Novel Immunotherapy Approaches Moving Through RCC Pipeline

Matthew R. Zibelman, MD

Immunotherapy combinations are showing significant potential for the treatment of patients with kidney cancer, according to Matthew R. Zibelman, MD.

“The combinations with immunotherapy and the oral tyrosine kinase inhibitors (TKIs) are very promising and may be better tolerated,” Zibelman said.

Much of the current focus has been on the combination of the PD-1 inhibitor nivolumab (Opdivo) and the CTLA-4 inhibitor ipilimumab (Yervoy), which has the potential to make its way into standard practice. Findings from the CheckMate-214 trial, which were presented at the 2017 ESMO Congress, demonstrated that this combination was associated with an improvement in overall survival compared with sunitinib (Sutent) in the frontline setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma.

OncLive: Please provide an overview of your presentation.

Is there a regimen that you find to be the most promising?

What does the safety profile look like for nivolumab and ipilimumab?

Are there any ongoing trials that you believe could show promise?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Advanced Renal Cell Carcinoma and Bladder Cancer, Zibelman, an assistant professor in the Department of Hematology/Oncology at Fox Chase Cancer Center, discussed the promise of immunotherapy combinations for patients with kidney cancer.Zibelman: I spoke about novel immunotherapy options for patients with kidney cancer. I reviewed immunotherapy options that are currently out there with the PD-1 pathway blockade. I also discussed the regimens that are coming on the horizon, which are mostly combinations with nivolumab and other checkpoint inhibitors, TKIs, and other novel agents, as well. Recently, there were data about nivolumab and ipilimumab that showed a benefit in the first-line treatment of patients. There is a high chance that this is going to be a combination we will be using in standard practice soon. The combinations with immunotherapy and the oral TKIs are very promising and may be better tolerated. As time goes on, it will be between those combinations and attempting to identify which groups are better for one versus the other. It is more toxic to give the combination. Ipilimumab and nivolumab clearly have increased toxicity, which does somewhat limit it. However, we are getting more used to managing that toxicity. About 40% of patients seem to have significant side effects, which needs to be taken into consideration. Combinations that have similar efficacy, but are even better tolerated, would a great asset to the treatment landscape.All of the phase III combination studies are quite promising. PD-1 pathway agents with the TKIs are all showing potential and may all end up with some similar information. They are all worthwhile.

Do you envision the future of this treatment landscape to be immunotherapy?

How do you determine sequencing of these agents?

Some that are just starting now have triple combinations. These studies will be interesting to see how those agents are tolerated. This is an exciting time in the field.Combination immunotherapy is where things are headed. Hopefully, we will have biomarkers to be able to determine who can receive single-agent immunotherapy and who needs a certain combination. To be able to use biomarkers to smartly show who is able to get each combination, and then change therapies based on that would be practice changing.There are no great data to guide us so far. For standard therapies after a first-line TKI, there are a few things you can look at, such as the tolerability of the agents. Nivolumab is generally well tolerated, which makes it attractive to a lot of patients. Some patients prefer taking oral agents, so that is when cabozantinib (Cabometyx) would be better. Additionally, patients with bone metastases seem to respond well to cabozantinib so that is another population who can receive it.

What are some other challenges?

What would you like the main takeaways to be from your talk?

Another consideration that I continue to struggle with is with patients who seem to be rapidly progressing right through their first-line therapy. We are not sure if we should give them nivolumab before the window of opportunity closes. If they respond, they'll have a long-term response versus giving cabozantinib, which a lot of patients seem to respond to and might help gain control of the cancer more quickly. That is a difficult population that remains to be a struggle.Sequencing and deciding what to use next is the big challenge. No one knows the answer and we are all just guessing. The good part about that is we have many good therapies that work and many of our patients will see a lot of these therapies, but knowing which one to choose next has no great answer.The main takeaways are that PD-L1 status is not important to decide who should receive nivolumab or any of those agents. It does not seem to be a factor for kidney cancer. Also, combination therapy looks promising. It is coming soon, but has side effects that patients need to be informed of prior to receiving therapy.