Metastatic Renal Cell Carcinoma Management: From Molecular Mechanism to Clinical Practice

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.

Keywords: immune checkpoints inhibitor; new biomarkers; renal cancer carcinoma; targeted therapy; tyrosine kinase inhibitor (TKI).

Figure 1

Representation of the main pathways involved in the mechanisms of tumorigenesis and proliferation of renal cancer cells and their targeted agents. PD1, programmed cell death-1 receptor; PD-L1, programmed death-ligand 1; CTLA4, cytotoxic T-lymphocyte-associated protein 4; CD80, cluster of differentiation 80; CD86, cluster of differentiation 86; MHC, major histocompatibility complex; PI3K, phosphatidylinositol-3-kinase; AKT, serine/threonine kinase 1; mTOR, mechanistic target of rapamycin; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor; cMET, mesenchymal epithelial transition factor; AXL, AXL receptor tyrosine kinase; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor.

Figure 2

Proposed therapeutic algorithm for the treatment of mRCC in and beyond the first-line setting. The choice of treatment is based on (1) i) patient characteristics: comorbidities, potential drug interactions with the concomitant therapy, occupation, patient preferences and the side effects that can affect the quality of life; ii) and tumor characteristics: histology, if it has a representative sarcomatoid component, the genetic structure, the tumor burden, site of metastases, and related symptoms. (2) MSKCC/IMDC prognostic classification; *if not previously carried out, **if the patient does not have autoimmune disease in the active phase, solid organ transplant, or interstitial pneumopathy or if the patient requires high doses of corticosteroids. TKI, tyrosine kinase inhibitor Pazopanib and cabozantinib are still not indicated as second-line treatment after immunotherapy; however, real-world analysis of patients treated with cabozantinib after anti-PD-1 treatment reported promising results.