Advanced kidney cancer is challenging to treat, and many patients suffer relapse after developing resistance to existing treatments. Now, a global phase 3 clinical trial led by Robert Motzer at the Memorial Sloan Kettering Cancer Center in New York, US, has demonstrated the potential of therapies combining an antiangiogenic agent called lenvatinib with one of two other drugs, pembrolizumab (an immune checkpoint inhibitor) or everolimus (an immunosuppressant).

“Advanced kidney cancer is a highly lethal malignancy,” says Motzer. “This trial was inspired by the exceptional activity we saw in a recent phase 2 trial of lenvatinib plus pembrolizumab.”

The researchers examined progression-free survival rates in a large, international patient cohort. They faced significant challenges to bring the trial together, having to not only co-ordinate it across 200 sites in 20 countries and meet different regulatory requirements but also to work against the backdrop of the COVID-19 pandemic. 

The team compared the effectiveness of lenvatinib plus pembrolizumab or everolimus against the most common first-line drug for the disease, sunitinib. They randomly assigned a total of 1069 patients between 2016 and 2019 to one of the three drug options, then monitored survival rates and adverse side effects. Lenvatinib plus pembrolizumab significantly outperformed the other two therapies, with 79.2% of patients in that group surviving to the two-year mark. This is an increase of almost 10% in survival rate compared to those on sunitinib alone. 

“We were pleasantly surprised by the efficacy of the lenvatinib plus pembrolizumab regimen, which showed the longest progression free survival we have yet recorded in a phase 3 trial for kidney cancer,” says Motzer. “Lenvatinib plus everolimus showed some benefit as well, but not to the same degree.”

There were side effects in almost every patient regardless of the drugs they were prescribed, with diarrhoea and hypertension being the two most common. The team used accepted methods to limit toxicity, such as interrupting or reducing treatment doses over time, and these  approaches worked to minimise adverse effects, allowing the patients to continue therapy. 

The team have since started a fresh phase 3 trial to compare lenvatinib plus pembrolizumab with other possible therapies.

“We will study tumours from the patient cohort to determine the mechanism of response,” says Motzer.  “Longer follow-up times will help us establish long-term survival chances and durability of response. Cost is an issue of high importance across many aspects of oncology and must be considered carefully, particularly given the extraordinary efficacy of this combined regimen.”

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