Sequencing Therapies for Advanced Renal Cell Carcinoma

Toni Choueiri, MD: If cabozantinib moves to the frontline setting as well, it’s already approved for a single agent in the frontline setting for intermediate, poor, and second-line cases based on the CABOSUN study. Now you have more evidence that it should be a first-line drug with nivolumab. It also helps the case with 3 ongoing studies. The first, by the name of COSMIC-313, also asks a different question: do we dare to dream to give 3 drugs rather than 2? We never thought about that. In intermediate- and poor-risk patients, patients are going to have nivolumab/ipilimumab/cabozantinib vs nivolumab/ipilimumab.

This is not for everyone; there could be toxicities, but it is also possible in these harder-to-treat renal cell cancers if we exclude the favorable-risk patients. What if we have an improvement here, not over sunitinib, but over a novel combination that should be considered a standard of care like nivolumab/ipilimumab? That’s the IO [immune-oncology]/IO combination. We have 3 vs 2. Since cabozantinib/nivolumab performed well against sunitinib, that gives a boost that maybe we should build and add a third drug. This trial is ongoing.

There’s another trial, Alliance, and it is important too. That doesn’t ask the question about 3 agents vs 2; it asks the question of 1 agent vs 2 vs 1, meaning what? You start by using nivolumab/ipilimumab, and based on the response—it’s a response-adaptive design—if you have a complete response, that’s great. You take the nivolumab maintenance for a year. If you have progression, which is 20% of patients, you transition to cabozantinib. It introduces cabozantinib. But in the 70% of patients who do not have a complete response or progressive disease by resistance but have PR [partial response] or SD [stable disease], we usually continue nivolumab. This may be where we should add cabozantinib. The study answered this question: is survival prolonged in these SD/PR patients when you add cabozantinib on top of nivolumab? This is also important.

The third study I mentioned is CONTACT-03, which is in a post-IO setting. It asks an important question about whether cabozantinib and another IO inhibitor, here atezolizumab, makes any sense, and would it be better than cabozantinib alone?

Sumanta K. Pal, MD: As I revise my algorithm for treating advanced kidney cancer in 2020, I typically tend to position cabozantinib with nivolumab up front. That tends to be my primary go-to regimen based on the data from the CheckMate 9ER trial. That's the first line of therapy. Beyond that, it's a little challenging to be definitive about options. I would say that lenvatinib with everolimus has some compelling data. We're going to be reporting out some data from a dose-finding study looking at that combination soon. I would suggest that tivozanib in areas of Europe where the drug is approved constitutes a reasonable option as well.

There are multiple options that one can consider in the second-line setting, but in the frontline setting, the preponderance of patients would probably get cabozantinib with nivolumab in my clinic, outside of a study.

Transcript Edited for Clarity