Basket trials: From tumour gnostic to tumour agnostic drug development

Abstract

Molecular profiling provides the insight that specific genetic alterations can be detected across a wide range of different histologically characterised tumour types. Thus, the basic concept of basket trials (BTs) to target those genetic alterations with the same anti-tumour agents independent of the underlying tumour type was tumour agnostic. BTs can be divided into tumour gnostic, tumour semi-gnostic, and tumour agnostic trials which cover BTs of the conventional and the complex multiple-parallel type. At the beginning of the use of BTs, the expectation that they would function agnostically was dominating. This period was followed by an avalanche of experiments, analyses, and commentaries that underlined the importance of the microenvironment of tumours and thereby the impact of tissue also on molecularly targeted therapies. Intra-tumour heterogeneity with the phenomena of both intrinsic resistant cancer cell subclones and treatment-emergent acquired mutations that result in drug resistance as well as the co-occurrence of multiple potentially actionable molecular alterations within a tumour necessitate combinatorial treatment. However, this setting has only scarcely been addressed by BTs so far. Each of the various subtypes of BTs has contributed to meet the main goal of drug development, the approval of the agents tested. The position of BTs within the drug approval process and their potential impact on the off-label use of targeted agents are referred to as well. This review highlights the achievements reached with BTs along with failures. Selected issues of controversy are critically discussed, and potential solutions are addressed.

Keywords: Actionability; Basket trials; Master protocols; Molecular profiling; Multiple-parallel basket trials; Tumour agnostic.