Gastric cancer: from biomarkers to functional precision medicine

biomarkers
drug development
gastric cancer
immunotherapy
oncology
precision medicine
targeted therapy
tcga subtypes
  • Current Landscape: Treatment for advanced gastric cancer is rapidly evolving beyond chemotherapy, with approved targeted agents including Trastuzumab (HER2), Zolbetuximab (CLDN18.2), and Pembrolizumab/Nivolumab (PD-L1).
  • Emerging Targets: Key areas of development include novel Antibody-Drug Conjugates (ADCs), the anti-FGFR2b antibody Bemarituzumab, and bispecific antibodies to overcome resistance mechanisms and improve response rates.
  • Precision Medicine Goal: The future of GC therapy relies on integrating multi-omics analysis (biomarkers) with functional drug testing on patient-derived models (organoids) to enable individualized treatment selection and improve patient survival.
Published

23 January 2026

PubMed: 40555635 DOI: 10.1016/j.molmed.2025.05.007 Overview generated by: Gemini 2.5 Flash, 10/12/2025

Overview and Context

This review provides an update on the evolving treatment strategies for advanced Gastric Cancer (GC), focusing specifically on immune and targeted therapies, and discusses how the integration of novel molecular and functional approaches can advance personalized medicine. GC remains a deadly disease, and treatment options for advanced stages are limited, prompting a rapid evolution in the therapeutic landscape.

Molecular Subtypes and Biomarkers

The molecular classification of GC is essential for biomarker-directed therapy selection. The Cancer Genome Atlas (TCGA) established four primary molecular subtypes:

  1. Chromosomal Instability (CIN): Comprising nearly half of GC cases (49.8%), this subtype is marked by frequent TP53 mutations and large-scale genomic rearrangements, including amplifications of Receptor Tyrosine Kinases (RTKs), which are potential actionable targets.
  2. Microsatellite Instability (MSI): Accounting for 21.7% of cases, this subtype is hypermutated due to defects in mismatch repair genes, resulting in higher immunogenicity and an enhanced response to immune checkpoint blockade.
  3. Genomically Stable (GS): This subtype (19.7%) has a low mutational burden, harbors few driver mutations, is often associated with diffuse GC, and typically responds poorly to chemo- and immunotherapy.
  4. Epstein-Barr Virus (EBV): The smallest subtype (8.8%), characterized by high frequency of PIK3CA alterations.

Current Approved Treatment Landscape

The standard treatment backbone for metastatic GC is a platinum-fluoropyrimidine doublet chemotherapy (e.g., FOLFOX or CapOx), which is complemented by targeted antibodies based on biomarker expression:

  • HER2-Positive Disease: Trastuzumab combined with chemotherapy is approved for first-line treatment. The anti-PD-1 inhibitor Pembrolizumab is also approved in combination with trastuzumab and chemotherapy for HER2-positive GC with PD-L1 Combined Positivity Score (CPS) $$1. The Antibody-Drug Conjugate (ADC) Trastuzumab Deruxtecan (T-DXd) is approved for second-line therapy in trastuzumab-refractory cases.
  • Immune Checkpoint Blockade: PD-1 inhibitors (Pembrolizumab or Nivolumab) are approved in combination with chemotherapy for PD-L1-expressing tumors (CPS $$1 or $$5, depending on the drug and HER2 status).
  • CLDN18.2-Positive Disease: Zolbetuximab, an anti-CLDN18.2 antibody, has recently been approved for first-line treatment in HER2-negative cases, based on Phase 3 trials demonstrating significant progression-free survival (PFS) prolongation.
  • Second-Line (HER2-Negative): The anti-VEGFR2 antibody Ramucirumab is standard of care, often combined with paclitaxel.

Emerging Targets and Future Directions

The field is rapidly advancing with several promising new drug classes and targets under investigation:

  • Antibody-Drug Conjugates (ADCs): The success of T-DXd has accelerated the development of ADCs targeting other antigens, including CLDN18.2, DKK1, TROP2, and CEACAM5, offering new avenues for targeted drug delivery.
  • FGFR2 Inhibition: The antibody Bemarituzumab, which targets the FGFR2b isoform, showed a compelling increase in median overall survival (24.7 months vs 11.1 months for placebo) in the FGFR2b-positive subgroup of the Phase 2 FIGHT trial, with Phase 3 trials currently ongoing.
  • Immunotherapy Combinations: Bispecific antibodies targeting PD-1 and other immunomodulatory proteins (like CTLA-4 or TIGIT) are in clinical trials as a potential next step to enhance antitumor immune responses beyond single checkpoint blockade.
  • DNA Damage Response/Cell Cycle: Although Phase 3 trials for PARP inhibitors (Olaparib) failed to meet their primary endpoint for overall survival, inhibitors of DNA damage response (DDR) kinases (ATM/ATR, CHK1/2, WEE1, CDK2) are being explored, particularly for CIN tumors.

Functional Precision Medicine

The ultimate goal is to move toward personalized oncology. This requires the integration of high-throughput molecular diagnostics and functional precision medicine. Functional drug testing on patient-derived models (like organoids or xenografts) is emerging as a critical tool to complement multi-omics analyses and predict therapy response, which is necessary to optimize treatment selection and improve patient survival.