Adjuvant therapy options in renal cell carcinoma — targeting the metastatic cascade

Localized renal cell carcinoma (RCC) is primarily managed with nephrectomy, which is performed with curative intent. However, disease recurs in ~20% of patients. Treatment with adjuvant therapies is used after surgery with the intention of curing additional patients by disrupting the establishment, maturation or survival of micrometastases, processes collectively referred to as the metastatic cascade. Immune checkpoint inhibitors and vascular endothelial growth factor receptor (VEGFR)-targeting tyrosine kinase inhibitors (TKIs) have shown efficacy in the treatment of metastatic RCC, increasing the interest in the utility of these agents in the adjuvant setting. Pembrolizumab, an inhibitor of the immune checkpoint PD1, is now approved by the FDA and is under review by European regulatory agencies for the adjuvant treatment of patients with localized resected clear cell RCC based on the results of the KEYNOTE-564 trial. However, the optimal use of immunotherapy and VEGFR-targeting TKIs for adjuvant treatment of RCC is not completely understood. These agents disrupt the metastatic cascade at multiple steps, providing biological rationale for further investigating the applications of these therapeutics in the adjuvant setting. Clinical trials to evaluate adjuvant therapeutics in RCC are ongoing, and clinical considerations must guide the practical use of immunotherapy and TKI agents for the adjuvant treatment of localized resected RCC.