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Precision Pathways in RCC: Translating Immunotherapy and Targeted Therapy Advances Into Personalized Patient Care

 

There is a lot of things that go into considerations for the selection of frontline therapy in RCC, including comorbidities, disease risk, efficacy of therapy, performance status, response to previous therapy, if they receive perioperative therapy, which we are going to talk about next, and then safety and adverse event management.

 

The treatment options really are IO/TKI or IO/IO. The options are listed here.

 

First-line Therapy for Patients With Clear Cell Histology

 

These are the NCCN categories for clear cell. Again, we have the three IO/TKI options. We have ipilimumab/nivolumab now as of last year is listed in the preferred as well category one for favorable. Then other recommended. We have single-agent TKI as well.

 

The Frontline Landscape of RCC and ccRCC

 

This is what we are going to cover. We are going to talk about:

 

• CheckMate 214;
• CheckMate 9ER;
• COSMIC-313;
• STELLAR-002; then,
• We will cover some non-clear cell updates as well.

 

CheckMate 214: Nivolumab + Ipilimumab vs Sunitinib in Previously Untreated Advanced ccRCC

 

As a reminder, CheckMate 214 is the original trial for which nivolumab/ipilimumab is approved in metastatic clear cell RCC. Here we have ipilimumab/nivolumab compared to sunitinib. The endpoints are listed here.

 

CheckMate 214: Final OS

 

We heard at ASCO last year the final overall survival data for this trial. About nine-year follow-up, which is amazing. We have long-term overall survival trended in favor of ipilimumab/nivolumab, as expected in all of the categories. Actually, we see a trend not significant, but we see a trend for the favorable risk. On the far right, you can see that the curves actually cross over. Now the hazard ratio is 0.8.

 

We see overall response rates of 39.5% versus 33%. The hazard ratio for the intention-to-treat population remains stable at the nine-year follow-up, and the long-term overall survival benefits were sustained in patients with intermediate and poor risk.

 

CheckMate 214: Final Duration of Response in ITT Population

 

The final duration of response is also incredibly meaningful. Nearly half of responders maintain long-term benefit at the eight to nine year cut-off. The difference of duration of response 48% versus 19% and the intermediate poor risk 50% versus 23% and the favorable risk 36%.

 

This is incredibly meaningful when deciding if this is a good option for any of the risk categories.

 

CheckMate 214: Clinical Implications for Management

 

The depth of response predicts durability. Patients achieving a CR or PR with ipilimumab/nivolumab may have long-term disease control, as 48% of responders maintain benefit at eight years and conditional survival improves over time. Patients with ipilimumab/nivolumab who survived the first three years have progressive improvements.

 

Ipilimumab/nivolumab enables prolonged treatment-free periods with preserved disease control. We know that TKI-based regimens often do have a sustained response, require continued dosing, so continued toxicity.

 

We also saw with the final update last year that patients with favorable risk may experience long-term benefits. Despite a lower initial overall response rate, there was a delayed overall survival benefit.

 

CheckMate 9ER: First-line IO-TKI Doublet in Previously Untreated Advanced/Metastatic RCC

 

Next, we are going to talk quickly through CheckMate 9ER. As a reminder, this is cabozantinib/nivolumab versus sunitinib.

 

CheckMate 9ER: Final PFS and OS

 

The final PFS and OS also presented last year at ASCO GU. Here, the PFS difference is 16.4 versus 8.3 months. The overall survival 46.5 versus 35.5. The overall response rates were 55.7% versus 27.4%. Median duration of responses were 22 versus 15.2 months.

 

Checkmate 9ER: Safety

 

Some of the safety that we can see with cabozantinib/nivolumab, we do suspect more of the immune-related adverse events, of course. Truthfully, sunitinib is not without toxicity as well. You still see a lot of toxicity with single-agent sunitinib. You could see more dermatologic toxicity when you add immunotherapy slightly more of the LFT abnormalities, slightly more diarrhea, but some of the others are pretty comparable between the two.

 

COSMIC-313: Cabozantinib + Nivolumab + Ipilimumab in Previously Untreated Advanced RCC

 

COSMIC-313 was presented also at ASCO GU last year. This was triplet therapy. We are now adding all three of the drugs we just talked about: cabozantinib with ipilimumab/nivolumab compared to placebo with ipilimumab/nivolumab. Here the primary endpoint was PFS and the secondary endpoint was OS.

 

COSMIC-313: Final Results

 

In terms of treatment exposure and dose modification, we actually see that only 58% of patients got through all four cycles of ipilimumab/nivolumab. Although the PFS was significant, the overall survival was not met. Here we also see when we added the cabozantinib to the ipilimumab/nivolumab, there was a lot more toxicity. You see a lot more LFT abnormalities, a lot more diarrhea. Some suspect that it is just prohibitive in terms of the toxicity of adding all three agents at the same time.

 

STELLAR-002: Zanzalintinib With IO in RCC (1L ccRCC Expansion Cohort)

 

We also have some data for the STELLAR-002, which is zanzalintinib. This is basically for some people coined as the better cabozantinib. It has a shorter half-life than cabozantinib. Here it was combined with nivolumab versus zanzalintinib with nivolumab and relatlimab. Again, this is all in untreated clear cell RCC.

 

STELLAR-002: ORR and PFS

 

Here the overall response rate was higher for the doublet arm, zanzalintinib/nivolumab versus zanzalintinib/nivolumab/relatlimab. Relatlimab is a LAG-3 monoclonal antibody. For those of you that treat melanoma, it is also approved in this space.

 

Here we also see the median PFS was greater in the doublet arm than the triplet arm, 18.5 months versus 13.0 months also as demonstrated on the curve on the right.

 

STELLAR-002: ORR and PFS Results

 

This is also demonstrating figures for the overall response and PFS. You can see on the left-hand side, there is actually a greater change from baseline with the doublet than the triplet on the right-hand side.

