Renal cell carcinoma - Emerging treatments

Belzutifan

Belzutifan is a hypoxia-inducible factor inhibitor. It is approved by the US Food and Drug Administration (FDA) for use in adults with von Hippel-Lindau (VHL) disease who require therapy for associated RCC not requiring immediate surgery. In an ongoing phase 2 trial, an overall response rate of 49% was reported in patients with VHL-associated RCC.[150]

Batiraxcept

Batiraxcept is a recombinant fusion protein dimer containing an extracellular region of human AXL combined with the human immunoglobulin G1 heavy chain (Fc), which demonstrates highly potent, specific AXL inhibition.[151][152] It has been granted fast track designation by the FDA for treatment of patients with advanced or metastatic clear cell RCC who have progressed after 1 or 2 prior lines of systemic therapy that include both immuno-oncology-based and vascular endothelial growth factor tyrosine kinase inhibitor-based therapies (either in combination or sequentially).

Dovitinib

An oral tyrosine kinase inhibitor (TKI) that targets both vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). It was compared to sorafenib as third-line therapy in patients who had been treated previously with another VEGF inhibitor and an m-TOR inhibitor. The two treatment arms showed similar progression-free survival (PFS) (3.6 and 3.7 months). Toxicities were also comparable.[153]

Novel combination targeted therapies

One open-label phase 3 trial comparing bevacizumab plus atezolizumab with sunitinib monotherapy supports use of the combination regimen for selected patients (tumours with positive PD-L1 expression) with advanced RCC.[154] Clinical trials are also exploring triplet combinations of targeted therapies.[155][156][157][158] In a phase 3 double-blind trial comparing ipilimumab, nivolumab, and cabozantinib triplet therapy with ipilimumab plus nivolumab doublet therapy in treatment-naive patients with metastatic RCC (intermediate- or poor-risk group), triplet therapy improved progression-free survival and objective response rate (but was associated with higher toxicity [79% vs. 56% grade 3 or 4 adverse events, respectively]).[159] Guidelines do not currently recommend triplet therapy with ipilimumab, nivolumab, and cabozantinib outside a clinical trial; further data is needed to determine overall survival outcomes and optimise patient selection.[160]

Indoleamine 2,3-dioxygenase (IDO) inhibitors

IDO inhibitors work to increase tryptophan and, thus, decrease T-cell anergy and inhibitory/regulatory T-cell recruitment. This immune modulatory pathway is being explored in RCC.[161]

Stereotactic ablative body radiotherapy for primary disease

Stereotactic ablative body radiotherapy (SABR) is being used in some centres for the treatment of primary RCC in a subset of patients who are ineligible for surgery; however, it is considered an emerging, non-invasive treatment option.[162][163][164] Pre-treatment biopsy confirmation is the preferred standard of care, although in some patients biopsy may not be feasible and radiological diagnosis (e.g., enlarging lesion on serial imaging) used.[164] The local control rate for SABR compares favourably with thermal ablation (radiofrequency ablation, cryoablation) and is associated with low toxicity rates.[164]

High-intensity focused ultrasound

In addition to procedures such as radiofrequency ablation and cryoablation, other locally ablative techniques are emerging as potential therapies for appropriate candidates with small renal masses.[165][166] Clinical trials and longer-term data collection will be required to establish the safety and efficacy of these treatments over time.

Dendritic cell vaccines

Dendritic cell vaccines in advanced RCC have shown promise in several studies, with larger study data still pending. The response rate in RCC from one meta-analysis of several small studies was found to be 12%.[167] However, its role and the option of combined approaches is ongoing.[168]

Autologous patient vaccines

There is some evidence suggesting that autologous patient vaccines in the adjuvant setting (high-risk RCC post-nephrectomy) improve progression-free survival.[169] One trial suggested that the vaccine-induced up-regulation of PD-1 and CTLA4 on circulating T cells may be of benefit in combining this option with immune checkpoint blockade.[170]