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Renal cell carcinoma (RCC) is an umbrella term for a collection of vastly different malignancies originating in the kidney, with varying prognosis and clinical behavior. On the broadest scale, RCC can be subdivided into the clear cell and non–clear cell categories. In 2016, the WHO released an updated classification that expanded the RCC subtypes on the basis of tumor histology, chromosomal alterations, and molecular pathways. As such, a "one size fits all" algorithmic approach cannot be applied to all patients with RCC and many gray areas in RCC management remain.

The RCC management options have dramatically evolved in recent years, leading to significantly improved patient outcomes. For instance, recent clinical trials established superior overall survival of combination immune checkpoint inhibitor (ICI) therapy with ipilimumab and nivolumab as well as ICI plus tyrosine kinase inhibitor (TKI) combinations including pembrolizumab and axitinib, nivolumab and cabozantinib, and pembrolizumab and lenvatinib.

As such, doublet therapies have become the new gold standard for untreated advanced clear cell RCC. However, optimal choice of therapy in this population remains unclear. Cross-trial comparisons are always problematic, partly because of diverse study end points and incongruent patient populations.

For instance, one variable to consider is the proportion of patients with prior nephrectomy within study cohorts. Small data sets suggest that metastatic sites may respond better to systemic therapy than primary renal tumors and, thus, patients treated with prior nephrectomy have a higher chance of complete response.

Furthermore, novel doublet regimens in the above trials were compared with the historic standard-of-care therapy with single-agent sunitinib, which is no longer used in untreated patients with advanced RCC. As the treatment paradigm for these patients rapidly evolves, clinical trials with more modern comparator arms are being designed such as the COSMIC-313 study ().

The evolution of therapies in RCC and associated improved patient outcomes is awe-inspiring. However, multiple ambiguities in patient management still exist. Careful consideration of unique tumor histology and molecular features, individual patient characteristics and preferences as well as treatment cost should take place when selecting optimal therapies for patients with RCC.

Read an interview about this clinical commentary here and additional expert commentary here.