 

AREN1721: IO-TKI for Advanced TFE/Translocation RCC

 

We are now diving into non-clear cell RCC. I guess I can pause. Are there any questions so far? Okay, perfect.

 

This trial was looking at axitinib/nivolumab in a specific type of non-clear cell, so translocation RCC. The primary endpoint here was PFS. Then arm B was axitinib by itself. Arm C was nivolumab.

 

AREN1721: Descriptive Statistics by Arm

 

It was closed due to poor accrual. We can see that this is a type of non-clear cell that tends to affect a much younger patient population. You can see the median age here is about 18. There were only 13 patients enrolled.

 

Here, if you look at the bottom, you can see that, again, it is hard to make assumptions from such a small cohort of patients, but very young patient population. The majority of patients had not received prior VEGF therapy.

 

There was a little bit more response rates with the TKI-based therapy, as you can see in the bottom row.

 

SUNNIFORECAST: IO vs SoC in nccRCC

 

SUNNIFORECAST was initially presented at ESMO two years ago and then it was published last year. This is looking at non-clear cell RCC and looks at ipilimumab/nivolumab versus standard of care for investigator's choice.

 

The one thing I want to point out is that the standard of care primarily included single-agent therapy, not IO/TKI. This was a lot of a trial. The majority of patients in the standard of care arm, if they received a doublet, it was not an IO/TKI and the majority received TKI by itself.

 

SUNNIFORECAST: OS (ITT Population)

 

Here the overall survival was significant at 12 months, 78% versus 68%. The median OS was not significant, although it trended in a positive direction, 33.2 months versus 25.2 months. We are not going through all of the subgroups because we have so much to cover in such a short amount of time, but again, this also included very heterogeneous patient population in this trial.

 

SUNNIFORECAST: Subgroup Analysis Organized by Combined Positive Score of Tumors

 

The subgroup analyses according to CPS. You can see that for the patients with a CPS under one versus greater or equal to one, you can see the curves on the right-hand side much more significant than on the left.

 

One of the takeaways from this update was that PD-L1 testing should be considered in non-clear cell RCC to guide treatment selection. We will pause at the end to hear what Brad and Brian have to say about their thoughts with ipilimumab/nivolumab in the non-clear cell space. Then we talked about the 12-month OS being significant, but the median OS not being reached.

 

ALTER-UC-001: Anlotinib + Everolimus as 1L Treatment for Advanced nccRCC

 

ALTER-UC-001. This is looking at anlotinib, which is a TKI that is available in China with everolimus or mTOR inhibitor. It was a single-center, single-arm, phase II study. The primary endpoint here was overall response.

 

ALTER-UC-001: Baseline Characteristics and PFS

 

You can see on the left-hand side that in terms of the pathologic diagnosis, over half of patients had papillary RCC. About 15% had each of collecting duct and translocation. Then one patient with chromophobe and a majority had metastatic disease to lymph nodes, followed by lungs. Here you see a median PFS of 20.8 months. Overall response of 54.5 months. Then you can see the curve displayed here as well.

 

Challenges Translating Clinical Research to Rare Variant Forms of nccRCC

 

There is a lot of challenges translating clinical research to rare variant forms of non-clear cell RCC because it is a heterogeneous group of patients. We often see papillary is the most common followed by chromophobe, followed by collecting duct, translocation, renal medullary, unclassified. Each are distinct subtypes. Yet clinical trials because of the low numbers group them together. There is limited level one evidence. We heavily rely on phase II data and retrospective series.

 

Some of the clinical modifiers can be taken into consideration, including nephrectomy status, risk score, histologic subtype. It is really important to think about pathologic review. There can be misclassification of rare subtypes that can lead to inappropriate treatment selection.

 

We do not have any biomarkers in any RCC at this point that are ready for prime time, but also not in non-clear cell RCC. We saw that the CPS greater or equal to one, predicted enhanced overall survival benefit with ipilimumab/nivolumab in the SUNNIFORECAST trial. We know that patients with TSC 1 and 2 mutations have molecular rationale for mTOR-based therapy, so everolimus-based therapy.

 

We know that MET alterations and FH deficiency could define an actionable subset of papillary RCC.

 

Practical Framework for Real-world Treatment Selection in Rare Variant Forms of nccRCC

 

This is a practical framework for real-world treatment selection and rare variant forms of non-clear cell. They preferred to include clinical trials, single-agent cabozantinib. We have two phase II trials cabozantinib/nivolumab or lenvatinib/pembrolizumab that are also listed here.

 

For the other recommended, we have HLRCC, which has erlotinib/bevacizumab. For TSC, we talk about mTOR. So everolimus is the preferred agent here.

 

We know that there is an approval for any VHL, Von Hippel-Lindau-associated tumor for belzutifan or HIF-2-alpha inhibitor. We are going to hear more about that in the more advanced setting.

 

A bit of a framework to think through non-clear cell is that you want to confirm the histology. There was a world health reclassification in 2022, and risk stratify assessing nephrectomy status, disease burden, matched treatment to biology and evidence and then prioritize clinical trial enrolment.

 

Notable 2026 ASCO Abstracts in RCC

 

I want to point out some notable abstracts. The first one is a prospective multi-center, phase Ib/II trial of first-line cadonilimab plus axitinib in advanced non-clear cell. It was actually presented this afternoon.

 

Cadonilimab is a first-in-class bispecific to PD-L1, CTLA-4 and then combined with axitinib. We heard this afternoon that there was an overall response rate of over 50% in this trial, and they have the dose confirmed. There seem to be a signal in the FH deficient. Again, it was a heterogeneous group and it was a small number of patients. So we cannot make conclusions. So very interesting nevertheless.

 

We will also hear on Monday some more exciting trials being presented, including CBM588, a probiotic as an adjunct to immunotherapy in frontline metastatic RCC. There is also two non-clear cell presentations that will be presented. So EGFR blockade in SMARCB1-deficient renal medullary carcinoma. We know this is the one associated with sickle cell trait. It is very aggressive. It is really interesting to see data emerge for this rare subtype.

