Clinical translation of CLDN18.2 and FGFR2b targeting in gastric cancer through assay thresholds and combination strategies

CLDN18.2-directed therapy has expanded biomarker-selected treatment options for gastric and gastroesophageal junction adenocarcinoma, whereas FGFR2b-directed therapy has shown clinical activity but remains investigational. Clinical interpretation depends on treatment-specific assays, thresholds, sampling quality, and the strength of evidence supporting each intervention. This review distinguishes evidence-supported clinical practice from exploratory biomarker strategies and author-proposed conceptual frameworks. We synthesized clinical and translational evidence across immunotherapy-era standards of care, emphasizing trial design, diagnostic variability, intratumoral heterogeneity, treatment deliverability, and implementation barriers. Evidence was organized into three levels: prospective evidence supporting current practice, emerging clinical or translational evidence, and author-proposed hypotheses requiring prospective validation. SPOTLIGHT and GLOW provide randomized phase III evidence for zolbetuximab plus chemotherapy in patients selected with a treatment-specific CLDN18.2 assay and threshold. FAST and FIGHT provide supportive phase II evidence, while FORTITUDE-101 supplies phase III evidence for FGFR2b enrichment but with attenuation of the overall-survival effect at longer follow-up; FGFR2b-directed therapy therefore remains investigational. Genomic profiling, transcriptomics, multiplex immunofluorescence, digital pathology, and artificial intelligence-assisted pathology may complement IHC, but none currently replaces a validated protein-based companion diagnostic. Re-testing, dependency-first selection, cutoff engineering beyond validated criteria, and the deliverability gate remain hypothesis-generating or selectively applicable strategies rather than established standards. Current clinical implementation should remain anchored to treatment-specific companion diagnostics, regulatory criteria, and prospective trial evidence. Complementary biomarkers and adaptive re-testing strategies are promising but require prospective validation. The dependency-first, cutoff-engineering, and deliverability frameworks are presented as research hypotheses and not as clinical recommendations.