Tumor-agnostic therapies (TATs)! |
This week, we will review the clinically approved tumor-agnostic therapies (TATs). TAT are biomarker-driven drugs, with different mechanisms of action, that specifically target cancer cells that express a given molecular alteration, independent of the cancer site, type, and histology 1. TATs are the main arsenal of precision oncology, the novel and individualized approach to cancer management that primarily relies on next-generation sequencing (NGS) to identify patient-unique molecular alterations. While there are no published clinical guidelines for TATs, the Japanese Society of Clinical Oncology (JSCO), the European Society of Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), Japanese Society of Medical Oncology (JSMO), and the Taiwan Oncology Society (TOS), have jointly published international expert consensus recommendations for TATs in patient with microsatellite instability and NTRK fusions in 2020 2. Since then, a total of seven TATs, targeting five unique alterations, have been FDA-approved for tissue-agnostic use in solid malignancies.
✅ Next-Generation Sequencing (NGS): the pillar of TATs
NGS has revolutionized the treatment paradigm for many solid malignancies, allowing the rapid, massive, and parallel DNA and RNA sequencing of tumor tissues3. Currently, the NCCN Biomarkers Compendium and the ESMO Precision Medicine Working Group recommend using tumor multigene NGS sequencing for broad molecular profiling and PD-L1 testing. Similarly, the Center for Medicare and Medicaid Services (CMS) provides National coverage for NGS testing, when testing is performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, for all patients with recurrent, relapsed, refractory, metastatic, or advanced staged (III and IV) cancer, making it widely available for practicing oncologists. It is via NGS testing that targets are identified and matched to specific therapeutic targets.
⭐ TATs: agents approved in clinical practice, and brief review of biomarkers
Currently, seven tumor-agnostic therapies are FDA-approved for routine clinical use when a CLIA-certified laboratory identifies a target. The table below summarizes the agents, drug class, mechanism of action, and target/indication: |
Table 1. Summary of FDA-approved TATs, drug class, mechanism of action, and biomarker/target. mAb: monoclonal antibody; PD1: programmed-death 1; PDL1-2: programmed-death ligands 1 and 2; dMMR: deficient mismatch repair; MSI: microsatellite instability, high; TMB-H: tumor mutation burden high; ATP: adenosine triphosphate
Notes on biomarkers -
dMMR/MSI-H: Deficient mismatch repair (MMR) system → mutations in one of the following MMR genes: MSH2, MSH6, MLH1, and PMS2 ⇒ accumulated frameshift mutations → somatic hypermutated status and microsatellite instability. ⇒ ↑↑↑ neoantigen.
- TMB-H: Tumor mutational burden, high, defined as ≥10 mutations/megabases of non-synonymous, somatic-only, mutations ↑↑↑ neoantigen.
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NTRK fusions: fusions within NTRK1, NTRK2, and NTRK3 genes, encoding tropomyosin receptor kinase (TRK) → constitutive activation of TRK and downstream oncogenic signaling (PI3K/AKT/mTOR, MAPK/ERK, PLC pathways.
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BRAF V600E: a point mutation in the serine/threonine kinase BRAF, with glutamic acid (E) replacing valine (V) and amino acid #600 → constitutive activation of BRAF, and downstream oncogenic MEK/ERK pathways.
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RET fusions: fusion secondary to chromosomal inversion/translocation → chimeric, constitutively active RET protein ⇒ activation of downstream oncogenic signaling (RAS/ERF, RAS/MAPK, PI3K/AKT, JNK)
📈 Landmark trials The table below summarizes the major results from the trial leading to the approval of the TAT: |
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