 

Finally, the cabozantinib/nivolumab approval that we saw as listed as a preferred option in NCCN. We will hear the final results of this trial on Monday as well.

 

Posttest 1

 

We will go through the posttest. You are seeing a 55-year-old male with IMDC favorable risk who received two years of ipilimumab/nivolumab seven years ago with complete response. His referring oncologist notes that early reports of CheckMate 214 suggest ipilimumab/nivolumab may not benefit favorable risk. What would you tell this patient now about the outcomes of favorable risk patients with ipilimumab/nivolumab based on the final analysis of the CheckMate 214?

 

1. Extended overall survival outcomes continue to favor sunitinib;
2. Extended overall survival outcomes with immunotherapy were similar to those with sunitinib;
3. Extended overall survival outcomes trended better than those treated with sunitinib; or
4. The extended overall survival outcomes were significantly better than sunitinib.

 

Great. It looks like everyone is paying attention. Good job.

 

Posttest 1: Rationale

 

That is the correct answer. It is trending better in favorable risk than it was before.

 

Posttest 2

 

The next question is a 64-year-old man with newly diagnosed RCC, again high-volume metastatic disease. Which of the following first-line regimens would you recommend? Again, let us say this is clear cell.

 

1. Immunotherapy monotherapy;
2. Double immunotherapy;
3. TKI/IO; or
4. TKI/TKI.

 

Great. Most people stuck with TKI/IO. Less people are choosing ipilimumab/nivolumab in this setting.

 

Posttest 2: Rationale

 

I do not think there is necessarily a right or wrong answer here. What you all picked is all reasonable. We will hear what our experts here think.

 

          Panel Discussion

 

On to our experts. What do you think about using ipilimumab/nivolumab in non-clear cell?

 

Dr. Bradley McGregor (Dana-Farber Cancer Institute): Yes, I use ipilimumab/nivolumab in majority of my patients with clear cell renal cell carcinoma. As we start looking at the different histologies, I am using it less and less.

 

When you look at those curves, you just do not see that durability. Like the whole reason for IO/IO is potentially that durability, that tail of the curve. I am using it in select cases, the sarcomatoid features just because they tend to respond poorly to TKI anyways. I am leaning more towards IO/IO, even like the chromophobe sarcomatoid. I am not checking PD-1 in these patients help guide therapy.

 

Dr. Brian Rini (Vanderbilt-Ingram Cancer Center): Yes, I agree. I tend to be an IO/TKI user. I tend to use lenvatinib/pembrolizumab. SUNNIFORECAST taught us that immune therapy is active, but again the control is basically pazopanib, which I would not expect to have much activity. I do not use PD-1/PD-L1 expression in any area of kidney cancer. I just do not think it is helpful.

 

Non-clear cell is this big bag of different histologies and biologies. Ever since I have been doing it, and we sort of do these trials, you get a little of this and a little of that. We are still a long way from truly biology specific therapy in non-clear cell.

 

There is more choices. Companies are doing a better job of actually doing trials in non-clear cell. That was not a thing. That did not exist before. There is far greater efforts and we have made progress. At the end of the day, we still treat them like clear cells, right?

 

Dr. Tawagi: Yes.

 

Dr. Rini: So the proof is still there.

 

Dr. McGregor: With the exception of medullary, right? Medullary collecting duct are very unique, specifically medullary where there is really chemotherapy, carbotaxol. We see the data from Pavlos like panitumumab. One of those patients is mine. He is seven years out from diagnosis, which is just one patient. It is good. It works. So more to see. That is already public, so it is out there. It is exciting data.

 

Dr. Tawagi: That is very exciting for historically such a difficult disease to treat.

 

I will let you take it away next. We are going to move on to the next section.

 

Dr. McGregor: Yes. Perfect. We are ahead of schedule.

 

Neoadjuvant and Adjuvant Horizons: Personalizing Therapy in Early-Stage Disease

 

Basically, we have heard a lot about what to do when a patient develops metastatic disease. Ultimately, I think that we may be curing some patients in nivolumab/ipilimumab, but we are not curing nearly enough patients. As we look to cure, it is going to be really in that perioperative setting.

 

For the first time in a while now, we are having advances showing that we can make a difference in the perioperative setting with adjuvant systemic therapy.

 

Pretest 3

 

Here is one question. This is a 54-year-old male. CT scan, abdominal pain, had a big renal mass, no associated lymphadenopathy. He undergoes uncomplicated right radical nephrectomy, revealing a pT3a grade 4 clear cell RCC with sarcomatoid differentiation. He comes in to discuss his treatment options following the surgery. Which of the following treatment options would you tell him has been shown to improve overall survival?

 

1. Durvalumab;
2. Durvalumab with tremelimumab;
3. Pembrolizumab; or
4. Pembrolizumab and belzutifan.

 

Okay. Majority are choosing pembrolizumab, and then we have a smattering of the other choices.

 

Kidney Cancer: Guideline Recommendations

 

As we think about how do we treat kidney cancer, look at the guidelines. Primary treatment for early-stage disease is going to be surgery. Ultimately, if a partial nephrectomy is feasible, that is indicated. If a patient is not able to have surgery, we can do SBRT in selected patients. I know we are doing more and more of that.

 

Once you have had that definitive local therapy, the question is, what do we do next? Ultimately, we now have some pretty compelling data that pembrolizumab should be offered to certain patients with stage II and patients with stage III disease if they have clear cell.

 

Those patients with non-clear cell, divergent histology, we actually do not have any data to-date that shows that perioperative therapy can improve outcomes, and then patients should be followed to progression.

 

Let us just go through the data a little bit.

 

Outline: Neoadjuvant and Adjuvant Therapy in Early-Stage Disease

 

This is what we are going to look at. What is the principles of adjuvant therapy? We are going to talk about KEYNOTE-564 with the five-year update. Then LITESPARK-022, which was presented earlier this year. The first trial showing combination therapy was effective in the adjuvant setting. Then it would not be a talk from me, on adjuvant on talking about STRIKE, Alliance trial. Then we are going to talk about how do we select the right patients for adjuvant therapy beyond clinical features with some of the newer data that is being presented at this meeting.

