Developing drugs for tissue agnostic indications: a paradigm shift in leveraging cancer biology for precision medicine.

Targeted therapies have reshaped the landscape of the development of cancer therapeutics. Recent biomarker driven, tissue agnostic clinical trials represent a significant paradigm shift in precision cancer medicine. Despite their growth in pre-clinical and clinical studies, to date only a few biomarker driven, tissue agnostic indications have seen approval by the FDA. These approvals include pembrolizumab in microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as well as both larotrectinib and entrectinib in NTRK fusion positive tumors. Complex cancer biology, clinical trial design, and identification of resistance mechanisms represent some of the challenges that future tissue agnostic therapies have to overcome. In this review, we present a brief history of the development of tissue agnostic therapies, comparing the similarities in the approval of pembrolizumab, larotrectinib, and entrectinib for tissue agnostic indications. We also explore the future of tissue agnostic cancer therapeutics while identifying important challenges for the future of drug targeting tissue agnostic indications will face.