Chandler H. Park, MD

Dr. Joshua Sabari, Dr. Petros Grivas, and Dr. Chandler Park discuss new developments in perioperative therapy for muscle-invasive bladder cancer.

Experts Discuss Next Steps in Perioperative Bladder Cancer Treatment  

Following the 2025 European Society for Medical Oncology (ESMO) Annual Congress held in Berlin, Germany, we sat down with three leaders in oncology to discuss new developments in perioperative therapy for muscle-invasive bladder cancer. 

Participating in the conversation were Dr. Joshua Sabari, Dr. Petros Grivas, and Dr. Chandler Park

Sabari is an assistant professor in the Department of Medicine at NYU Grossman School of Medicine and serves as director of High Reliability Organization Initiatives at Perlmutter Cancer Center. Park is a medical oncologist specializing in genitourinary medical oncology at the Norton Healthcare Institute in Louisville, Kentucky. Grivas is a professor in the Clinical Research Division at Fred Hutch, where he also serves as medical director for Local and Regional Outreach and for the International Program. He additionally holds a professorship in the Division of Hematology and Oncology at the University of Washington School of Medicine.

Park began by explaining that some perioperative approaches involve three cycles of Padcev (enfortumab vedotin-ejfv) plus Keytruda (pembrolizumab) before surgery, followed by cystectomy and then additional Padcev afterward, depending on patient tolerance. He noted that other regimens incorporate immunotherapy alone in the postoperative setting without EV. The distinction is significant because Padcev-related toxicities, such as neuropathy and rash, can influence whether patients complete therapy after surgery.

Grivas emphasized the importance of individualized treatment planning, saying not all patients can continue therapy due to side effects. He highlighted ongoing research efforts to better identify which patients benefit from adjuvant therapy through clinical characteristics and tools such as circulating tumor DNA. Determining whether all patients require adjuvant therapy, only selected patients, or whether adjuvant Keytruda alone may be sufficient remains an active area of study.

The panel also discussed the significance of pathological complete response, defined as no detectable cancer in surgical tissue following neoadjuvant treatment. Historically, patients achieving pathological complete response after chemotherapy have demonstrated approximately 85% to 90% cure rates. Longer follow-up is still necessary to confirm whether similar outcomes apply in the immunotherapy era. Grivas added that differences in surgical technique, pathology methods, and clinical trial design can influence how results are compared across studies.

The experts agreed that perioperative approaches in muscle-invasive bladder cancer continue to evolve. Ongoing data will clarify optimal sequencing, guide toxicity management, and support long-term improvements in patient outcomes.

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Articles

Recent discussions at the 2025 ESMO Congress highlighted advancements in perioperative therapy for muscle-invasive bladder cancer. Experts, including Drs. Sabari, Grivas, and Park, explored treatment regimens involving Padcev and Keytruda, emphasizing the need for individualized treatment plans due to potential toxicities. The role of adjuvant therapy and the significance of pathological complete response were also discussed, with ongoing research aiming to optimize patient outcomes. The evolving landscape of perioperative approaches underscores the importance of continued research to refine treatment strategies and improve long-term results.

Expert oncologists offer closing thoughts on emerging therapeutic strategies, unmet needs, and the future of kidney cancer treatment.

Future Outlook of Kidney Cancer Treatment

How I envision kidney cancer in the future is, that kidney cancer, if you think about it, is a cancer that starts in the kidney. But everybody diagnosed with kidney cancer has a unique kidney cancer, even though it's called clear cell. The analogy I use to show you the heterogeneity or how variable kidney cancer is this; we all know about COVID-19. COVID-19 is a virus that goes into the air, goes into our lungs, and there are different variants.

