Molecular oncology: what is needed to speed access to innovative therapies in clinical research?

PURPOSE OF REVIEW: A better understanding of the biology of cancer cells has led in the past 20 years to more and more molecular and immunological driven treatment strategies impacting both clinical trials and day-to-day practice. The aim of this review is to describe new approaches to conduct clinical trials in this area to speed up drug development and increase access to innovation for cancer patients. RECENT FINDINGS: The design of an early phase trial has an impact on its clinical benefit. Trials deriving from a specific biomarker or histologic characteristic (also known as enrichment design) are more likely to demonstrate benefit than trials based on a more conventional design. However, the increase of low incidence cancer molecular subtypes poses a major hurdle in the clinical management and drug development research for cancer patients. SUMMARY: With the identification of news targets and the subsequent introduction of precision medicine, new strategies and tools are needed to provide access to biomarker identification and target-oriented clinical trials to all cancer patients. We propose to set up a new patient-centered model to conduct clinical trials allowing simply to 'bring the trial to the patient'.

A Rare Case of Hepatic Vanishing Bile Duct Syndrome Occurring after Combination Therapy with Nivolumab and Cabozantinib in a Patient with Renal Carcinoma.

Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) significantly improve the outcomes of patients with advanced clear cell renal cell carcinoma (ccRCC); however, high-grade toxicities can occur, particularly during combination therapy. Herein, we report a patient with advanced metastatic ccRCC, who developed grade 4 cholestasis during combined therapy with nivolumab and cabozantinib. After the exclusion of common disorders associated with cholestasis and a failure of corticosteroids (CS), a liver biopsy was performed that demonstrated severe ductopenia. Consequently, a diagnosis of vanishing bile duct syndrome related to TKI and ICI administration was made, resulting in CS discontinuation and ursodeoxycholic acid administration. After a 7-month follow-up, liver tests had returned to normal values. Immunological studies revealed that our patient had developed robust T-cells and macrophages infiltrates in his lung metastasis, as well as in skin and liver tissues at the onset of toxicities. At the same time, peripheral blood immunophenotyping revealed significant changes in T-cell subsets, suggesting their potential role in the pathophysiology of the disease.