Abstract
(1) Background: The oncology field has drastically changed with the advent of precision medicine, led by the discovery of druggable genes or immune targets assessed through next-generation sequencing. Biomarker-based treatments are increasingly emerging, and currently, six tissue-agnostic therapies are FDA-approved. (2) Methods: We performed a review of the literature and reported the trials that led to the approval of tissue-agnostic treatments and ongoing clinical trials currently investigating novel biomarker-based approaches. (3) Results: We discussed the approval of agnostic treatments: pembrolizumab and dostarlimab for MMRd/MSI-H, pembrolizumab for TMB-H, larotrectinib and entrectinib for NTRK-fusions, dabrafenib plus trametinib for BRAF V600E mutation, and selpercatinib for RET fusions. In addition, we reported novel clinical trials of biomarker-based approaches, including ALK, HER2, FGFR, and NRG1. (4) Conclusions: Precision medicine is constantly evolving, and with the improvement of diagnostic tools that allow a wider genomic definition of the tumor, tissue-agnostic targeted therapies are a promising treatment strategy tailored to the specific tumor genomic profile, leading to improved survival outcomes.