Site - and histology - independent indications of medicinal products in oncology

The development of drugs approved for a site and histology-independent indication is based on the identification of biological drivers that define cancer course across anatomical sites and histologies. Therefore, the selection of patients responsive to a specific drug occurs by identify a specific molecular alteration in the tumor, and not based on the site and/or histology of the tumour, the latter being the common way to develop the anticancer treatments so far. When cancer cells harbour a specific molecular alteration which is believed acting as an oncogenic driver, it is anticipated that molecularly targeted treatments would be effective against a spectrum of biomarker-defined tumour types, rather than being restricted to the site of tumour origin. This revolutionary approach to drug development has thus led to a paradigm shift in some cancer therapies: from drug indicated for a tumor originating in a specific part of the body (e.g. lung, breast, colon etc.) to drugs indicated for a multitude of tumour types as long as they express a specific driver mutation. However, such new type of indication is challenging the existing diagnostic, drug development, regulatory and reimbursement frameworks worldwide. The processes that led to the clinical development, approval, national market entry, and post-marketing monitoring of the first two medicinal products which were granted a site and histology independent indication in the European Union, namely the NTRK inhibitors larotrectinib and entrectinib, will be reviewed and discussed. Additional drugs received site and histology independent indications in the US, including immune checkpoint inhibitors. The differences in the regulatory approach between the two health authorities, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) related to the assessment of site and histology-independent indication for anti-PD1 drugs in microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) solid tumors will be analysed, as well as the FDA indication granted to pembrolizumab in solid tumors based on Tumor Mutational Burden (TMB). The peculiarity of such molecular alterations, together with the controversies around those approvals, will be discussed. Finally, the situations where an indication of a targeted therapy, initially approved from one tumor type, was then extended to a site and histology-independent one will be presented, with reference to the FDA approvals of the combination dabrafenib plus trametinib for BRAF V600E positive solid tumors, and selpercatinib in solid tumors with RET gene fusion.