"Richness of Choices" Available in Kidney Cancer, But Patient Selection Is Key

Eric Jonasch, MD

Between the frontline and second-line settings, there are multiple treatment options available for patients with renal cell carcinoma (RCC), but it is critically important for oncologists to decide on an agent with a patient’s characteristics—and goals—in mind, according to Eric Jonasch, MD.

“That gives you an idea of which agent to give to them and, when they’re on the agent, you’re making sure that you maintain channels of communication so you can listen to what the side-effect profile is that they’re developing,” said Jonasch, who chaired the 2017 OncLive^® State of the Science Summit on Genitourinary Cancers. “You can react in a way that the patient can have maximum quality of life; that is critical. It is probably true for all oncology treatments, but it’s especially true for these targeted agents.”

While the second-line setting had a recent emergence of FDA-approved agents with cabozantinib (Cabometyx), nivolumab (Opdivo), and the combination of lenvatinib (Lenvima) and everolimus (Afinitor), researchers are also discussing the frontline potential of cabozantinib, based on results from the phase II CABOSUN study.

In the trial, cabozantinib reduced the risk of progression or death by 34% versus sunitinib (Sutent) as frontline treatment for patients with metastatic RCC. Additionally, the median progression-free survival (PFS) was 2.6 months higher with cabozantinib versus sunitinib, and the overall response rate (ORR) was 46% versus 18%, respectively. However, longer follow-up is needed, said Jonasch.

OncLive: Can you provide an overview of your presentation on RCC?

In an interview during the meeting, Jonasch, professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, spoke on the evolving choices for patients with RCC in these settings, as well as the remaining challenges in the field.Jonasch: The presentation tonight really was to summarize first- and second-line treatment for RCC in 2017. We have had a lot of approvals in the last couple of years, and these obviously make the decisions for which agents to use and what sequence a little bit more interesting.

We have, for example, recent data on cabozantinib in the frontline setting, which has not yet been approved. I want to talk a little bit about why it is that we don’t think it’s quite ready for primetime—although it may be with further analysis.

You made a couple of statements about frontline cabozantinib. What is the rationale that this agent might not yet be ready for this setting?

I’m also going to talk in the second-line setting about the richness of choices we have with agents like nivolumab, cabozantinib, and also lenvatinib and everolimus. Those various agents obviously have distinct properties, side effects, and may also be valuable for one patient more than the other, depending on what their comorbidities are. It’s certainly very interesting; it is an exciting time for RCC. I hope this is going to be helpful for people.The CABOSUN study randomized a bit more than 150 patients between sunitinib and cabozantinib. These individuals had intermediate- and poor-risk features. The PFS for cabozantinib was clearly superior to that of sunitinib, but there were a couple of things about the trial.

First, it did not have independent review. Second, a number of individuals who were on sunitinib came off very early in the study, which may have skewed the curves somewhat in favor of cabozantinib. We are awaiting independent review of these data and, if they do really show that cabozantinib is superior to sunitinib, it’s going to be an agent that we can think about in individuals who have intermediate- and poor-risk features.

Do you foresee there being potential combination treatments with cabozantinib?

The other thing that cabozantinib seems to be doing is bone in a positive way—in a way that agents like sunitinib and pazopanib (Votrient) don’t. If we do get approval in the frontline setting for cabozantinib, it will give us options for individuals who have bone-predominant metastatic disease, or also high burden of disease where you really need to get tumor reduction in a rapid fashion.A number of companies are trying to combine cabozantinib with checkpoint antibodies. So far, these data suggest that it is combinable and we need to see whether or not this actually turns into a viable option from an efficacy perspective.

While there are plenty of choices currently available, are there now also sequencing challenges?

Cabozantinib has some very interesting properties, in terms of being an AXL and MET inhibitor, which may modulate the immune system in ways that some of these other agents don’t. Therefore, it may be a superior agent compared with, for example, axitinib (Inlyta), which is a very simple VEGFR inhibitor.The major sequencing challenges are going to be with, for example, in the second-line setting, do you start with a checkpoint antibody such as nivolumab, or do you move to a multikinase inhibitor like cabozantinib? This is one of the big choices people need to make.

Does the future of this landscape encompass immunotherapy combinations, or regimens with a mix of immunotherapy and targeted agents?

You are the chair of this State of the Science Summit. Why should healthcare professionals attend this type of event?

The good thing about nivolumab is that it’s really well tolerated for the majority of patients who receive it. There is a subset of individuals who really benefit from it. In that regard, it’s a great drug. However, for individuals it doesn’t work for—and if you need to get a response quickly—this agent will not serve this patient. Knowing whom to give it too, and whom to give a drug such as cabozantinib to is important. At this point in time, we don’t have good predictors of which agent should be given to which patient.It’s going to be a bit of both. It’s really going to be a question of figuring out which patient should get which combination.There are a huge number of things that are happening for prostate cancer, bladder cancer, and kidney cancer at this point in time. For the practicing oncologist, it must be overwhelming to really stay on top of what’s happening in [all of these areas]. This provides a succinct and efficient way of speaking with and learning from experts in these various disciplines.

Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial [published online November 14, 2016]. J Clin Oncol. doi:10.1200/JCO.2016.70.7398.