JULY 2023LIFE SCIENCES REVIEW 19in multiple tumor types among biomarker defined populations within the same trial structure. The overarching protocol should be designed to answer multiple questions, constituting a collection of trials and cohorts that share key design components for better coordination than that of individual trials conducted independently. The selection of endpoints, comparators and statistical analysis are critical to define for different tumor types in each of the trial arms or cohorts.Another key consideration is to preselect patients for therapies using a predictive biomarker. Novel discoveries have led to the development of drugs tailored to the molecular profile, thus increasing a demand for finding appropriate biomarker-selected patients. Histology-agnostic trial design has greatly facilitated the evaluation and approval of new drugs within small cohorts of orphan cancers which previously challenged the design of histology-dependent molecular trials. The emergence of mutational signature allows for tailoring of therapy treatment to target the patients' genetic aberrant and their independent tumor types. The biomarker test then needs to be analytically validated and its clinical utility established in order to be applied to patient selection.The FDA requires substantial evidence of efficacy and safety based on direct or surrogate markers of clinical benefit. For example, in the case of larotrectinib and entrectinib, the rarity of the NTRK fusions resulted in a lack of feasibility for a standalone analysis, thus necessitating a larger, pooled analysis. While randomized clinical trials may not be feasible for enrolling multiple tumor types, larger confirmatory post-marketing studies are likely required to confirm tissue-agnostic activity for approval. The lack of a comparator group prevents a survival-based efficacy assessment, necessitating the use of surrogate endpoints like objective response rate (ORR). Future approvals should pay heed to strong scientific rationale and consistent clinical response for all studied tumor types, as well as follow up on the accelerated approval of the large confirmatory, non-randomized clinical trials.Tissue-agnostic drug approvals represent a paradigm shift in drug development, and agnostic-histology approvals will continue to increase and improve with an enhanced understanding of cancer biology and therapeutics development, along with improved technology. Clinical investigators and regulators should be prepared to address potential challenges to support the development of new promising agents to treat cancer. Tissue-agnostic drug approvals represent a paradigm shift in drug development, and agnostic-histology approvals will continue to increase and improve with an enhanced understanding of cancer biology and therapeutics development, along with improved technology
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