Robert J. Motzer

There has been no clear standard for clear-cell kidney cancer that progresses after immunotherapy; this is the first phase 3 to show a HIF-2 alpha inhibitor combination beating a standard tyrosine kinase inhibitor on progression-free survival in that setting. Whether it changes practice depends on the final overall survival analysis and on regulators, since the interim survival difference did not reach significance and the combination brings the toxicity of two drugs.

Patients with newly diagnosed advanced clear-cell kidney cancer should receive an immunotherapy-based combination; lenvatinib plus pembrolizumab gives the highest response rate and longest PFS of the available options, at the cost of more side effects requiring dose adjustment. Sunitinib alone is no longer an appropriate standard. Choosing among the combinations depends on risk group, symptoms, comorbidity and the value placed on treatment-free survival, which favours nivolumab plus ipilimumab in intermediate and poor risk.