 

Principles of Adjuvant Therapy in RCC

 

This is RCC, but this is really any disease, right? Ultimately, for an effective adjuvant therapy, there needs to be a disease that we need to treat. At the same time, we need to have a host capable of responding to therapy and a tumor capable of responding to therapy.

 

Now with kidney cancer, we have no idea how to pick biomarkers in the metastatic setting. It is sort of more throw things and see what sticks. We do have this hope that we can hopefully find the right patients who actually have disease that we need to treat.

 

RCC Risk Models Need Refinement

 

As we go through, we think about which patients need therapy. We have a lot of different risk models out there. You can pick one and be familiar with it. I tend to use the ASSURE nomogram just because it is pretty easy. I can go to the website and just Google it and put the stuff in, and I get a nice curve, can go with the patient.

 

There is different ways to look at this, but each one has different factors that go into place. Usually they involve the TNM. Then they look at grade, size, necrosis beyond that. They give you an idea of how the patient is going to do. As I point out, some of them are better than others. Some of them are easier than others, but none of these are perfect.

 

Ultimately, here in 2026, we are really left with the criteria for the existing trials to help guide who should get adjuvant therapy.

 

Summary of Adjuvant IO Trials in RCC

 

TKIs were tried for a long time and they were all essentially negative. No TKI adjuvant trial was shown to improve overall survival. Sunitinib for a year did improve DFS, albeit with significant toxicities. Then we had multiple IO trials. This is a summary of all that are done. A lot of these actually did not meet the primary endpoint of improving disease-free survival.

 

IMmotion010 with atezolizumab versus placebo was a negative trial. CheckMate 914 with nivolumab/ipilimumab for six months or nivolumab for six months, again did improve DFS overall survival.

 

PROSPER RCC, really good cooperative group trial looking at the role of perioperative immunotherapy, although I would caution that it really, truly was not neoadjuvant chemotherapy. Patients only got one dose of nivolumab. It could have been like a week before surgery. This included divergent histologies, no benefit.

 

Then we had the clear positive trial, KEYNOTE-564 with pembrolizumab, which not only improved DFS but overall survival.

 

Then RAMPART, which we are starting to get data trickling in, we saw the data for durvalumab/tremelimumab presented at ESMO with some quality of life data at ASCO GU, and we look forward to hearing the data on the monotherapy with durvalumab tomorrow.

 

KEYNOTE-564: Adjuvant Pembrolizumab vs Placebo for ccRCC

 

Taking a step back and just highlighting the KEYNOTE-564 trials. Again, this was a multi-center, double-blind, randomized phase III trial looking at the role of adjuvant pembrolizumab. Just want to point out, as we look at this, because this is where we are at today, is who was enrolled in this trial is really how we can decide who we can offer adjuvant therapy to.

 

This is T2 grade 4 clear cell, or T3 any grade, T4 any node positive, as well as this M1 NED. These are patients who had treatment for their primary. In addition, they had treatment for metastasis had to be surgery in this trial, excluded bones or brain within a year of their initial kidney treatment.

 

Patients are randomized to pembrolizumab every three weeks for 17 doses versus placebo. Key primary endpoint was DFS and the key secondary endpoint was overall survival.

 

KEYNOTE-564: Baseline Characteristics

 

Just taking a look at the baseline characteristics, who is actually in this trial? What we expect to see, mean age around 60. I just do want to point out because everyone thinks, “Well, maybe this is all driven by this M1 NED group.”

 

Majority of these patients were M0 intermediate high. This is going to be the T2, T3N0, that was 85%, 87% of the patients. The majority of the patients that you would probably think about offering in clinic. The M0 high-risk was quite low, 8%, M1 NED was right around 6%.

 

As you start thinking about the geographical location, that may come into play if you are questioning, “Well, is this effect of just getting immunotherapy at any point in time where the patient is not able to get immunotherapy in the metastatic setting?” That being said, about 35% were outside of the North America or the European Union.

 

PD-L1 status reported, again, I do not use that in clinic, so that is not that important to me. Sarcomatoid features is notable, just given what we know about nivolumab/ipilimumab with response rates are much higher with IO. We think it may be predictor of response to immunotherapy. So right around 10% of the patients had sarcomatoid features present.

 

KEYNOTE-564: Eligibility Groups and Predicted DFS

 

I do want to take a step back and say, “Well, this is great. This is a patient population and this is the patients we can consider adjuvant therapy for.” If you just look at the eligibility criteria of what was in here, it is very clear. This is a very heterogeneous group of patients. Even though this is considered like the clinically high-risk, if you start looking at these patients that are from different data sets, a T3 grade 1 to 2, their five-year overall survival was 77%; T3 grade 3, down to 65%; T3 grade 4, even lower; high-risk, 36%.

 

Even though we have these different models in place that have the highest risk, even this group of patients in this trial has a diverse risk. If you start using the ASSURE nomogram in the clinic and you counsel a patient in clinic, you put in the features and you change one thing, you can really see how each of these factors can impact the risk of recurrence.

 

KEYNOTE-564: OS and DFS in the ITT Population

 

That being said, in the patient population that was studied in this trial, there was a clear improvement in disease-free survival, hazard ratio right around 0.7, that seems to maintain the curves separate early and they maintain that separation now with the six-year follow-up.

 

This translated into a statistically significant improvement in overall survival with about 6% to 7% absolute improvement in overall survival at that six-year follow-up. So hazard ratio of OS 0.66, hazard ratio for DFS 0.71. Again, it is a clinically and statistically significant data for our patients.

