Tumor-Agnostic Drug Development

The growth in the availability of comprehensive, clinical-grade molecular profiling platforms has led to a rise in the number of predictive biomarkers that have been incorporated into therapeutic paradigms for various cancers. These advances in sequencing have likewise led to an increase in the identification of novel, putative genomic and genetic biomarkers of therapeutic efficacy. Drug development paradigms have had to adapt to a number of challenges in this era, including the decreasing frequencies of these alterations and their identification across multiple tumor histologies.1,2 Select clinical trials have thus evolved to incorporate a strong focus on tumor-agnostic drug development, a strategy for enriching for novel targets regardless of tumor site of origin. Tumor-agnostic patient inclusion on clinical trials is not a novel concept. The classic phase I dose escalation design that attempts to establish a recommended phase II dose is a histology-independent endeavor that only subsequently selects for specific cancers in later-phase testing.3-5 The conceptual advance with tumor-agnostic drug development is that trial designs have co-opted this strategy by specifically enrolling molecularly enriched patients to establish efficacy data in phase I expansion cohorts and phase II studies.6,7 In general, these studies fulfill the following features that are typical of a “basket trial”: (1) cancers are enriched for one or more molecular alterations, (2) these alterations have a reasonable likelihood of predicting response to a particular therapy based on preclinical functional and/or computational modeling, and (3) these alterations are found across a variety of cancers.8,9 The first generation of basket trials was characterized by the exploration of a validated biomarker in one histology and the exploration of the predictive nature of that biomarker in other cancers. The VE-BASKET trial is an example of such an approach, leveraging the known efficacy of BRAF-directed therapy in BRAFV600E-mutant melanomas.10 In this phase II, multicenter, international trial, 122 patients with seven different BRAFV600E-mutant nonmelanoma cancers, including gastrointestinal, thoracic, head and neck, thyroid, and hematologic malignancies, were treated with vemurafenib. Noteworthy activity was achieved in non–small cell lung cancer and Erdheim–Chester disease (overall response rates of 43% and 42% respectively), resulting in the U.S. Food and Drug Administration (FDA) granting breakthrough designation for the latter. Moreover, substantial activity was noted in patients with