Thesis title: 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 etc.) to drug 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 state of art of site and histology independent indications granted in the EU and in the US will be presented in this thesis, starting from the first two medicinal products approved with a site and histology independent indication in the EU, the NTRK inhibitors larotrectinib and entrectinib, describing their clinical development, regulatory approval, national market entry, and post-marketing monitoring.
Further, the peculiarity of microsatellite instability-high/mismatch repair deficient and Tumor Mutational Burden as biomarkers for anti-PD(L)1 immunotherapy drugs will be analysed, highlighting the different regulatory approach between the EMA and the FDA.
Finally, the extension by FDA to a site and histology-independent indication of targeted therapies for BRAF mutation and RET gene already approved will be presented.
This review will allow to discuss the peculiarity and the limitations of the clinical development of drugs aimed to a site and histology-independent treatment, the challenges encountered during the regulatory review along with the regulatory instruments in place, up to the hurdles and possible solutions for the market access and implementation of biomarker-driven therapies in the real-world setting.