 

LITESPARK-022: Pembrolizumab ± Belzutifan for Advanced RCC

 

I will also comment at what cost. If we look at the data in the study, about 10% of patients needed high-dose steroids for control of immune-related adverse events. There was less than 2%, but very real adrenal insufficiency, type 1 diabetes. When we are talking about the adjuvant therapy, when a patient may not need therapy is something we need to counsel patients on.

 

This has been FDA-approved. It is something that I talk with all my patients about in the clinic, although I will say that a lot of patients may decide they do not want to do it. As I go through the ASSURE nomogram and I say a T3 grade 2 tumor, where they may have a 12% risk of recurrence, and then a couple of years, you do that hazard ratio and the absolute benefit is 3%. It is like, “Well, maybe it is not for me.” So it should be offered to patients where it is indicated, but not all patients will certainly pursue it.

 

The question is, can we do better? In the absence of markers of residual disease, can we get better results with better drugs? That was the idea behind the LITESPARK-022. This was a large trial that was basically started as soon as pembrolizumab came out.

 

When they looked to get pembrolizumab for a year, they did every six-week dosing for up to nine cycles with or without belzutifan, which is a HIF-2 inhibitor. This was a double-blind, placebo-controlled trial in terms of the belzutifan. The exact same entry criteria as the KEYNOTE-564, with the exception that we went to two years for the M1 NED as opposed to just 12 months.

 

Again, same endpoints, DFS. Key secondary endpoint of overall survival.

 

LITESPARK-022: Pembrolizumab With and Without Belzutifan DFS and OS After 28 Mo of Follow-up

 

Here we saw data presented earlier this year. There was actually an improvement in disease-free survival. We can see that at two years, 80.7% versus 74%. That is a statistically significant improvement. Overall survival, incredibly immature as we look at this data right now.

 

It is compelling that a combination therapy may offer improved outcomes long-term. We need longer term follow-up to really determine what is the overall survival benefit going to need to be. Belzutifan is associated with toxicities. Anemia is nearly universal. Hypoxia can happen rarely less than 10% of time, but can be certainly very impactful for our patients.

 

LITESPARK-022: Adverse Events

 

As you see here, when you look at toxicities, 52% greater than grade 3 versus 30% in the pembrolizumab arm. Very few treatment-related deaths. The rates of immune-related adverse reactions were not any higher when we start adding in the belzutifan, but you can see 84% had some degree of anemia, and that anemia could be grade 3 or higher.

 

In the metastatic setting, I use EPO a lot to control the anemia with belzutifan. It is much harder to do in the adjuvant setting, where you are unclear about the benefit, and it involves extra visits and lab draws. So a lot to come out of this if this were to be approved in the adjuvant setting, which, again, we expect to hear an answer in the near future about its role there.

 

Again, no overall survival benefit has been reported to-date.

 

STRIKE (A032201): Short-term Intensified Pembrolizumab and Tivozanib for High-Risk Renal Cell Carcinoma

 

As you look at this trial that I designed four years ago, and it finally opened a year ago. The question is, “Well, can we improve outcomes beyond pembrolizumab?”

 

LITESPARK-022 shows us that combination therapies can be effective. Pembrolizumab and belzutifan, we actually have no data for that combination. In metastatic setting, we have data with pembrolizumab plus TIGIT plus belzutifan. Modest response rates in the 40s.

 

Why not try an IO/TKI? That is the basis behind STRIKE. This is short-term intensified pembrolizumab with tivozanib for high-risk renal cell carcinoma. This is open through the Alliance in 400 sites. We are basically taking the KEYNOTE-564 criteria and saying let us try pembrolizumab. At the same time, could we do a short course of TKI six months understanding in the adjuvant setting? These TKIs are not tolerated very well with pembrolizumab.

 

So the TKI we chose uses tivozanib given its very favorable toxicity profile. Full dose tivozanib with pembrolizumab versus pembrolizumab with primary endpoint of DFS. Then we are looking at overall survival, tolerability, safety. Quality of life, we are collecting blood for biomarker for MRD analysis in the future.

 

This trial is open. I would encourage you, if you have it open, to hopefully support it, and we can help answer this important question and collect samples that will help us decide who really needs therapy in the future.

 

IMmotion010: Adjuvant Atezolizumab vs Placebo in Resected RCC

 

To that point, where are we in terms of adjuvant therapy, predicting who needs therapy? We know we saw data today when we started looking at the role of ctDNA. ctDNA is great in urothelial carcinoma. We have an FDA approval for atezolizumab based on ctDNA positivity. There is data presented today from Toni Choueiri looking at ctDNA analysis in the KEYNOTE-564 trial. It does not really work that well.

 

Yes, ctDNA positive patients do worse. They derive a benefit for pembrolizumab. It was less than 10% of patients who were actually ctDNA positive. So it is not a great marker to predict who does not need therapy, right? Just because you are negative does not mean you are not going to relapse and do not benefit from immunotherapy.

 

That being said, there is some excitement around the role of KIM-1. KIM-1 or Kidney Injury Molecule-1, not a great name. This is markedly elevated in kidney cancer. As I alluded to earlier, IMmotion010 was atezolizumab versus placebo and very similar patient population to the KEYNOTE-564, so for the M1 NED group. A negative trial, but they started looking at KIM-1.

 

Circulating Protein Biomarker in RCC: Kidney Injury Molecule-1

 

Again, KIM-1 not expressed by healthy kidney injury molecules. It is expressed in the setting of renal injury, but it is markedly higher in the setting of metastatic renal cell and specifically any renal cell but specifically clear cell and papillary. We had some nice data presented earlier this year from a poster showing that chromophobe actually does not secrete KIM-1 at all.

 

Elevation of KIM-1 in Plasma Years Before RCC Diagnosis

 

Elevation of KIM-1 can be seen in the plasma years before diagnosis. This is looking at patients from the EPIC study. Among 180 patients with RCC, KIM was elevated in banked plasma up to five years prior to diagnosis versus matched controls.

