Therapeutic sequencing in advanced renal cell carcinoma: How to choose considering clinical and biological factors

Renal cell carcinoma (RCC) represents the third most frequent urological cancer, accounting for 3% and 5% of all malignancies, in women and men, respectively (Siegel et al., 2021).

Nearly 25% of RCC patients are diagnosed with synchronous metastases and around 30% of patients with localized disease will develop metastases (Siegel et al., 2021). Metastatic RCC (mRCC) is a fatal disease, with a 4-year median OS < 50% (Albiges et al., 2020).

RCC is a heterogeneous disease with several genetic and molecular alterations (Alaghehbandan et al., 2019). It is well known that angiogenesis plays a critical role in the pathogenesis, proliferation and metastatic spread of RCC (Canino et al., 2019). In clear cell renal cell carcinoma (ccRCC) subtype, the role of the mutations in the Von Hippel Lindau (VHL) tumor suppressor gene, leading to an overexpression of the hypoxia-induced factors (HIFs) and increasing angiogenesis, is clearly defined (Batavia et al., 2019). Hyperactivity of HIF-α induces dysregulated production of angiogenetic factors, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). The activity of these factors is associated with oncogenesis and enhanced RCC metastatic potential (Clark, 2009).

In addition, a crucial molecular signaling involved in the RCC pathogenesis is represented by the phosphatidyl-inositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway which hampering HIF-1 expression stimulates neo-angiogenesis and consequently cancer cells proliferation (Pal and Quinn, 2013).

The understanding of this biological landscape led to development of therapies targeting VEGF and mTOR pathways including a monoclonal antibody directed against VEGF (bevacizumab), several tyrosine kinase inhibitors (TKIs) that act blocking both angiogenesis and growth-stimulating proteins (sunitinib, pazopanib, sorafenib, tivozanib, axitinib, cabozantinib, lenvantinib) and two mTOR inhibitors (temsirolimus and everolimus). These drugs quickly entered in clinical practice, shifting the systemic treatment of this tumor from the “cytokine era” to the “targeted therapy era” (Barata and Rini, 2017).

Increasing evidence demonstrated a unique immune microenvironment in RCC compared to other solid tumors providing a strong rationale for the use of immune checkpoint inhibitors (ICIs) (Xu et al., 2020).

In RCC, angiogenesis stimulates tumor immune evasion. VEGF inhibits the differentiation of dendritic cells from monocytes, increases the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs) and interferes with maturation of CD4 + and CD8 + T cells (Zhou et al., 2020, Ohm et al., 2003). Furthermore, proangiogenic factors induce T cell exhaustion increasing PD-L1 expression on dendritic cells and stimulating CTLA-4 and PD-1 on immune cells (Gavalas et al., 2012, Voron et al., 2015). VEGFR-TKIs favor the activity of immune surveillance system cells (Buttigliero et al., 2018). This strong biological rationale allowed the advent of the dual ICIs combinations (nivolumab + ipilimumab) and ICI plus TKI combinations (pembrolizumab + axitinib, avelumab + axitinib, nivolumab + cabozantinib and pembrolizumab + lenvantinib) which replaced targeted therapies as first line treatment for patients with mRCC. However to date there are no available data regarding the choice of the best therapeutic sequence in mRCC patients. In addition, in daily clinical practice few prognostic factors are useful in advanced RCC. The two currently validated prognostic risk indexes are the Memorial Sloan-Kettering Cancer Center (MSKCC, Motzer et al., 1999) and the International Metastatic RCC Database Consortium (IMDC, Heng et al., 2009).

In this review we summarize the main results of trials investigating ICIs combinations in the first line treatment of mRCC. In addition, we analyze the clinical and biological criteria that could guide physicians in the choice of first line treatment, and we will try to hypothesize the best therapeutic sequence for each mRCC patient focusing on resistance mechanisms to ICIs combinations.

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