Review of Adjuvant Therapies in Renal Cell Carcinoma: Evidence to Date

Abstract

In 2018, there were 400,000 new cases of renal cell carcinoma (RCC) globally, with 175,000 deaths attributable to the disease. Three quarters of patients have potentially curable localised disease at diagnosis; however, recurrence rates are as high as 40% following surgery. There are currently no adjuvant therapies in routine clinical use which reliably improve outcomes. Effective adjuvant therapy is an urgent unmet need to reduce recurrence risk and improve outcomes. Early efforts explored chemotherapy, radiotherapy, cytokine therapy, hormonal treatments and tumour cell vaccines as adjuvant therapies, however, have yielded disappointing results. More recently, interest shifted to evaluating tyrosine kinase inhibitors (TKIs) in the adjuvant setting, as they improve outcomes in metastatic disease. Five phase III clinical trials testing adjuvant use of a range of TKIs have been performed, with the results of a sixth trial awaited. Unfortunately, these studies have thus far yielded conflicting and disappointing results, and there is currently no strong evidence for routine adjuvant TKI therapy. In parallel, novel immunotherapy treatment approaches have recently been developed, transforming the management of a range of malignancies, particularly through immune checkpoint inhibitors (ICIs). These approaches are well established in the metastatic context in RCC, as well as in the adjuvant treatment of melanoma. On this basis, five phase III trials are currently ongoing to test the efficacy of a range of ICIs in adjuvant RCC patients, with initial results expected over the next few years. In this article, we review the current evidence for adjuvant therapies in RCC, discuss ongoing clinical trials and suggest directions for future work to address this unmet need.

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

Figure 1

Mechanism of action of TKIs used in metastatic RCC. Kinases regulating angiogenesis are frequently overexpressed in RCC, culminating in increased tumour vascular supply. VHL inactivation leads to overexpression of pro-angiogenic factors including VEGF via increased HIFα expression. HIFα is also upregulated via PI3K/mTOR signalling. VEGF binds to VEGFR1/2/3 on endothelial cell surfaces, promoting angiogenesis. Additional cell surface receptors regulating angiogenesis include PDGFR (platelet-derived growth factor receptor), FGFR (fibroblast growth factor receptor), tyrosine-protein kinase MET (hepatocyte growth factor receptor), AXL oncogene (tyrosine-protein kinase receptor UFO) and proto-oncogene tyrosine-protein kinase receptor RET. A range of TKIs have been developed targeting various aspects of these signalling pathways. Adapted by permission from Springer Nature © (2017). Posadas EM, Limvorasak S, Figlin RA. Targeted therapies for renal cell carcinoma. Nat Rev Nephrol. 2017;13(8):496–511.13

Figure 2

Mechanism of action of ICIs. In response to recognition of TA presented by cancer cells, T-cell activation depends on coalescence of a range of signals including co-stimulation by CD80/CD86 which bind to CD28 on the T-cell. Cancer cells evade the immune response via competitive binding of CD80/CD86 to CTLA-4 and via binding of PD-L1/PD-L2 to PD-1, inhibiting T-cell activation. Antibodies targeting CTLA-4, PD-1 and PD-L1 prevent activation of immunosuppressive signals, thus enhancing host immune responses against cancer cells. Adapted by permission from Springer Nature © (2020). Xu W, Atkins MB, McDermott DF. Checkpoint inhibitor immunotherapyin kidney cancer. Nat Rev Urol. 2020;17(3):137–150.16