 

Serum KIM-1 is a Circulating Biomarker Associated With Outcomes in Adjuvant RCC

 

It is very interesting that it is associated in the IMmotion010 as a circulating biomarkers associated with outcomes in adjuvant RCC. We can see that patients who are KIM-1 high post-surgery, that is a poor prognostic marker. They had a higher risk of relapse.

 

When those patients then got adjuvant atezolizumab, we were able to flip. That is showing that this selected for patients at a higher risk of relapse and patients actually benefit from atezolizumab, whereas those patients where KIM-1 low, they have a lower risk of relapse and there is no benefit to atezolizumab.

 

It is intriguing, a biomarker analysis looking at that study. This is not something that is available. It is not an FDA. There is CLIA-certified labs, but it is not a readily available test. At this point, it should not be used yet to make clinical decisions, but there is a lot of interest in it.

 

Persistent Plasma Levels of KIM-1 Post Nephrectomy Is Prognostic

 

Again, if you look at other trials, persistent levels of KIM-1 post nephrectomy remains prognostic. This is looking at ASSURE trial, CheckMate 914, IMmotion010.

 

NeoAvAx: Avelumab Plus Axitinib as Neoadjuvant Therapy in Intermediate to High‑Risk Localized RCC

 

More to come. ctDNA is certainly not something we can use right now using current assays. As we look at potentially better next generation assays, that may change.

 

KIM-1, more to come. We look forward to seeing further analysis from the KEYNOTE-564.

 

We know in other cancers, melanoma, for instance, or even bladder cancer now, that perioperative immunotherapy improves outcomes, right? Giving the immunotherapy before the surgery when there is maybe more the tumor is in place, you have a better, different immune environment that can lead to improved outcomes. There has been opportunities to try to look at this in kidney cancer.

 

The NeoAvAx, which is looking at avelumab plus axitinib in neoadjuvant therapy in intermediate to high-risk localized RCC. This was clear cell, again patients received axitinib plus avelumab. They were looking at radiographic response looking at PR and then secondary endpoints looking at long-term toxicity EFS and overall survival. There was some pretty encouraging results that were seen in some early analysis.

 

PELUR: Neoadjuvant Lenvatinib Plus Pembrolizumab in ccRCC

 

We have another trial looking at neoadjuvant plus lenvatinib plus pembrolizumab. Again, 23 patients. What these trials are showing is that it is feasible to give IO/TKI in the neoadjuvant setting. As you start thinking about this as a large scale model, I think the question is really going to be, how do we identify these patients in the real-world? Because it is not a standard of care to do a biopsy before you go nephrectomy.

 

Patient comes with a renal mass. It is seven centimeters localized. Will I take it out, right? So we do not get that biopsy. As we see, both of these trials are only clear cell. So you have to have clear cell.

 

The second thing is you start looking at T3. How do we decide T3? We are not great at doing that on imaging. Do you get an MRI on every patient? Do you have an expert radiologist?

 

As we start thinking about bringing this up to scale and how do we identify these patients, there is going to be challenges. It is something that we can certainly think about doing, and there is trials that are in development right now through the Alliance trying to hopefully answer that question.

 

RAMPART: Adjuvant IO for Resected Primary RCC

 

Finally, we are just going to talk about the most recent data. Again, we talked about IO, PD-1 blockade alone. We talked about adding targeted therapy. Then what about [inaudible]. We saw this did not work with the addition of ipilimumab to nivolumab, despite the extended dose of ipilimumab. A lot of toxicities, patients had to stop early. It was only six months. A lot of unanswered.

 

This is RAMPART, which is looking at adjuvant IO for resected primary renal cell carcinoma. They used a Leibovich score. Instead of just doing TNM, they use a Leibovich score which takes in TNM as well as grade and size, different factors into play.

 

Patients were randomized to durvalumab alone, durvalumab with tremelimumab with only two doses of tremelimumab or active monitoring. This was in Europe. There was no placebo.

 

We have seen data presented for durvalumab/tremelimumab versus active monitoring already. We will see the data on durvalumab monotherapy versus active monitoring tomorrow. What I will note is this trial actually did include patients with divergent histology, so non-clear cell was included.

 

RAMPART: Baseline Characteristics and Unique Eligibility Using Leibovich Score Calculation

 

As you start looking at this, again, it is unique eligibility using the Leibovich score, which again is listed here. If you look at the age randomization, right around 60, similar to what we saw with the KEYNOTE-564. 16%, 17% of the patients were actually the divergent histology, the non-clear cell.

 

If you look at the Leibovich score breakdown, about 44%, 45% were the intermediate, about 50% were high-risk and only 5% were M1 NED. So quite low.

 

RAMPART: DFS Among the ITT Population, High Risk, and Intermediate Risk

 

Here was the data that we saw presented last year, that intention-to-treat population. There was statistically significant improvement with durvalumab/tremelimumab versus monitoring. If you break that down a little bit further and say, “Well, what about using a Leibovich score. Do all patients benefit the same?” We see those patients with high-risk clearly benefit, but not those with intermediate risk.

 

RAMPART: Adverse Events

 

This is associated with significant adverse events, more than we saw with KEYNOTE-564, actually cross-trial comparisons, but it is very real. 32% of patients had discontinued treatment for toxicities. We see diarrhea. Colitis was by far and away the number one.

 

Notable 2026 ASCO Abstracts in RCC

 

We look forward to seeing the monotherapy, as we alluded to. I already talked about the data on ctDNA. Ultimately, at the end of the day, adjuvant pembrolizumab should be offered to our patients. What is their experience? If patients get toxicity, what are their impact on that? Very interesting abstract looking at decision regret and toxicity perception in those patients who received adjuvant pembrolizumab. So I really try and take that patient voice into the decision-making process.

 

Posttest 3

 

We are going to go back to our question again. Remember, this is our patient, resected T3 grade 4 clear cell disease, sarcomatoid differentiation. Which of the following has been shown to improve overall survival?

 

1. Durvalumab;
2. Durvalumab/tremelimumab;
3. Pembrolizumab; or
4. Pembrolizumab/belzutifan.

 

We got even more the correct answer.

