Evolving Systemic Treatment Landscape for Patients With Advanced Renal Cell Carcinoma

Purpose To outline current practices and challenges in the systemic management of patients with advanced renal cell carcinoma (RCC). Design We conducted a focused review of hallmark randomized controlled trials informing the systemic treatment of patients with RCC. We concentrated on trials informing the use of combination therapies, therapy in both treatment-naïve and previously treated patients, sequential treatment strategies, and schedules. Results The systemic treatment of advanced RCC has experienced tremendous progress over the past 15 years. An improved understanding of the canonical pathways implicated in RCC pathogenesis has resulted in the development of molecularly targeted and immunotherapy options for patients. These therapies have replaced cytokine-based treatments as the standard of care for patients with advanced RCC. Until recently, sequential vascular endothelial growth factor (VEGF)–targeted therapy or VEGF-targeted therapy followed by mammalian target of rapamycin inhibition has been the prevailing treatment paradigm for patients. However, newer agents such as cabozantinib and nivolumab have challenged this traditional approach. In addition, combination treatments including nivolumab plus ipilimumab and atezolizumab plus bevacizumab have transformed the RCC treatment landscape, and other doublet combinations in clinical testing will likely continue to alter the treatment paradigm in RCC. Currently, factors that inform treatment selection between different therapy options include performance status, comorbidities, prognostic risk stratification, treatment adverse event profile, and mode of administration, with no Level I evidence for predictive biomarker use in clinic. Conclusions The treatment options for advanced RCC are rapidly evolving since the introduction of VEGF-targeted therapy, immunotherapy with checkpoint blockade and, more recently, combination regimens. Despite the success of these regimens, advanced RCC remains a largely incurable disease, and additional strategies are warranted.