Drug Development in Tissue-Agnostic Indications

Simple Summary The primary goal of any intervention in oncology is to improve overall survival and/or quality of life. The gold-standard approach to demonstrate that this goal has been achieved is a randomized controlled clinical trial. A better understanding of cancer biology has led to the molecular segmentation of cancer, with some molecular alterations occurring across cancer types. Whereas the ancestral paradigm of drug development has evaluated new drugs in specific cancer types, the development of drugs targeting rare molecular alterations across cancer types has challenged this ancestral paradigm. Novel clinical trial designs have emerged to address this new paradigm, including basket trials and precision medicine trials that use each patient as his/her own control to assess the efficacy of a new treatment. We review here the opportunities and challenges of these new clinical trial designs. A better understanding of cancer biology has led to the development of targeted therapies specifically designed to modulate an altered molecular pathway in the cancer cells or their microenvironment. Despite the identification of molecular targets across cancer types, most of targeted therapies were developed per cancer type. In this ancestral paradigm, randomization was the gold-standard approach for market access. Randomization of large patient populations was feasible for drugs developed in common cancer types but more challenging in rare cancer types. The traditional paradigm of drug development in oncology was further challenged by the ever-expanding molecular segmentation of cancer with ever-smaller subgroups of patients who might benefit from specific targeted therapies or immunotherapies and the identification of molecular alterations against which drugs may be effective across cancer types. In this novel drug development paradigm, novel ways of evaluating the efficacy of drugs are highly needed in these small patient populations. One approach is to use each patient as his/her own control by comparing the efficacy of a drug to the efficacy of prior treatments received. This approach allows to overcome patient heterogeneity, especially in a tissue-agnostic drug development paradigm.