Understanding the Promise and Challenges of Tumor-Agnostic Therapy: Could One Size Really Fit All?

Tumor-agnostic therapies represent an evolving approach in oncology, shifting from conventional histology-based treatment models to strategies guided by molecular alterations. Regulatory approvals of therapies targeting tumors harboring genomic alterations such as NTRK and RET fusions, BRAF V600E mutation, and those with deficient mismatch repair (dMMR) and a high tumor mutational burden (TMB-H) have demonstrated clinical activity across multiple cancer types. However, responses to these therapies are not uniform across all tumors. This review examines the variability of clinical outcomes across different cancer histologies and the challenges associated with this tumor-agnostic treatment paradigm. Despite sharing the same molecular alterations, some malignancies, including pancreatic and colorectal cancers, demonstrate lower response rates due to tissue-specific resistance mechanisms such as bypass signaling pathways and co-occurring genomic alterations. We discuss how these biological differences influence treatment response and their implications for future drug development and clinical trial design. Addressing these biological and clinical complexities will be essential to optimize the use of tumor-agnostic therapies across diverse cancer types.