Immunotherapy a Mainstay in Kidney Cancer, Novel Approaches on Horizon

Mario Sznol, MD

Immunotherapy agents have quickly become a standard choice in both the frontline and second-line settings of renal cell carcinoma (RCC), explains Mario Sznol, MD.

Nivolumab (Opdivo), which was approved by the FDA for the treatment of metastatic RCC after the failure of an angiogenesis inhibitor in November 2015, is proving to be an appropriate choice for select patients, Sznol says.

The CheckMate-025 study, which led to the FDA approval, compared the efficacy of nivolumab with everolimus (Afinitor). In the study, patients who received nivolumab had a median overall survival of 25.0 months compared with 19.6 months in those who received everolimus (HR, 0.73; P = .002).

Aside from nivolumab, high-dose interleukin-2 (IL-2) is also a go-to regimen for patients.

Building on this foundation, emerging anti—PD-1/PD-L1 therapies are on the horizon to potentially provide additional options to patients. Ongoing studies are also looking at combination strategies, such as checkpoint inhibitors plus VEGF-targeted agents.

OncLive: What should oncologists understand about immunotherapy in RCC?

In an interview with OncLive, Sznol, a professor of Medicine (Medical Oncology) at Yale Cancer Center, discusses the current state of immunotherapy in RCC, emerging agents and combinations in the field, and the challenges that arise with finding biomarkers.Sznol: I want them to understand that immunotherapy should be considered as both a frontline and second-line option for metastatic kidney cancer. Although the targeted agents against VEGF give us a lot of activity, they usually don’t give us durable remissions. Once you come off of those agents, the disease usually progresses and patients usually progress while they are on those agents.

In some cases, patients on immunotherapy can get durable remissions. With high-dose IL-2, some patients can possibly be cured of their disease, or at least have very long remissions that can last for many yeas.

I think physicians ought to be first thinking about immunotherapies, try and give patients durable remissions, and then come back with targeted agents when those fail.

How are you currently treating patients in the second-line setting?

Obviously, every patient is different. Some of them must get VEGF inhibitors or mTOR inhibitors first.The first question is, “How do we treat frontline?” We’re trying immunotherapies in the frontline setting, even though they’re not approved. We either give IL-2 or anti—PD-1—if we can get it—or we put them on a clinical trial that is an anti–PD-1 combination.

Does the survival benefit that nivolumab has shown set a new standard?

We try to give them a second-line immunotherapy if we’re able to. If those agents fail, then we give them a VEGF-targeted agent. However, in patients who receive an antiangiogenesis agent first, like sunitinib or axitinib (Inlyta) where they have had a couple lines of antiangiogenesis agents, we give nivolumab. Now, we have an interesting third-line option—though it is not an immunotherapy—which is cabozantinib (Cometriq).In a sense, yes. However, although nivolumab is a good agent, we have a long way to go.

How do you have the conversation on immunotherapy with your patients?

It does improve survival. There are few patients who have long durable remissions, but we are not curing the majority of patients. Yes, it sets a new standard. However, maybe ipilimumab/nivolumab may be the next step. VEGF-targeted agents with anti—PD-1/PD-L1 might be the next step.If they are appropriate candidates, I basically tell them there are 3 therapies. There are immunotherapies, VEGF-targeted therapies, or the mTOR inhibitors. I try and explain the risks and benefits of each, but I try and emphasize that the immunotherapies can, in some patients, give durable remissions, and actually have a favorable toxicity profile in general.

What are some emerging immunotherapy options in the field of RCC?

Are there ongoing studies exploring these combinations?

I usually try to get them to accept those therapies first—even IL-2, which can be a very difficult therapy to give. It can still produce durable remissions in 5% to 10%. I would rather go in that direction first, and I emphasize the potential long-term benefit of the immunotherapy agents. I also explain that, if they don’t respond to those agents, we still have very good agents against VEGF or mTOR inhibitors that we can give in the second- or third-line settings.Anti—PD-1 has been shown to prolong survival after progression on antiangiogenesis agents in metastatic renal cell carcinoma. There are at least 2 promising combinations coming forward. One of them is an anti–PD-1 agent in combination with an anti–CTLA-4 agent. The other one involves anti–PD-1 agents in combination with agents targeted against VEGF.One of the most exciting studies completed accrual: ipilimumab (Yervoy) and nivolumab versus sunitinib (Sutent). We are just waiting for the results to come out.

What other novel approaches or treatments are being explored?

There is another study looking at bevacizumab (Avastin) in combination with atezolizumab, which is very interesting compared with sunitinib. The results of that trial will be very interesting, because that’s our first proof of concept of a VEGF inhibitor with an anti—PD-1/PD-L1 agent. There are other trials looking at anti–PD-1 agents with VEGF or mTOR inhibitors.Beyond the ipilimumab/nivolumab combination and the anti—PD-1/VEGF antagonist combinations, we have to look for other agents and treatment strategies.

For example, there are novel approaches to giving IL-2. The agent can produce cures, although it has to be given at high doses and can be toxic. There are modified versions of IL-2 that perhaps can give us the same biologic activity, and maybe even more biologic activity with less toxicity. There are also delivery vehicles. For example, IL-2 can be placed in nanoparticles together with other agents.

What are the checkpoint inhibitors that are in development?

There are other checkpoint inhibitors that are being developed that look promising, either alone or in combination. We don’t know what is going to work, but at least there are many things that are in development. Something is likely to show improved activity.There are several of them coming. One of them is anti—B7-H3, which is being developed and is expressed very highly in multiple malignancies, either alone or in combination.

There are other checkpoint inhibitors that are not so well known and may be developed in the future—such as CD200—which is a very interesting target.

Some antibodies will come down the road against TIGIT, which is another immune checkpoint receptor. However, there are many of these. I could go on for hours. We still don’t know which of these are going to be the best ones.

What are the challenges in finding a biomarker for these agents?

It’s not just checkpoint inhibitors. It’s also a costimulatory agonistic fused together with checkpoint inhibitors. There are modulators, with their metabolism, that may increase T-cell activity within the tumor microenvironment. When you put all of those agents together, there are a lot of promising things in development.Finding a biomarker for immunotherapy agents is going to be very difficult. We certainly know that, if we have more T cells in the tumor microenvironment, you’re likely to respond to these agents. However, it’s difficult. When you give ipilimumab and nivolumab, PD-L1 goes out the window as a biomarker for that combination.

As it turns out, in kidney cancer, PD-L1 is not a very good biomarker for nivolumab because the improved survival is seen, whether you were PD-L1—positive or negative. The PD-L1–positive patients seem to have an overall worse prognosis, even though they benefitted from nivolumab. PD-L1 positivity is a prognostic biomarker that seems to identify a group of patients who do worse overall. We’re trying to explain that.