2020 Top Stories in Renal Cell Carcinoma: Management of Renal Cell Carcinoma: Overview of Changes in the Past Decade

Multiple changes have occurred in the management of renal cell carcinoma in the course of the past decade. Over the past 3 to 4 years, the changes in the first-line landscape represent perhaps the promising for patients. First, with the introduction of nivolumab with ipilimumab based on data presented in 2017, we saw the potential for complete responses on the order of 10% with durable responses in many more patients. Then, shortly thereafter, we saw two key datasets using the VEGF-TKI backbone of axitinib in the KEYNOTE-426 clinical trial^1,2 and the JAVELIN Renal 101 trial,³ respectively. These studies compared axitinib with pembrolizumab and axitinib with avelumab to sunitinib.

In 2020, the landscape has further evolved with what I feel to be the most compelling of these four datasets with the CheckMate 9ER clinical trial.⁴ The CheckMate 9ER trial took the bold move of comparing cabozantinib, not at the standard dose of 60 mg, but at a lower dose of 40 mg, in combination with nivolumab to sunitinib therapy. The study showed an impressive improvement in overall survival and a doubling of progression-free survival from 8 to 16 months. The margin of benefit in this population was perhaps the largest in terms of progression-free survival, and I would argue that the population of patients assessed herein have been the most challenging. Overall, 30% of patients had de novo metastatic disease with their kidney still intact. In addition to this, there was a smaller proportion of favorable-risk patients than in studies such as KEYNOTE-426. With these considerations in mind, the combination of cabozantinib with nivolumab should represent a front-line standard for the majority of patients. Of course, we can apply our existing knowledge of cabozantinib in the context of these data. We know that cabozantinib has particular activity in the context of bony metastases, making this regimen attractive within this population. Perhaps owing to the lower dose of 40 mg of cabozantinib, the toxicity of the regimen appeared to be very manageable in this diverse population of patients.

Forthcoming studies will evaluate the activity of cabozantinib with atezolizumab in patients who have received checkpoint inhibition already. This is the so-called CONTACT-03 study⁵ that I am running with Toni Choueiri. This study is an ambitious effort that will take patients who have received prior checkpoint therapy and treat them with a regimen of cabozantinib with atezolizumab, which we assessed in the context of COSMIC-021. Data from COSMIC-021 were recently presented at ESMO 2020,⁶ with a publication forthcoming. It will be exciting to see where cabozantinib-based combinations evolve in the future, and I am intrigued by the possibility of better outcomes that this portends for patients.