Immunotherapy Is Changing First-Line Treatment of Metastatic Renal-Cell Carcinoma

Abstract

The incidence of renal-cell carcinoma has been increasing each year, with nearly one third of new cases diagnosed at advanced or metastatic stage. The advent of targeted therapies for metastatic renal-cell carcinoma (mRCC) has underscored the need to subtype tumors according to tumorimmune expression profiles that may more reliably predict treatment outcomes. Over the past 2 decades, several vascular endothelial growth factor (VEGF) and tyrosine kinase inhibitors have been the mainstay for first-and second-line treatment of mRCC. Very recently, immunotherapy checkpoint inhibitors have significantly changed the treatment landscape for patients with mRCC, particularly for first-line treatment of intermediate to poor risk mRCC patients. Now, combination immunotherapy as well as combinations of immunotherapy with targeted agents can significantly alter disease outcomes. The field of immuno-oncology for mRCC has unveiled a deeper understanding of the immunoreactivity inherent to these tumors, and as a result combination therapy is evolving as a first-line modality. This review provides a timeline of advances and controversies in first-line treatment of mRCC, describes recent advances in understanding the immunoreactivity of these tumors, and addresses the future of combination anti-VEGF and immunotherapeutic platforms.

Comparative Efficacy of First-Line Immune-Based Combination Therapies in Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-Analysis

“…Over the past few years, the treatment for metastatic renal cell carcinoma with clear cell component (mRCC) has drastically changed with the introduction of targeted therapy, immunotherapy, and a better understanding of RCC biology [ 1 , 2 , 3 , 4 ]. So far, the first-line and second-line systematic therapies for mRCC have been mainly composed of agents targeting the vascular endothelial growth factor receptor (VEGFR) and inhibiting the mammalian target of rapamycin (mTOR), with the last in class being axitinib and cabozantinib [ 5 , 6 ].…”

An Illustrative Case of Combination Cabozantinib/Nivolumab for Progressive Metastatic Renal Cell Carcinoma (mRCC)

“…These pathways are regulated by direct immunosuppression by angiogenic factors and promotion of immune regulatory cells during angiogenesis. In clear cell renal carcinoma, inactivation of the von Hippel‐Lindau (VHL) protein leads to accumulation of hypoxia‐inducible factor 1α (HIF‐1α), which promotes angiogenic pathways; furthermore, HIF‐1α also promotes immunosuppressive factors including programmed death ligand‐1 and activate inflammatory cells such as myeloid‐derived suppressor cells (MDSCs) [3]. VEGF inhibitors theoretically modulate the immune microenvironment by increasing infiltrating T cells, changing the macrophage phenotype from M2 to M1, and potentially increasing major histocompatibility complex I expression and therefore tumor antigen presentation [4].…”

The Changing Therapeutic Landscape of Metastatic Renal Cancer

“…In this scenario, T-regulatory cells play a significant role in regulating the immune response to what the body recognizes as foreign [1,2]. Targeting immune checkpoints in clear cell renal cell carcinoma (CCRCC) is being extensively analyzed currently [3,4,5]. The pitfalls of the clinical translation of PD-1/PD-L1 blockade have also been critically reviewed [6,7,8].…”