 

          Posttest 3: Rationale

 

Yes. Pembrolizumab right now is the only one that has been shown to improve overall survival. Hopefully, that is going to change with trials that are in development right now or that have been completed with the LITESPARK-022. We are going to have more options to improve outcomes.

 

Hopefully, we will be able to better identify which patients need therapy through better MRD assessments.

 

Panel Discussion

 

With that, we can open up to discussion. One of the things we always think about is how does this perioperative therapy change our experience in the clinic when we talk to patients?

 

Dr. Tawagi: Yes. There is actually a question on here. One of the question is for the tornado plot for pembrolizumab/belzutifan. Does this still represent hypoxia? Several patients may be hypoxic without dyspnea. So wonder what the true rate of hypoxia was?

 

Dr. McGregor: On this trial, whenever I use belzutifan, yes, most patients with belzutifan never actually feel. They do not feel it. You have to educate patients. They need to be checking the pulse ox at home on a regular basis. You need to call them if they have those.

 

Patients on the trial would have pulse ox done in the clinic all the time. Patients were monitored quite closely.

 

Dr. Rini: You may have alluded to this, but pembrolizumab/belzutifan is not approved, but say it is. Would you use it in clinic or would you wait for survival?

 

Dr. McGregor: I would wait for survival at this point in time. If you look at those curves, the survival curves are very close to each other. I like subjecting patients to more therapy in the same way they may not need disease. I want to make sure I can improve survival.

 

Dr. Rini: Yes. Karine, do you agree?

 

Dr. Tawagi: I agree with the caveat that for a younger patient that had high-risk features, I would be inclined to see if I could get it approved in the absence of overall survival data. I would love to have it.

 

Dr. Rini: Yes, would not preclude you from using it.

 

Dr. Tawagi: If I have a 40-year-old patient that has high-risk resected. We have the STRIKE trial, so I would of course enroll the patient on STRIKE. If I did not, then I maybe would consider it just because, I do not know you want to. I know there is a 10% rate of transfusions or ESAs and all of that. You would think that a young patient would have the reserve that they would not have that issue per se with belzutifan. For the most part I would say, no, I would not use it, but I may be compelled.

 

Dr. McGregor: I get that I want to do more for the high-risk patient, but is belzutifan the answer there? If you look at the plots again, you should look at subgroup analysis like the M1 NED, there really was not a big group. So there was no difference in that group.

 

I am wondering what is the belzutifan doing? Is it truly improving outcomes for the highest risk patients or is it giving a benefit in those maybe different patients? I do not know.

 

Dr. Rini: I would suspect it is probably doing more in the lower risk.

 

Dr. McGregor: That was my guess. We do not know.

 

Dr. Rini: We do not know, and we just need more data like a lot of things. Codi[?], did you want to ask a question?

 

Speaker: [Inaudible].

 

Dr. Rini: It is a good point. I would not tell Mark you compared it to sunitinib. First of all, it will get approved based on DFS. I do not think there is any doubt about it. I have no inside knowledge but I think that is fair.

 

Going to many ad boards after that data was presented, a lot of people felt like they wanted to wait. Remember, even in high-risk kidney cancer, half the patients do not recur, right? The trouble with giving adjuvant pembrolizumab monotherapy is you only have the chance to harm 50% of the people, right? You cannot help people who do not have a risk of recurrence.

 

Now you are doubling down on that. Now you are doubly harming those people who do not have that risk of recurrence for a significant benefit. I would say is I do not call it marginal, but it is not an overwhelming. If there is survival, then okay, we might think about it a little differently. To your point, I do not know every clinician…

 

The palatability of pembrolizumab plus belzutifan is different than sunitinib also. Right when that data came out, the IO trials were starting. It was just the timing was poor as well. I have given it to exactly one patient, so I do not use a lot. But your point is a great one.

 

In terms of neoadjuvant therapy, I have done a lot of neoadjuvant trials. I love it, but it is just like it has not gone anywhere in 25 years. It is a really hard place to sit because we do not have pathCR like bladder.

 

Dr. McGregor: Correct.

 

Dr. Rini: We do not have the endpoints. I am just not really sure what the path forward is. I do not know what your thoughts are.

 

Dr. McGregor: No, I agree. The neoadjuvant space, the therapy space is very challenging. Because again we do not generally get tissue before surgery. So you have to do that in clear cell. As you look forward, we have seen so far, at least with short courses like pathCRs are not really happening in the kidney. The thought is maybe it does something that affects the metastatic disease.

 

Really, when you do it, you are going to be looking at event-free survival as a meaningful endpoint, which is going to take more time. You are not going to get that quick pathCR surrogate, but it is not stopping the attempts.

 

Dr. Rini: It is not stopping the trials, yes. Karine, I do not know if you have thoughts.

 

Dr. Tawagi: Yes, I do not think in the localized setting, but sometimes in the downstaging of oligometastatic, maybe those people have a role for neoadjuvant type therapy and then more definitive therapy after.

 

Dr. McGregor: The struggle should not stop us from moving forward. Trying to do a well-designed neoadjuvant trial could be certainly very meaningful for the field. It is just going to make sure you are very methodical in selecting the right patients for the trial.

 

Dr. Rini: Yes. I would love to see neoadjuvant pembrolizumab versus adjuvant versus both, right?

 

Dr. McGregor: Right. Exactly.

 

Dr. Rini: It will never happen, but I would love to see that trial. Based on what we see in melanoma and other cancers, the neoadjuvant has been gangbusters. Like just neoadjuvant, right? VOLGA we will see in bladder cancer, which will show us the same thing.

 

Dr. McGregor: Trials like that are in development right now with the cooperative group. So hopefully more to come.

 

Refractory Renal Cell Carcinoma: Multidisciplinary Insights and Future Directions

 

Dr. Rini: Great. I am going to bring it home here. I am going to talk about refractory kidney cancer.

