The Therapeutic Landscape of Renal Cell Carcinoma: From the Dark Age to the Golden Age

Summary: Oncologic treatments for renal cell carcinoma (RCC) have undergone a major revolution in the past 2 decades, moving away from the pre-2004 Dark Age during which interleukin 2 and interferon-α were the only therapeutic options and induced treatment responses in only 5% to 10% of patients with metastatic disease. The development of anti-angiogenic tyrosine kinase inhibitors against vascular endothelial growth factor receptor 2 and inhibitors of mammalian target of rapamycin complex 1 in 2005 introduced the Modern Age with better overall and progression-free survival and a greater number of patients (30%-40%) responding to and (∼80%) benefiting from these targeted therapeutic agents. The coming of age of the immuno-oncology era with the use of immune checkpoint inhibitors (ICIs) have ushered us into the Golden Age of metastatic RCC care, in which combined administrations of two ICIs (anti–programmed cell death protein 1/programmed death-ligand 1 and anti–cytotoxic T-lymphocyte-associated protein 4 or one tyrosine kinase inhibitor plus one ICI (anti–programmed cell death protein 1/programmed death-ligand 1) have recast the treatment landscape of clear cell RCC, the most common RCC subtype, with an approximately 60% response rate and an approximately 90% disease control rate that further improves metastatic RCC survival. Exciting clinical trials are in the pipeline investigating complementary/synergistic molecular mechanisms, based on studies investigating the biology, pathology, and genomics of renal carcinoma and the respective treatment outcome. This will enable us to enter the Diamond Age of precision medicine in which a specific treatment can be tailored to the specific biological and pathologic circumstance of an individual kidney tumor to offer more effective yet less toxic therapy.