Michael Serzan, MD, Dana-Farber Cancer Institute, discusses some of the latest advancements in the treatment of renal cell carcinoma and future research on the horizon. He presented on these updates at the 2024 Community Oncology Conference.

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My name is Michael Serzan. I'm a medical oncologist at the Dana-Farber Cancer Institute, specializing in treating patients with genitourinary cancer. That includes kidney cancer, bladder cancer, prostate cancer, and testicular cancer.

Can you outline the most significant recent advancements in the treating renal cell carcinoma (RCC) and how these developments differ from previous standards of care?

I think one of the hottest areas of kidney cancer research has been in the adjuvant setting. We know that for probably the last 30 years or so, we've done adjuvant trial after adjuvant trial, and they've all been negative. They showed no improvement in the ability of these medications to prevent the recurrence of kidney cancer after a high-risk surgery.

Some of the data that came out recently was from the KEYNOTE-564 study, which was for patients with high-risk resected clear cell kidney cancer, who were then randomized to receive either pembrolizumab or placebo. This trial was initially reported a few years ago and showed an improvement in disease-free survival, thus preventing the cancer from coming back after surgery.

We just heard an update in January 2024 at a meeting at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) in San Francisco that showed updated data that pembrolizumab led to an improvement in overall survival when compared to placebo. And this has really been an astronomical improvement in the standard of care for patients who have had surgery.

However, our enthusiasm is somewhat tempered by other clinical trials that have been conducted using a similar design. So, there was the IMmotion010 study, which was, again, for patients with resected kidney cancer randomized to either atezolizumab, a programmed death-ligand 1 (PD-L1) inhibitor, or placebo. And, unfortunately, that trial showed that the atezolizumab did not improve disease-free survival nor overall survival.

Lastly, we also have data from the CheckMate 914 study, which was again, nivolumab vs placebo for patients with high-risk resected kidney cancer. And that study similarly did not show improvement in disease-free or overall survival.

While we certainly have evidence to support the use of pembrolizumab from a very positive trial, we also temper some of those expectations with 2 negative trials were reported over the last few years. These are often some of the longest consultations I have with my patients about the true risk of their cancer coming back. What is the likelihood that they'll benefit from immunotherapy? And being very frank about the side effects of treatment. It’s certainly a hot area of discovery of trying to find better biomarkers to select patients in the adjuvant setting. Certainly, an area of tremendous growth over the last few years.

How do these updates influence the selection of treatment modalities for patients with different stages of RCC?

I think the advances in the adjuvant setting will definitely impact how we treat patients with metastatic disease who unfortunately develop disease recurrence. At present, for patients who have de novo metastatic disease—those who do not receive adjuvant therapy—the standard of care is immunotherapy plus either a vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) or dual immune therapy. And over the last few years, we've seen a lot of updates on trials such as CheckMate 214, which was comparing ipilimumab plus nivolumab vs sunitinib. About 8 years from the initial study cutoff, we see that ipilimumab and nivolumab prolongs overall survival and has a plateau on the progression-free and overall survival curves when compared with sunitinib. Now, ipilimumab and nivolumab are currently only US Food and Drug Administration (FDA) approved for patients with International Metastatic RCC Database Consortium (IMDC) intermediate or poor risk disease. However, when we look at the data in aggregate over the last 8 years, we see that the patients with favorable risk disease actually do garner benefit from ipilimumab and nivolumab.

We see a splaying of the overall survival curves where sunitinib initially performed better, but now we see ipilimumab and nivolumab has better long-term outcomes than if you start with sunitinib. And then we also have three FDA-approved and National Comprehensive Cancer Network (NCCN) guidelines–recommended combinations of anti-programmed cell death protein 1 (PD1) therapy plus VEGF-TKI, so that's cabozantinib and nivolumab, lenvatinib and pembrolizumab, axitinib and pembrolizumab. And again, this is for patients with de novo metastatic clear cell kidney cancer.

We see all these combinations have improved response rates, improved progression-free survival, and improved overall survival when compared with sunitinib, which was the standard of care. So, do I choose ipilimumab and nivolumab, or do I choose VEGF-TKI plus IO combinations? A lot of that really depends on some clinical factors. So, whether or not there have been sarcomatoid features, the burden of disease—is this a patient who needs a quick response, [or] a patient with, for example, a bone metastasis or brain metastasis. Or, on the flip side, is this is a younger patient where we're really trying to prioritize the long-term outcomes and try to get a sustained treatment response with ipilimumab and nivolumab.

While we have very robust data in the first-line and metastatic setting, I think this is kind of a brave new world that we're thinking about where the adjuvant setting, if patients have already received the anti-PD1 adjuvant therapy, should we give them one of these combinations or should we move on to some other options for them?

One of the trials that investigated this space was a CONTACT-03 study, which was a large phase 3 clinical trial of patients who experienced disease progression on an immunotherapy combination. They were randomized to either receive cabozantinib (a VEGF-TKI) plus atezolizumab (a PD-L1 inhibitor), or cabozantinib. Unfortunately, this study showed there was no benefit to adding atezolizumab to cabozantinib. There was no improvement in response rate, progression-free survival, or overall survival. In fact, we saw more side effects with the atezolizumab plus cabozantinib combination.