So the original variant and the alpha,…the beta, and the delta. Each variant is different from the first one. So, everybody diagnosed with kidney cancer, cancer started in their own body. Based upon the DNA of the kidney there was transformation into a cancer stage. So everybody with kidney cancer, everybody [with] clear cell kidney cancer has a unique variant. So, we need to get better … at [coming up] with a personalized treatment. If 70,000 to 80,000 people get diagnosed with kidney cancer in America, that's 70,000 to 80,000 different variants of kidney cancer.

How do I envision going forward? There are some really good provocative studies where you check the biopsy of the kidney cancer and they do genetic signatures, whether it is DNA of each person’s specific cancer DNA in the kidney cancer or the mRNA. Which is what the messenger RNA is. Which is something that kidney cancer becomes, it becomes a protein. And they're actually checking that to see what would be the best treatment for that specific patient.

For instance, we were talking about some patients that we give immunotherapy [IO], i.e., nivolumab and ipilimumab. For some patients I give lenvatinib and pembrolizumab, others I give cabozantinib and nivolumab, and then for others I give pembrolizumab and malaita, or axitinib. So in the future, what they're doing is this study right now, Dr Brian I. Rini [, MD,] is leading and it's called the OPTOC RCC [NCT05361720]. They're actually checking the mRNA of these person-specific cancers and they're trying to figure out which treatment is best based on that person's unique, clear-cell kidney cancer.

That's where it's going. It's going towards precision treatment, personalized treatment, where instead of having 4 different FDA [the United States Food and Drug Administration]-approved treatments, now we'll know which of those 4, is the best. Based upon that person's unique mRNA signature based on their clear-cell kidney cancer.

The other thing is, and this is very promising,[in] 2019, you know, the Nobel Prize [in Physiology or Medicine] was awarded to, a group of scientists, most notably from Dana-Farber. And what they found is a gene called the Von Hippel-Lindau gene. They found out the pathway that led to clear-cell kidney cancer, so patients tend to have this Von Hippel-Lindau mutation, and if they do, they're at a higher risk of developing kidney cancer. By going through this pathway, they found that the mechanism or the path is kind of blocked by an area called the HIF-2 alpha transcription factor.

So we have medications that are in clinical studies right now. They're called HIF-2 alpha transcription factor inhibitors, [such as] busudanulfan. And the studies look very promising. So this treatment is going to go up the line of treatment. In fact, we had this clinical study in many centers as well, where you have pembrolizumab and lenvatinib and we also had this third medication called busudanulfan, this HIF-2 alpha transcription factor. And that's going to be emerging for another treatment for kidney cancer.

The other thing that's moving forward in terms of kidney cancer is going to be the imaging. For instance, we have different types of imaging for cancers. We're very familiar with something called a PET scan. When we do a PET scan, it's called positron emission tomography. They inject a positron-emitting medication called FDG [fludeoxyglucose] into the blood, which binds to areas that are very active, i.e., cancer cells. So we use FTG PET for lung cancer and lymphoma. Recently we have something called PSMA PET. PSMA is also a PET scan. But instead of FTG, they use PSMA and PSMA stands for prosthetic specific membrane antigen, so specific for prostate cancer. So in the future, they're going to have a PET scan specifically for kidney cancer. And there was some emerging data at the ASCO [the American Society of Clinical Oncology yearly meeting] recently here in 2023.

In the future, we will be able to pick up cancer of the kidney much faster. You might ask, well, when do we need that? Our patients, who had kidney cancer, had the cancer removed with radical nephrectomy or total nephrectomy. They take everything out. So we have an FDA medication called pembrolizumab. And pembrolizumab is used for adjuvant treatment. That means after you get the cancer out, you give immunotherapy [IO] for up to 1 year and try to prevent the cancer from coming back. The problem with IO is that some of these patients might already be cured and we might be over treating these patients. In fact, studies have shown up to 10%, 1 out of 10 people that we give IO, can create a permanent side effect, such as a thyroid condition. I've had patients diagnosed with diabetes. I've had patients diagnosed with adrenal insufficiency. So in the future, what's going to happen is they're going to have this PET scan specifically for kidney cancer after they have surgery, and this will be able to pick up cancer to see if they truly need IO after surgery.

