Combination drug regimens for metastatic clear cell renal cell carcinoma

Abstract

Renal cell carcinomas (RCC) make up about 90% of kidney cancers, of which 80% are of the clear cell subtype. About 20% of patients are already metastatic at the time of diagnosis. Initial treatment is often cytoreductive nephrectomy, but systemic therapy is required for advanced RCC. Single agent targeted therapies are moderately toxic and only somewhat effective, leading to development of immunotherapies and combination therapies. This review identifies limitations of monotherapies for metastatic renal cell carcinoma, discusses recent advances in combination therapies, and highlights therapeutic options under development. The goal behind combining various modalities of systemic therapy is to potentiate a synergistic antitumor effect. However, combining targeted therapies may cause increased toxicity. The initial attempts to create therapeutic combinations based on inhibition of the vascular endothelial growth factor or mammalian target of rapamycin pathways were largely unsuccessful in achieving a profile of increased synergy without increased toxicity. To date, five combination therapies have been approved by the U.S. Food and Drug Administration, with the most recently approved therapies being a combination of checkpoint inhibition plus targeted therapy. Several other combination therapies are under development, including some in the phase 3 stage. The new wave of combination therapies for metastatic RCC has the potential to increase response rates and improve survival outcomes while maintaining tolerable side effect profiles.

Keywords: Renal cell carcinoma; Immunotherapy; Targeted therapy; Vascular endothelial growth factor; Programmed-death receptor 1; Programmed-death receptor ligand-1; Tyrosine kinase inhibitors

Core tip: The treatment of metastatic clear cell renal cell carcinoma (ccRCC) remains a challenge given the broad spectrum of disease presentations and outcomes, variety of treatment options without clear optimal sequencing, and the low rate of complete response to systemic monotherapy. The core of this work reviews the current status of systemic combination drug options in the treatment of metastatic ccRCC, encompassing the novel combinations of tyrosine kinase inhibitors and immune checkpoint inhibitors, with a focus on rationale for use, efficacy, and side effect profiles. We also discuss the role of biomarkers in the development of future therapeutic options.