Now, there are some other studies that are investigating the same approach that are due to read out probably over the next year or so. But, by and large, it's changed my practice that I don't routinely re-challenge patients with anti-PD1 or anti-PD-L1 therapies if they've already progressed on an anti-PD1- based therapy. We need an active clinical investigation in our field to determine how to treat those patients.

With the emergence of new therapeutic options, how do you anticipate these updates will impact the overall survival rates and quality of life for patients with RCC?

It’s worth taking a step back. Maybe 10, 15 years ago, we had very few treatments for patients with clear cell kidney cancer. And we had some medications which could treat disease, but didn't make a big impact on overall survival or only a small subset of patients benefitted.

Now, we really do have an embarrassment of riches. We've got immunotherapy options. We've got VEGF-TKI therapies that continue to push the standard of care forward such that many patients are living past the 1-, 2-, 3-, 4-, even 5-year mark, either with their cancer in a durable remission off-therapy or garnering a continued response while on a VEGF-TKI therapy.

We’ve seen survival improve, but we also have to be mindful of what is the quality of life that we're subjecting patients to. What's the impact of being on a VEGF-TKI, for example, and experiencing things like cardiovascular disease, advanced kidney disease. On the flip side, what are some of the side effects of immunotherapy? We've had about a decade to help understand and really get better at managing some of these chronic toxicities, but some of them are long lasting. Things like hypothyroidism, type 1 diabetes, and there's certainly some rare subtypes that are quite difficult to diagnose and quite difficult to treat.

And so, as we kind of push this field forward, we want to be mindful obviously not only of improving some of our outcomes but also trying to look at what's the patient's experience, and how are we both maximizing the quantity of life as well as the quality of life as we push the field forward.

Are there any promising avenues for further research or potential breakthroughs on the horizon?

One of the areas of investigation that is very active over the last several years is trying to understand some of the rarer subtypes of kidney cancer.

We know about three-quarters of patients will be diagnosed with a clear cell variant of kidney cancer, but that other 25% of patients have these rare, what we used to call, non-clear cell or variant histology kidney cancers, and these include papillary kidney cancer, chromophobe kidney cancer, translocation kidney cancer, SMARCB1-deficient kidney cancer, and some of the more rare kind of molecularly defined variants that we previously just lumped all together. And what we've found is that if we use some of the medications that we use in the clear cell population, including VEGF-TKIs and immunotherapies, we've been able to get some nice responses to treatment.

Although the response rates, the progression-free survival, [and] the overall survival is somewhat lower than the clear cell variant, we've been able to use a lot of these same medications and have patients benefit from them in the kind of non-clear cell cohorts. What we're really trying to do is understand what some of the genes and the back pathways are that are driving some of these cancers and then find particular treatments that target those pathways and really shut down the tumor growth. So, I think that's certainly an area of a lot of in that active investigation.

And then a secondary active area is a brand new medication and that was just FDA approved in December 2023. A medication called belzutifan, which is a hypoxia-inducible factor 2 alpha (HIF2α) inhibitor and really takes advantage of the underlying biology for many patients with clear cell kidney cancer. We know almost across the board that patients with clear cell kidney cancer have a mutation in the BHL gene, which leads to an increase in the HIF2α molecule and richly angiogenic or vascularized tumors. And what this belzutifan medication does is it shuts down that HIF2α molecule inside of the cancer cell. And this was the subject of the Nobel Prize in 2018 won by Dr Bill Kalan.

This medication has made its way into the clinic. We just heard data in the fall of 2023 of belzutifan, which was used for patients who had already received immunotherapy, who had already received a VEGF-TKI therapy. And patients either received belzutifan or everolimus (a mammalian target of rapamycin [mTOR] inhibitor). That type of a standard of care in this heavily pretreated population.

We saw that belzutifan improved response rates and improved progression-free survival when compared with everolimus. It also has a different toxicity profile based on its mechanism of action than the immunotherapy or the VEGF-TKI therapies. And so, again, it's now FDA approved and NCCN guideline recommended.

If it works in patients who have advanced disease, a lot of our investigations are now trying to move it up earlier in the disease and use it in combination with immunotherapy or VEGF-TKI therapies. We also want to use it sometimes even in the adjuvant setting. Trying to understand patients who are trying to get a nice response to this medication and using it as a single agent and in combination.

Kidney cancer is certainly an area of active investigation, and we are really encouraged by some of the long-term data that we're seeing from the immunotherapy combinations. But, I think we still have a lot of work to do because unfortunately most patients will not sustain a long-term durable response to some of our existing treatments. We're really trying to understand patients who are going to have a good response and patients who are going to develop early resistance, and what new pathways and new medications that we can use are to try to salvage those patients who unfortunately don't receive a positive response.