Target-Driven Tissue-Agnostic Drug Approvals-A New Path of Drug Development

Abstract

The regulatory approvals of tumor-agnostic therapies have led to the re-evaluation of the drug development process. The conventional models of drug development are histology-based. On the other hand, the tumor-agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology. The basket-like clinical trials with multiple cohorts allow clinicians to evaluate pan-cancer efficacy and toxicity. There are currently eight tumor agnostic approvals granted by the Food and Drug Administration (FDA). This includes two immune checkpoint inhibitors, and five targeted therapy agents. Pembrolizumab is an anti-programmed cell death protein-1 (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. The 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 a BRAF^V600E 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: V-Raf murine sarcoma viral oncogene homolog B V600E (BRAFV600E); dabrafenib and trametinib; dostarlimab-gxly; entrectinib; larotrectinib; microsatellite instability-high (MSI-H); neurotrophic tyrosine kinase (NTRK); pembrolizumab; precision oncology; rearranged during transfection (RET); selpercatinib; tissue-agnostic drug development; tumor mutational burden-high (TMB-H).

Figure 1

Overview of the FDA-approved tumor-agnostic treatment. Abbreviations: Microsatellite instability-high (MSI-H); mutations/megabase (mut/Mb); deficient mismatch repair (dMMR); programmed cell death protein-1 (PD-1); programmed cell death ligand-1 (PD-L1); tumor mutational burden-high (TMB-H); B-Raf pro-to-oncogene serine/threonine kinase (BRAF); human epidermal growth factor receptor 2 (HER2); mitogen-activated protein kinase (MEK); neurotrophic tyrosine receptor kinase (NTRK); rearranged during transfection (RET). X denotes the site of the action of the drug via their mechanism of action.

Figure 2

Timeline of FDA-approved immune checkpoint inhibitors for tissue-agnostic indications.

Figure 3

Timeline of FDA-approved targeted therapy for tissue-agnostic indications.