Novel clinical trial designs emerging from the molecular reclassification of cancer

Abstract

Next-generation sequencing has revealed the disruptive reality that advanced/metastatic cancers have complex and individually distinct genomic landscapes, necessitating a rethinking of treatment strategies and clinical trial designs. Indeed, the molecular reclassification of cancer suggests that it is the molecular underpinnings of the disease, rather than the tissue of origin, that mostly drives outcomes. Consequently, oncology clinical trials have evolved from standard phase 1, 2, and 3 tissue-specific studies; to tissue-specific, biomarker-driven trials; to tissue-agnostic trials untethered from histology (all drug-centered designs); and, ultimately, to patient-centered, N-of-1 precision medicine studies in which each patient receives a personalized, biomarker-matched therapy/combination of drugs. Innovative technologies beyond genomics, including those that address transcriptomics, immunomics, proteomics, functional impact, epigenetic changes, and metabolomics, are enabling further refinement and customization of therapy. Decentralized studies have the potential to improve access to trials and precision medicine approaches for underserved minorities. Evaluation of real-world data, assessment of patient-reported outcomes, use of registry protocols, interrogation of exceptional responders, and exploitation of synthetic arms have all contributed to personalized therapeutic approaches. With greater than 1 × 10¹² potential patterns of genomic alterations and greater than 4.5 million possible three-drug combinations, the deployment of artificial intelligence/machine learning may be necessary for the optimization of individual therapy and, in the near future, also may permit the discovery of new treatments in real time.

Keywords: N‐of‐1; cancer; personalized medicine; precision medicine; tissue agnostic.

FIGURE 1

New era of multiomics. Genomics is the tip of the iceberg. The transcriptome, proteomics, functional impact, epigenetic changes, metabolomics, immunomics, and the microbiome are all tools that will be integrated into future precision medicine therapeutic approaches. Artificial intelligence can help guide interpretation and integration of multi‐omics data to optimize therapy. Created with biorender.com.

FIGURE 2

Transition from drug‐centered therapeutic strategies (the drugs are the center of the universe, and patients are found to fit the drugs based on their diagnostic category; hence, all patients within a diagnostic category receive the same drugs, and the efficacy of the drug regimen in that subgroup of patients is evaluated) to a patient‐centered (N‐of‐1) focus (patients are the center of the universe, and drugs are found to fit the patient's tumor's unique portfolio of molecular aberrations; hence, every patient receives a personalized set of drugs) for precision medicine trials. In the patient‐centered (N‐of‐1) trials, the efficacy of the algorithm that matches patients to drugs, rather than the efficacy of individual drug regimens, is evaluated. Created in biorender.com.