I think some of the unmet needs that remain are now that we have effective treatment strategies in advanced or metastatic kidney cancer, how do we optimally sequence these therapies? So we are finding good candidates for each combination and giving patients combinations in a sequence of each treatment is life-extending.

But how can we sequence so that we're finding different treatment resistance mechanisms and also trying to tailor our sequential therapies to conquer those treatment resistance paradigms? Are there other emerging agent treatment strategies? Absolutely. There are many agents, an early clinical investigation includes cellular therapies like CAR T cells [chimeric antigen receptor T cells], as well as novel IO targets like LAG3 [lymphocyte activation gene 3] and TIGIT [T-cell immunoreceptor with immunoglobulin and ITIM domain]. So a lot more to come, I think, for kidney cancer. And then finally, there is a whole HIF-2⍺ agent called busudanulfan, which is right around the corner in terms of its approval for advanced stages of kidney cancer. It's currently approved purely for patients with Von Hippel-Lindau syndrome. We're about to see a very large trial report out showing benefit in the refractory kidney cancer cohorts so I'm excited about that and about where it will bring busudanulfan in other stages of kidney cancer.

Thank you for joining me to learn about advanced kidney cancer. We hope you found this educated patient 

Transcript is AI-generated and edited for clarity and readability.

Videos

Chandler H. Park, MD, discusses the role of support groups and outlines resources available to patients with kidney cancer.

Advice for Patients with Advanced Renal Cell Carcinoma

 One thing about kidney cancer is the strong support systems in place. We have kidney cancer support groups. And a lot of the leading cancer centers have patient support groups that meet monthly. We have care navigators. Something I highly encourage when you or a family member has a diagnosis of kidney cancer is talking to a local oncologist and asking about the local support groups. A lot of these local groups, I've been to a couple, are so warm and inviting. Patients diagnosed with kidney cancer discuss their experiences and treatment side effects. So, I would highly encourage everybody to talk to the cancer center that you live by and ask them for the kidney cancer support groups. They're in most of the major cities.

An overview of the treatment protocol for patients with advanced RCC who are receiving IO/TKI or IO/IO combination therapy.

Combination Immunotherapy for Treating Advanced Renal Cell Carcinoma

 The last combination immunotherapy [IO] is nivolumab and ipilimumab together. This can be a very tough regimen. And the reason is with the other combinations, you only had one IO. With this medication, you have a nivolumab, which is a PD, ie, an IO checkpoint inhibitor. Then you add a second checkpoint inhibitor called ipilimumab, which is a CTLA-4. Now, what's the problem and what's the benefit of this combination? The benefit is, of all 4 different combinations t we have right now, this tends to have the highest duration of response. Duration of response means that you give the treatment a year from now, maybe 2 years from now.

They did a 5-year update. If the patients respond, are they going to continue to respond? Some of the updated data have shown up to 25% to 30% of the patients who respond tend to respond. But the question is, at what price? Using an analogy, I played baseball when I was younger, in high school and middle school. And as a baseball player, you could always try to hit and get a home run. But if you try to home run every time your strikeout rate goes up. Some baseball players, choke up…and try to get singles and doubles and they have a higher average and more of a contact. So using that analogy, if you used nivolumab and ipilimumab, you have a higher chance of a homerun, i.e. complete response [CR], ie, duration of response. But the problem is if you strike out because if you do IO, it either works or it doesn't work. If the IO doesn't work, that means it could be 3 months of not receiving any treatment. If the patient doesn't receive any treatment for 3 months, the cancer can spread. So that's what I think about for my patients.

