Paradigms in cancer drug development: A universe with many galaxies

Cytotoxic chemotherapeutics (CHTs) have been the backbone cancer therapy for many years. Recently, a rapidly growing body of evidence has demonstrated the interdependence of cancer genetics, epigenetics, and immunology, giving rise to the generation of new promising compounds. The development of new molecularly targeted agents (MTAs), immune checkpoint-targeted monoclonal antibodies (ICT mAbs), and epigenetic drugs (EPDs) has increased the ready-to-use arsenal for patients with different cancers, but at the same time, has resulted in many substantial changes in clinical trial design, altering the early drug development (EDD) landscape. Despite sharing common developmental principles, the significant differences in their mechanisms of action (MoAs) have led researchers to reconsider previous assumptions regarding the design and execution of Phase I clinical trials (Ph1), leading to the recognition of four established paradigms in oncology. In this chapter, we review drug development evolution with a broad view of the major differences in EDD between these four paradigms, namely CHTs, MTAs, ICT mAbs, and EPDs, addressing many of the controversial issues and challenges that helped shape them. Only a comprehensive view of their main characteristics will enable successful design of future therapeutic options.