Immunotherapy for the first-line treatment of kidney cancer has “curative potential”

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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 care to their needs, one expert said.

The use of immunotherapy in the treatment of patients with kidney cancer has particularly shown its curative potential. Even so, the number of options available to patients can make navigation difficult for patients, especially with limited use of biomarkers to determine what works best for them, said Dr. Hans Hammers, Associate Professor of Internal Medicine in the Department of Hematology-Oncology at UT Southwestern Medical Center in Dallas, Texas at the CURE® Educated Patient® Kidney Cancer Summit.

CURE® also spoke to Hammers to learn more about how the field has changed from shrinking tumors to potentially healing patients, and where treatment options might head in the future.

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

Hammers: The problem is that there are now multiple frontline treatment options to choose from, and it is important that patients are educated to make decisions with their health care provider so that they are comfortable with the decision they are making. It is important to understand what drugs make up these prominent treatment options; for example the combination of immunotherapeutic drugs only as one option or the combination of a drug that targets the blood supply and the other (that) targets the immune system. There are some differences, and it is part of the conversation we have with colleagues who sometimes prefer one or the other and how we best tailor it to the patient. It is important that patients understand the basic principles of frontline therapy.

We have limitations on biomarkers … and their usefulness in kidney cancer. Many patients say, “I want my tumor to be sequenced, and based on that, I want to tailor my therapy to it.” That’s not how it works. Right now, with kidney cancer, we don’t really have a situation like lung cancer, where there are certain mutations that would dictate what type of therapy we would start with. Biomarkers like PD-L1 expression, for example … these are all things we see in kidney cancer, but we don’t really use them. They really don’t make enough distinction between patients who may or may not benefit from the respective therapies.

There will probably also be a change in frontline therapy in the sense that, in addition to the currently available duplicates of either dual immune checkpoint inhibitors or the tyrosine kinase inhibitor or VEGF and PD-L1 inhibitors, we are now focusing on triple- Moving Therapies To. These clinical trials have started (patients). We are waiting for the readout (of the data). One of the ongoing studies examining various triplet therapies at the forefront (setting). The field is moving even further towards combination therapies, and biomarkers in this area will be even more difficult than where they are now.

We should keep doing biomarker studies as we feel there may be some patients who don’t benefit much from the currently available immunotherapy approach. And it is important to identify these patients early and then possibly refer them to other approaches to immunotherapy that may be necessary to benefit from immune checkpoint inhibitors. There is much to do. And just because we have high response rates in advance doesn’t mean that we will never have biomarkers.

How does immunotherapy compare to the standard of treatment before immunotherapy became so popular?

The class of drugs that dominated treatment were the VEGF tyrosine kinase inhibitors. They are small molecules that do not target the kidney cancer cell; it targets the blood supply directly. And it is important to know that kidney cancer cells are very resistant even to classic chemotherapy. The classic chemotherapy that we use for lung cancer, breast cancer, colon cancer (and other cancers) doesn’t work for kidney cancer, so we had very little in the early 2000s. And then, since Sutent (Sunitinib) and its many family members were approved, we’ve essentially used those compounds until 2018, when we got nivolumab (Opdivo) approval. The difference in terms of these therapies … there is clearly some value in the use of these drugs. You can shrink tumors (and) keep them suppressed. Patients … can use some of these agents in sequence and live longer, but we have never cured patients with this therapy.

Immunotherapy, on the other hand, has curative potential. Each of us now has patients with a remarkable response to immunotherapy … and they show no progression. Any other therapy before you had to stay on the drug. For example, the moment you stopped taking these VEGF inhibitors, the vasculature would recover and the tumor would continue to grow. If you respond to immunotherapy it is clearly documented that you can stop there often, or if you have been forced to stop there due to significant side effects, it can benefit patients for long periods of time. I think we are healing some patients. … I would say it is a word that we are getting used to more and more often today when talking to patients, a feeling for the curative potential of immunotherapy. It is still a small minority who feel they have acted or eradicated the tumors in this vein, but it is real and we think some patients may not die of kidney cancer if they have been exposed to immunotherapy . I think that’s the discussion about how to provide the best immunotherapy possible, but we also want response rates and disease control, etc.

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

The main side effects of immunotherapy are certainly autoimmune diseases. What the drugs do is to break down the brakes on the immune system. … Cancer and normal organs use certain means to defend themselves against an overactive or overactive immune system. And when you take those brakes off, you hope the immune system will chase the cancer, but it can certainly chase the host as well and cause vital organs to become inflamed.

The main difference between such side effects and side effects of targeted therapy or chemotherapy is that they are much less predictable. It’s like throwing which one you get. Some patients don’t get it, and some patients get really severe, life-threatening inflammation of vital organs such as the lungs, liver, colon, and others.

The other main difference is that these side effects usually do not improve when we stop therapy, but rather that they require active intervention with immunosuppressive drugs such as prednisone. However, once we start treatment, usually within a few days, the side effects may improve and patients can be slowly weaned from the steroids. The impact on quality of life can be minimal if the patient reports the side effects in a timely manner and (receives) timely treatment of the side effects.

Can you elaborate on the triple therapies? And is adding more immunotherapies harmful in terms of side effects?

Currently we have two main options 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 compared to combining one of the pills just mentioned. If you are using two immunotherapies like dual inhibition, the response rate is around 40%. If you combine a pill and another therapy, the response rate, i.e. the significant shrinkage of tumors, is again higher, in the range of 60 to 70%. Well over half of it (answer), if not more, is driven by the pills, which on their own normally have no healing potential. So what you get when you add the pill is the higher response rate. When you have a patient with a large tumor burden that they are symptomatic of, there is much more security in getting the cancer under control early.

What is really well documented now with combo immunotherapy is that after five years we have long-term survivors where the patients just don’t seem to be making any progress. And that’s very comforting, and we don’t yet know if this can only be achieved with the PD-1 inhibitor. There is some data to suggest that CTLA-4 inhibition may not be that important in other cancers, but it does appear to be important in kidney cancer, by looking at what we’ve learned over time like that long-term outcome and duration of response are with therapies that include only a PD-1 inhibitor or the PD-1 and CTLA-4 inhibitors. But … the likelihood of autoimmune side effects is significantly increased. If you’re only exposed to a PD-1 inhibitor, with or without a VEGF inhibitor, the chance of using steroids to control inflammation of vital organs is only in the 15% range. When you add a CTLA-4 inhibitor it goes up to 30% or 35%. However, when it’s properly monitored, it’s really not that daunting.

This interview has been edited for the sake of clarity and conciseness.

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