Precision Medicine for Molecularly Targeted Agents and Immunotherapies in Early-Phase Clinical Trials

Abstract

Precision medicine in oncology promises the matching of genomic, molecular, and clinical data with underlying mechanisms of a range of novel anticancer therapeutics to develop more rational and effective antitumor strategies in a timely manner. However, despite the remarkable progress made in the understanding of novel drivers of different oncogenic processes, success rates for the approval of oncology drugs remain low with substantial fiscal consequences. In this article, we focus on how recent rapid innovations in technology have brought greater clarity to the biological and clinical complexities of different cancers and advanced the development of molecularly targeted agents and immunotherapies in clinical trials. We discuss the key challenges of identifying and validating predictive biomarkers of response and resistance using both tumor and surrogate tissues, as well as the hurdles associated with intratumor heterogeneity. Finally, we outline evolving strategies employed in early-phase trial designs that incorporate omics-based technologies.

Keywords: early-phase trials; immunotherapy; precision medicine.

Figure 1

Roadmap of how patients are referred, matched, and enrolled onto different types of early-phase trials depending on their molecular profiles. Patients with refractory cancers who provide their consent will undergo molecular profiling of tumor and surrogate tissues as illustrated above. Abbreviations: NGS, next-generation sequencing; WES, whole-exome sequencing; WGS, whole-genome sequencing; IHC, immunohistochemistry; cfDNA, circulating cell free DNA; CTCs, circulating tumor cells.