Tumor-Agnostic and Histology-Tuned Targeted Therapies in Gastrointestinal Cancers: NTRK and RET Fusions and the Evolving Role of Molecular Basket Strategies.

Tumor-agnostic targeted therapy has expanded precision oncology by allowing selected molecular alterations to guide treatment across conventional organ boundaries. In gastrointestinal (GI) cancers, however, actionability is not uniformly independent of histology. This narrative review examines NTRK and RET fusions as paradigmatic tumor-agnostic targets and contrasts them with histology-tuned or GI-specific fusion-directed strategies, particularly NRG1 fusion-positive pancreatic adenocarcinoma and cholangiocarcinoma. Targeted PubMed/MEDLINE and regulatory-agency searches were updated through August 3, 2026. In the initial 55-patient larotrectinib analysis, ORR was 75% by independent review and 80% by investigator assessment; the subsequent expanded pooled analysis reported an investigator-assessed ORR of 79%. By contrast, the dedicated NAVIGATE GI cohort reported an independent-review ORR of 28% across GI cancers and 44% in colorectal cancer. These estimates derive from different cohorts and assessment methods and should not be interpreted as a formal cross-trial comparison. Mature TRIDENT-1 data support repotrectinib in both TRK inhibitor-naive and pretreated disease, including solvent-front mutations. Selpercatinib received traditional US approval in July 2026, whereas zenocutuzumab provides GI-specific options for NRG1 fusion-positive pancreatic and biliary cancers. We separate two dimensions of clinical portability: whether response magnitude is preserved across histologies and whether drug choice, combination, or treatment sequence must be modified for a specific tumor type. MSI-H/dMMR shows high magnitude portability with histology-specific positioning, whereas available dedicated GI data for NTRK fusion illustrate that a tumor-agnostic label does not guarantee a uniform effect size across histologies. Practical implementation requires quantitative prevalence estimates, appropriately selected DNA- and RNA-based testing, recognition of false-positive and false-negative pan-TRK immunohistochemistry, molecular tumor-board interpretation, timely access, and resistance-informed reprofiling. Tumor-agnostic approvals create opportunities, but GI-specific biology determines how reliably and when those opportunities should be used.