If I patient in front of me is very symptomatic and doesn't make it through the IO, they might not get the second treatment, so that's what I look at. Now, in terms of the complete response and the response rate, the response rate was around 40%, which is a little bit on the lower side. The progressive disease was 18% to 20%, which means 1 out of 5 people when they get this medication 3 months from now, the cancer is going to spread as opposed to cabozantinib-nivolumab, which was about 5% to 6%. And pembrolizumab-lenvatinib, which was also 5% to 6%. So those are the high-level overviews.

Now, what about the adverse effects of this dual checkpoint inhibitor, since you're really revving up the engine, and really revving up the IO in your body, you tend to have more IO adverse effects. So what are the IO adverse effects? The IO adverse effects tend to be more thyroid conditions, patients can end up with low thyroid. So we check the thyroid levels more often, maybe every 6 weeks. We had this condition called adrenal insufficiency. Adrenal insufficiency means right about our kidneys, we have these hormones called adrenal glands, and the adrenal glands release hormones such as cortisol to keep our blood pressure up and so on. More of these patients can have this adrenal insufficiency because the cortisol level is low.

As a physician, we have to put our thinking caps on. With low cortisol levels you look at the potassium level, is the blood pressure low, and whether the patient’s performance status is weaker. If I check a 9 am cortisol level and it’s low, I put them on hydrocortisone. So those at the high level for all of the different trials, there are benefits of the combination and there's also downsides of the combination. To recap, if I use the IO and a tyrosine kinase inhibitor [TKI], you have a much higher response rate, ie, 70%, for instance, for the lenvatinib, and pembrolizumab, 70% to 71% of the patients respond. If you use the nivolumab and ipilimumab, only 40% respond. But if they respond, they can have a long-term duration of response.

In terms of the adverse effects of nivolumab and ipilimumab, they tend to be harder at the beginning of the treatment. You have to look for thyroid conditions, diarrhea, fatigue, coughing, and adrenal insufficiency. In terms of the TKI and the IO combination, you have to think more about high blood pressure, diarrhea, and hand-foot disease, where their hands are feet are red. So that's how I customize which patients get which treatment.

 This is a great question for patients receiving treatments and how they are logistically delivered in our cancer center. For ipilimumab-nivolumab, this combination is a pure IO combination that's given IV [intravenously] once every 3 weeks over the course of 4 cycles. Followed by nivolumab on its own every 4 weeks or so, based on the patient and all of those are IV infusions. When we add in the anti-VEGF [vascular endothelial growth factor] component, these are often given in pill form. So these are oral administration that patients take at home. If it's axitinib, it's actually given twice a day. Cabozantinib and lenvatinib, are agents given once a day. But these are oral pills that patients would take at home.

On the management of toxicities, when we're thinking about these treatment effects and if patients experience adverse events, if it's a pure IO combination, we often will start with either topical steroids for rashes or oral steroids if it's diarrhea or elevated liver function or something else that's related all to the immune activation. If it's on the anti-VEGF treatments and more likely associated with the pills, we will often hold the pills to start. And then also try to treat the adverse effects.

If it's something like hypertension, for example, we will often be increasing the blood pressure medications or adding another blood pressure medications for patients that are already on them, and then also hoping to treat through some of those toxicities by continuing the anti-VEGF blockade. If it's something like really bad diarrhea, then holding the VEGF therapy while we get a clearer picture. Figuring out if it is from the VEGF therapy or the IO with a very low threshold to add systemic steroids to calm down the immune system. We've seen over these large trials that adding the steroids for treatment of the immune activation and the toxicities do not affect the overall efficacy of the treatments themselves so I think patients should feel that as we're managing and treating the toxicities, their cancer is still being treated. And [they should] not be afraid if they have toxicity to mention those to their doctors so that the care team can really help them manage the very severe toxicities that they're having.

Chandler H. Park, MD

Experts Discuss Next Steps in Perioperative Bladder Cancer Treatment

Future Outlook of Kidney Cancer Treatment

Advice for Patients with Advanced Renal Cell Carcinoma

Combination Immunotherapy for Treating Advanced Renal Cell Carcinoma

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