Agnostic-Histology Approval of new drugs in Oncology: are we already there?

Over the last years, several molecular aberrations have been unevenly described across cancers, although the distinct functional relevance in each biological context is not yet fully understood. Novel discoveries have led to the development of drugs tailored according to the molecular profile of patients, thus increasing the likelihood of response among biomarker-selected patients. In this context, there has been a progressive redefinition of a precision medicine framework where evidence-based development and earlier approvals might be now driven by this molecular information. Innovative trial designs have greatly facilitated the evaluation and approval of new drugs in small cohorts of orphan cancers in which histology-dependent molecularly-defined trials might be logistically difficult. However, accelerated approvals based on this agnostic-histology development model have brought new clinical, regulatory and reimbursement challenges. In this article we will highlight many of the biologic issues and clinical trial design challenges characterizing the development of tissue-agnostic compounds. Also, we will review some of the key factors involved in the development of pembrolizumab and larotrectinib, the first 2 drugs that have been approved by the US Food and Drug Administration in an histology-agnostic manner. Since we anticipate that agnostic-histology approvals will continue to grow, we aim to provide an insight into the current panorama of targeted drugs that are following this strategy and some premises to take into consideration. Clinicians and regulators should be prepared to overcome the associated potential hurdles, ensuring that uncertainties are dealt properly and allowing that new promising agents arrive faster into the market.

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