlled trials.

Bavituximab plus pembrolizumab was well tolerated but showed modest activity, with greater benefit in biomarker-defined subgroups, supporting the biomarker-driven development of tumour microenvironment-targeting combinations in advanced gastric/GOJ adenocarcinomas. NCT04099641.

Exploratory analyses suggested no survival benefit with trastuzumab use across multiple versus single LOT(s) (nominal p=0.96); however, sequential use of ≥2 HER2-targeted therapy types with distinct mechanisms of action (MoAs) may be associated with longer survival compared to a single type (nominal p=0.009)...Exploratory analyses suggested possible associations between HER2-targeted therapy and improved outcomes; however, inherent biases preclude causal inference. The sequential use of HER2-targeted therapies with distinct MoAs may be associated with clinical benefit, requiring prospective validation (NCT05606094).