Thein, K.Z.; Myat, Y.M.; Park, B.S.; Panigrahi, K.; Kummar, S. Target-Driven Tissue-Agnostic Drug Approvals—A New Path of Drug Development. Cancers 2024, 16, 2529, doi:10.3390/cancers16142529.
Thein, K.Z.; Myat, Y.M.; Park, B.S.; Panigrahi, K.; Kummar, S. Target-Driven Tissue-Agnostic Drug Approvals—A New Path of Drug Development. Cancers 2024, 16, 2529, doi:10.3390/cancers16142529.
Thein, K.Z.; Myat, Y.M.; Park, B.S.; Panigrahi, K.; Kummar, S. Target-Driven Tissue-Agnostic Drug Approvals—A New Path of Drug Development. Cancers 2024, 16, 2529, doi:10.3390/cancers16142529.
Thein, K.Z.; Myat, Y.M.; Park, B.S.; Panigrahi, K.; Kummar, S. Target-Driven Tissue-Agnostic Drug Approvals—A New Path of Drug Development. Cancers 2024, 16, 2529, doi:10.3390/cancers16142529.
Abstract
The regulatory approvals of tumor agnostic therapies have led to reevaluation of the drug development process. Conventional models of drug development are histology-based. On the other hand, tumor agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology. Basket-like clinical trials with multiple cohorts allow clinicians to evaluate pan-cancer efficacy and toxicity. There are currently 8 tumor agnostic approvals granted by the Food and Drug Administration (FDA). This includes two immune checkpoint inhibitors, and 5 targeted therapy agents. Pembrolizumab is an anti-PD-1 antibody that was the first FDA approved tumor agnostic treatment for unresectable or metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors in 2017. It was later approved for tumor mutational burden-high (TMB-H) solid tumors, although the TMB cut-off used is still debated. Subsequently, in 2021, another anti-PD-1 antibody, Dostarlimab was also approved for dMMR solid tumors in the refractory setting. Patients with fusion-positive cancers are typically difficult to treat due to their rare prevalence and distribution. Gene rearrangements or fusions are present in a variety of tumors. neurotrophic tyrosine kinase (NTRK) fusions are present in a range of pediatric and adult solid tumors in varying frequency. Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase (NTRK) fusion-positive cancers. Similarly, selpercatinib was approved for Rearranged During Transfection (RET) fusion-positive solid tumors. FDA approved the first combination therapy of dabrafenib, a B-Raf Proto-Oncogene Serine/Threonine Kinase (BRAF) inhibitor, plus trametinib, a mitogen-activated protein kinase (MEK) inhibitor for patients 6 months or older with unresectable or metastatic tumors (except colorectal cancer) carrying BRAFV600E mutation. The most recent FDA tumor agnostic approval is of fam-trastuzumab deruxtecan-nxki (T-Dxd) for HER2-positive solid tumors. It is important to identify and expeditiously develop drugs that have the potential to provide clinical benefit across tumor types.
Keywords
Tissue agnostic drug development; Pembrolizumab; Microsatellite instability-high (MSI-H); Tumor mutational burden-high (TMB-H); Dostarlimab-gxly; Larotrectinib; Entrectinib; Neurotrophic tyrosine kinase (NTRK); Dabrafenib and trametinib; V-Raf Murine Sarcoma Viral Oncogene Homolog B V600E (BRAFV600E); Selpercatinib; Rearranged during transfection (RET); Precision oncology.
Subject
Medicine and Pharmacology, Oncology and Oncogenics
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
