Precision before incision: neoadjuvant tumor-agnostic therapies

The emergence of tumor-agnostic therapies has fundamentally transformed precision oncology. Traditionally developed and approved for metastatic disease, nine therapies spanning immunotherapy, targeted agents, and antibody-drug conjugates now demonstrate a compelling rationale for earlier deployment in the neoadjuvant setting. This review examines the paradigm shift from last-resort to first-consideration approaches. Key advantages of neoadjuvant, biomarker-guided therapy include intervention prior to the development of therapeutic resistance, optimal immune system engagement, and opportunities for organ preservation. Single-agent programmed cell death protein-1 blockade has achieved a 100% complete response rate in mismatch repair-deficient rectal cancer with preserved organ function. Neurotrophic tyrosine receptor kinase (NTRK), rearranged during transfection (RET), and B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitors have demonstrated substantial responses that enable curative-intent surgery across malignancies. As precision oncology matures, the neoadjuvant tumor-agnostic approach exemplifies optimized therapeutic sequencing, potentially improving patient outcomes and quality of life.