Developing Drugs for Tissue‐Agnostic Indications: A Paradigm Shift in Leveraging Cancer Biology for Precision Medicine

Abstract

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 preclinical and clinical studies, to date only a few biomarker‐driven, tissue‐agnostic indications have seen approval by the US Food and Drug Administration (FDA). These approvals include pembrolizumab in microsatellite instability‐high or mismatch repair deficient 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 that drugs targeting tissue‐agnostic indications will face.

Precision Medicine in Osteosarcoma: MATCH Trial and Beyond

“…Moreover, the availability of molecular targeted drugs is necessary, especially for more vulnerable populations such as paediatric patients or patients with a rare oncological disease, including OS patients. Recent advances in our understanding of molecular oncogenesis allowed for the stratification of malignancies into molecularly similar tumours, both within and across the tissue of origin, thus leading to the establishment of improved therapeutic treatments [ 27 ]. This strongly suggests that the development of targeted therapies can be better informed by tissue agnostic clinical trials, which represent a significant paradigm shift in precision medicine for cancer patients [ 27 ].…”

The Changing Face of Oncology Research, Drug Development, and Clinical Practice: Toward Patient‐Focused Precision Therapeutics

“…The Changing Face of Oncology Research, Drug Development, and Clinical Practice: Toward Patient-Focused Precision Therapeutics Karthik Venkatakrishnan 1,2, *, Piet H. van der Graaf 3,4 and Sarah A. Holstein 5, * Improved understanding of cancer biology fueled by a rapid escalation in our ability to harness multidimensional population data, coupled with diversification in therapeutic modalities through innovations in biotechnology, have transformed oncology therapeutics in recent years. This issue of Clinical Pharmacology and Therapeutics ( Figure 1) provides a tour of selected innovations in precision medicine, model-informed drug discovery and development frameworks, and the evolving clinical trial and regulatory landscape that have nurtured patient-focused oncology research, development, and clinical practice.…”

“…2 The field of solid-tumor oncology has begun to develop tissue agnostic therapies, such as the use of immune checkpoint inhibitors for microsatellite instability-high, or mismatch repair-deficient tumors, or the use of agents that target neurotrophic tropomyosin-related kinase fusions. 3,4 Tissue agnostic therapies, as well as precision oncology in general, require the identification of biomarkers and the development of uniformed testing for these biomarkers. 5 However, thus far, there continues to be heterogeneity in the assays used to measure particular biomarkers, uncertainty as to how to define the cutoffs that will determine whether a therapy will be offered to a particular patient, and uncertainty as to how to incorporate the results of many different biomarkers in the case of a complex system, such as the immune response.…”

Discovery of Next-Generation Tropomyosin Receptor Kinase (TRK) Inhibitors for Combatting Resistance Associated with Protein Mutation

“…ETV6-TRKC, QKI-TRKB, and TPR-TRKA) have been found and established as oncogenic drivers in lung cancers (prevalence of 3.3%) 8,9 , colorectal cancers (2.2%) 8 , glioblastomas (2.5%) 10 , pediatric gliomas (7.1%) 10 , thyroid cancers (16.7%) 11,12 , and mammary analogue secretory carcinoma (> 90%) 13 . Recently, an "age-and tumoragnostic" therapy, also well-known as a basket trial, was performed in patients with tumors harbouring the identical NTRK fusion partner, has reshaped the landscape of molecular targeted cancer therapies and represents an important milestone in precision medicine 14 . Thus, targeting TRK is an attractive therapeutic strategy for a wide variety of cancers.…”