Adjuvant Therapy for Renal Cell Carcinoma: Hype or Hope?

Abstract

Renal cell carcinoma (RCC) is the third most common genitourinary cancer accounting for approximately 180,000 deaths worldwide in 2020. Although over two-thirds of patients initially present localized disease, up to 50% of them may progress to metastatic disease. Adjuvant therapy aims to reduce the recurrence risk and improve outcomes in several types of cancers but is currently an unmet need in RCC. The results achieved with tyrosine kinase inhibitors in metastatic RCC led to the evaluation of these target therapies in an early setting with conflicting results for disease-free survival and no overall survival (OS) benefit. Likewise, the results of immune checkpoint inhibitors (ICIs) in an adjuvant setting are conflicting. Available data did not show an improvement in OS with ICIs in the early phase, although a positive trend for pembrolizumab has been recorded, receiving the Food and Drug Administration's approval in this setting. However, the disappointing results of several ICIs and the heterogeneous pattern of RCC warrant biomarker identification and subgroup analyses to evaluate which patients could benefit from adjuvant therapy. In this review, we will discuss the rationale for adjuvant treatment in RCC, summarizing the results of the most important adjuvant therapy trials and current applications, to outline possible future directions.

Keywords: adjuvant therapy; cancer immunotherapy; checkpoint inhibitors; renal cell carcinoma; tyrosine kinase inhibitors.

Figure 1

Molecular and immunotherapy targets evaluated in adjuvant RCC. ICIs of PD-1 disrupt its interaction with PD-L1, leading to enhanced T-cell proliferation and activation. Antibodies targeting PD-L1 prevent its interaction with PD1 on CD8 T cells, allowing their activation. Anti-CTLA-4 antibodies allow CD28 to bind to its receptor, B7, and activate naïve CD4 T cells. Antiangiogenetic targets include TKIs on VEGFR. mTOR inhibitors prevent tumor growth. TAM, tumor-associated macrophage; RCC, renal cell carcinoma; ICIs, immune checkpoint inhibitors; PD-1/L-1, programmed cell death 1/ligand-1; CTLA4, cytotoxic T-lymphocyte antigen 4; TKIs, tyrosine kinase inhibitors; VEGFR, vascular endothelial growth factor receptor, mTOR, mammalian target of rapamycin; TAM, tumor-associated macrophages. Created in BioRender.com.