Immunotherapy for Frontline Treatment of Kidney Cancer Has ‘Curative Potential’

Reviewing frontline treatment options for patients with metastatic kidney cancer can be challenging, but understanding some basic concepts and what may be best for the patient allows them to tailor the care to their needs, an expert said.

The use of immunotherapy has made an impact in the treatment of patients with kidney cancer, especially with its curative potential. Despite this, the number of available options available for patients can make it difficult for patients to navigate, especially with limited use of biomarkers to determine what will work best for them, said Dr. Hans Hammers, associate professor of internal medicine in the division of hematology-oncology at UT Southwestern Medical Center in Dallas, Texas, at CURE®’s Educated Patient® Kidney Cancer Summit.

CURE® also spoke with Hammers to learn more about how the field has changed from shrinking tumors to potentially curing patients, and where treatment options may be heading in the future.

CURE®: Why did you think it was so important for patients with kidney cancer to learn more about the frontline setting?

Hammers: The issue is that there are now several frontline treatment options to choose from, and it is important for patients to be educated to make decisions with their health care provider to be comfortable with the decision that they make. It’s important to understand what kind of drugs compose these prominent treatment options; the combination, for example, of just immunotherapy drugs as one option or the combination of a drug that targets the blood supply and the other one (that) targets the immune system. There are some differences there, and it's part of the conversation that we still have even among colleagues who prefer one or the other sometimes and how we best tailor them to patients. It's important for patients to understand the basic principles of frontline therapy.

With regards to biomarkers, we have limitations … and their usefulness in kidney cancer. A lot of patients say, ‘I want my tumor sequenced, and then based on that, I want to have my therapy directed towards that.’ That's not the way it works. Right now, in kidney cancer, we don't really have a situation as in lung cancer, where you have certain mutations that would dictate what kind of therapy we would start with. Biomarkers such as PD-L1 expression, for example, … these are all things that we see in kidney cancer, but we don't really use them. They really don't differentiate enough between patients who benefit from the respective therapies or not.

There's probably a change coming also in frontline therapy in the sense that besides the currently available doublets of either dual immune checkpoint inhibitors or the tyrosine kinase inhibitor, or VEGF and PD-L1 inhibitors, we’re now moving towards triple therapies. These clinical trials have accrued (patients). We're waiting for readout (of the data). One of the trials that is actually ongoing is looking at different triplet therapies in the frontline (setting). The field is even moving further into combination therapies, and biomarkers in that space will be even more challenging than where they are now.

We should still pursue biomarker studies because we do feel there might be some patients who don't get much benefit at all from the currently available immunotherapy approach. And it's important to identify these patients early and then potentially direct them to other approaches to immunotherapy that might be necessary to derive any benefit from immune checkpoint inhibitors. There's a lot of work to be done. And just because we have high response rates upfront does not mean we will never have biomarkers.

How does immunotherapy compare with what the standard of care was before immunotherapy became so prominent?

The class of drugs that dominated the treatment really were the VEGF tyrosine kinase inhibitor. They are small molecules that don't target the kidney cancer cell; it directly targets the blood supply. And what's important to know is that kidney cancer cells themselves are actually very resistant to classic chemotherapy. The classic chemotherapy that we use in lung cancer, breast cancer, colon cancer (and other cancers) does not work in kidney cancer, so we had very little in the beginning of the 2000s. And then, since the approval of Sutent (sunitinib) and its many family members, we have used these agents upfront until essentially 2018, then we got the approval of nivolumab (Opdivo). The difference with regards to those therapies, … there's clearly value in using these drugs. You can shrink tumors (and) keep them suppressed. Patients … can use some of these agents sequentially and live longer, but we never cured patients with this therapy.

Immunotherapy, on the other hand, does have a curative potential. All of us now have had patients with a remarkable response to immunotherapy … and they don't show any progression. With any other therapy before, you had to stay on the drug. The moment you stop, for example, these VEGF inhibitors, the vasculature would recover and the tumor would continue growing. If you have an immunotherapy response, it’s clearly documented that you can oftentimes stop there, or if you were forced to stop there because of significant side effects, patients could continue to benefit for long periods of time. I do believe we are curing some patients. … I would say it's a word that we get used to using more frequently now when we talk to patients, a sense of curative potential with immunotherapy. It's a small minority still that we feel as behaving that way or the tumors are eradicated in that sense, but it’s real and we think that some patients may not die from the kidney cancer if they had exposure to immunotherapy. So I think that's the discussion is how do we deliver the best possible immunotherapy but we also want to increase response rates and disease control, etc.

Despite the benefits of immunotherapy, are there some common side effects and can they be easily managed?

Certainly, the main side effect from immunotherapy is autoimmune disease. what the drugs do is that they take down the brakes of the immune system. … So the cancer as well as normal organs use certain tools to defend itself against an overly active or overactivated immune system. And when you take these brakes away, you hope that the immune system goes after the cancer, but it can also certainly go after the host and cause inflammation of vital organs.

The main difference between these kinds of side effects and side effects from targeted therapy or chemotherapy is that they are much less predictable. It's like rolling the dice which one you're going to get. Some patients get none and some patients get really severe, life-threatening inflammation of vital organs such as the lung, the liver, the colon and others.

The other main difference is that those side effects do not improve typically if we stop therapy, but rather they require active intervention with immune-suppressive drugs such as prednisone. Once we initiate the treatment, though, typically within even just a few days, the side effects can improve and patients can be slowly weaned off the steroids. The impact on quality of life can be minimal if the patient reports the side effects in time and (receive) timely treatment for the side effects.

Can you go into more detail about triple therapies? And is adding more immunotherapies harmful in terms of side effects?

Currently, we have essentially two major choices that patients have: one is dual immune checkpoint inhibition with a drug called (Opdivo) or ipilimumab (Yervoy). They target two different immune checkpoints of the immune system versus the combination of one of the pills that we just mentioned. If you use two immunotherapy such as dual inhibition, the response rate is around 40%. If you combine a pill and another therapy, the response rate, meaning the significant shrinkage of tumors, is higher, in the range of 60% to 70%, again. A good half of that (response), if not more, is driven by the pills, which by themselves don't typically have curative potential. So what you get by adding the pill is the higher response rate. If you have a patient with a large tumor burden from which they have symptoms, there's much more assurance to get the cancer under control early.

What's really now well-documented with combination immunotherapy is that five years out, we have long-term survivors where patients simply don't seem to progress. And that's very reassuring, and we don't know yet if that can be achieved with just the PD-1 inhibitor, there's some data to suggest that CTLA-4 inhibition it may not be so important other cancers, but it seems to be important in kidney cancer just by looking at what we learned over time, what the long-term outcome and the durability of the response is with therapies that are just one PD-1 inhibitor or the PD-1 and CTLA-4 inhibitor. But … the chance for autoimmune side effects is clearly increased. If you're just exposed to a PD-1 inhibitor with or without the VEGF inhibitor, the chance to need steroids to control inflammation of vital organs is only in the range of 15%. If you add CTLA-4 inhibitor, it goes up to 30% or 35%. However, if appropriately monitored, it’s really not that discouraging.

This interview has been edited for clarity and conciseness.

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