Abstract
The therapeutic sc"enario of metastatic renal cell cancer (mRCC) has noticeably increased, ranging from the most studied molecular target therapies to those most recently introduced, up to immune checkpoint inhibitors (ICIs). The most recent clinical trials with an ICI-based combination of molecular targeted agents and ICI show how, by restoring an efficient immune response against cancer cells and by establishing an immunological memory, it is possible to obtain not only a better radiological response but also a longer progression-free and overall survival. However, the role of tyrosine kinase inhibitors (TKIs) remains of fundamental importance, especially in patients who, for clinical characteristics, tumor burden and comorbidity, could have greater benefit from the use of TKIs in monotherapy rather than in combination with other therapies. However, to use these novel options in the best possible way, knowledge is required not only of the data from the large clinical trials but also of the biological mechanisms, molecular pathways, immunological mechanisms, and methodological issues related to both new response criteria and endpoints. In this complex scenario, we review the latest results of the latest clinical trials and provide guidance for overcoming the barriers to decision-making to offer a practical approach to the management of mRCC in daily clinical practice. Moreover, based on recent literature, we discuss the most innovative combination strategies that would allow us to achieve the best clinical therapeutic results.
Highlights
Renal cancer is the 10th most common cancer in Italy, with approximately 13,400 new cases per year [1], 70–80% have clear cell histology, while papillary, medullary, chromophobe, and other forms classified as non-clear cell histology are rare
Literature data on new therapeutic indications with cabozantinib in both the first and second lines [5, 6], nivolumab after anti-VEGF tyrosine kinase inhibitors (TKIs) progression [7], nivolumab combined with ipilimumab in naive patients with poor prognostic factors, and pembrolizumab combined with axitinib in all prognostic subgroups [8], have modified the prognosis of patients with metastatic renal cell cancer (mRCC)
A microenvironment response exists: tumors treated with anti-angiogenic agents present an inflammatory infiltrate consisting mainly of regulatory T cells (CD4+FOXP3+) and express high levels of progressive disease (PD)-L1, demonstrating the conditions associated with a worse prognosis [31]
Summary
Renal cancer is the 10th most common cancer in Italy, with approximately 13,400 new cases per year [1], 70–80% have clear cell histology, while papillary, medullary, chromophobe, and other forms classified as non-clear cell histology are rare. To make the best use of new drugs and associations and to propose new therapeutic sequences, better knowledge is required of the data derived from the large clinical trials and of the basic biology, the complexity of involved molecular pathways, the immunology of tumours, and methodological problems related to both new response criteria and new endpoints. In this complex scenario, this review aims to provide a practical approach to the management of advanced renal cancer, framing the new results in daily clinical practice and providing points for reflections to overcome decision-making barriers based on physician therapeutic choice
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