Metastatic Clear-Cell Renal Cell Carcinoma in the Era of Immune Checkpoint Inhibitors: Therapies and Ongoing Trials

Simple Summary Renal cancer is within the top 10 most common malignancies worldwide, of which clear cell histology represents the most common subtype in this cancer. Within the past few years, immunotherapy has been approved as a first-line therapy for metastatic renal cell carcinoma. Immunotherapy is a highly effective treatment that enhances the immune system's ability to attack tumor cells. However, there are a subset of patients whose cancer progresses while on immunotherapy. These patients are then treated with a clinical trial which involves new combinations and types of therapies. This review article aims to summarize the most current data regarding first-line treatments and ongoing clinical trials in the expanding treatment landscape for metastatic renal cell carcinomas. Immune checkpoint inhibitors (ICI) are now the bedrock for the treatment of metastatic renal cell carcinoma (RCC). Clear cell RCC (ccRCC) represents the most common subtype of this malignancy. Herein, we explore the therapeutic landscape of ccRCC by discussing the standard of care whose backbone consists of immune checkpoint inhibitors (ICI) and vascular endothelial growth factor inhibitors (VEGF). For ccRCC, pembrolizumab-axitinib, pembrolizumab-lenvatinib, and avelumab-axitinib or nivolumab-cabozantinib are now FDA-approved frontline options for all risk groups while nivolumab-ipilimumab is reserved for intermediate- and poor-risk groups. Monotherapy with pembrolizumab or nivolumab is a potential option for patients who are unable to take VEGFR-tyrosine kinase inhibitors. While outcomes have improved with the adoption of ICI therapies, many patients develop therapy-resistant disease, creating an unmet need for further investigation. The efficacy of novel therapies as well as novel combinations in the post-ICI era is unclear. This review summarizes the most significant clinical trials involving dual ICI/ICI and ICI/VEGFR therapies, in addition to other selected combination therapies that are likely to inform management in the near future.