 

Pretest 4

 

Pre-test number four. You are considering a patient on belzutifan/lenvatinib which is a combination just presented data I will show you. That was LITESPARK-011. During the discussion, which talks would you explain was the one most frequently observed in LITESPARK-011, again, which was lenvatinib/belzutifan versus cabozantinib that you will be monitoring? Is it:

 

1. Anemia;
2. LFT elevation;
3. Diarrhea; or
4. Hypertension.

 

Almost uniformly for anemia. Yes, it is the right answer. Anemia is common. We will go over it at the end.

 

Pretest 5

 

Next question. 68 female, who got a nephrectomy four years ago, did not get adjuvant therapy. Two years later, then she presents with lung and liver metastases, was started on pembrolizumab/axitinib with initial PR but then progressed after 18 months. At this point, has high-volume symptomatic disease with bone pain and weight loss. So a second line patient but with high-volume disease. Which option among these four has the highest objective response rate?

 

1. Belzutifan monotherapy;
2. Lenvatinib/belzutifan;
3. Casdatifan, which if you do not know, is a HIF inhibitor; or
4. Tivozanib.

 

My questions must have been easier than your questions. Okay, lenvatinib/belzutifan, 88%. We will talk about all this.

 

Stage IV and Relapsed Disease

 

This is the NCCN guidelines on stage IV and relapsed disease. The left-hand column says it all, like preferred is none. As the frontline in adjuvant space that you just heard about has really undergone a transformation in recent years, the refractory space has been reshuffled, and lagged behind until recently with some data.

 

Basically everything else falls into the other. This is how it plays out in practice, right? We all give adjuvant. We all give a little bit different frontline. That splay is even more present in the refractory space. I just have my sequence that I do and Brad and Karine, their sequences. It is not right or wrong.

 

Generally, I think, absolutely, once you get past first-line IO therapy, you are not curing patients. Then it is just a matter of what is your favorite regimen or drug for disease control and toxicity and what are you comfortable with? That is true in all lines. It is especially true in the refractory setting.

 

Key Randomized Trials in Patients With Previously Treated Advanced RCC

 

These are just a rundown of trials in refractory kidney cancer going from left to right, older trials. The AXIS trial which led to its registration. Nivolumab, this is the initial trial that led to its registration. CheckMate 025. Cabozantinib. Lenvatinib/everolimus was a randomized phase II. Then you get into some of the phase IIIs more recently with tivozanib and then most recently with belzutifan.

 

If you look about halfway down to that objective response rate, they are pretty consistent in that 20% range, 20%, 25%. Lenvatinib/everolimus stands out. It is also only a randomized phase II. The others are phase IIIs for what it is worth. You see survivals maybe in that two-year range, not quite. Almost no matter how you slice it, refractory kidney cancer response rate has been in this range. Again, all these regimens come with their share of side effects. We will talk a little bit more in detail.

 

Outline for Refractory Renal Cell Carcinoma: Multidisciplinary Insights and Future Directions

 

We are going to talk about LITESPARK-005 which was belzutifan monotherapy. LITESPARK-011 which was lenvatinib/belzutifan. ARC-20 is with that casdatifan and PEAK-1. Again, there is other HIF inhibitors that are coming.

 

Then the last three, the last part of my talk will be about some of the novel therapies that are starting to emerge.

 

LITESPARK-005: Belzutifan vs Everolimus in Advanced ccRCC After Prior VEGF TKI/IO Therapy

 

This is LITESPARK-005. It was the registration study for belzutifan. There had been single-arm trials of belzutifan in a lot of different settings. Response were in the 20%, 30%, very well tolerated. Its calling card then and now is its tolerability.

 

This was the registration trial. You see one to three prior systemic regimens. All patients had at least one prior immune therapy and at least one prior VEGF therapy. 750 patients randomized equally, looking at PFS and OS.

 

Everolimus was the comparator. This trial was written a really long time ago. Was an old standard of care at the time. I do not give much single-agent everolimus now, so probably not the most contemporary standard of care but the control arm nonetheless.

 

LITESPARK-005: PFS and OS

 

Here is the PFS and OS. It is a little bit interesting. If you look at median PFS is identical. Those curves essentially overlap until you get to about six months and past that 50%, past the median. Then you see this almost immune-like tail of the curve with belzutifan. This is probably for a few reasons.

 

Mostly, belzutifan is not a quick acting drug. When I am putting a patient on belzutifan monotherapy, I tell them, “Hey, we may not see anything on your first scan at three months or even your second scan. It is just not a drug you expect to act right away.”

 

If I had a patient with high-volume symptomatic disease, belzutifan monotherapy would not be my drug of choice, assuming I had some other TKIs that I have not given them.

 

You see the hazard ratio is significant, 0.75. That is obviously entirely made up of that tail of the curve. Most impressive if you look at that two-year landmark, 4% versus 17%. There is still almost 20% of patients in this very refractory setting who are still on drug with disease control two years later.

 

When I first saw these data, I guess a couple of years ago, now that is what struck me. It was not the medians, obviously, which are not different or even the hazard ratio, which is okay, not amazing. It was that tail of the curve, which is notable in a refractory setting.

 

Unfortunately, survival was not positive. You start to see a little bit of separation, maybe a 12 or 15 months or so. Then a lot of censoring after two years. A little difference in the medium, but again, a hazard ratio of 0.92 not significant.

 

LITESPARK-005: ORR and DoR

 

This is response rate and duration of response. On the left, the table of response rate, 23%. One of the other notable things for me was that the response rate. A phase III trial is a great equalizer, right? The results are always worse than the phase III than the phase II. This actually held up, not for the PFS but for the response rate, it was almost identical to the prior studies.

 

You see there are CRs. I do not know that I see that many CRs in clinical practice, but I think it is possible. The Achilles heel of belzutifan, if you look at that response table is progressive disease in 34%. Again, it is not a quick acting drug. The response rate is 20-some-percent but it is not 80%. Again, there are a third of patients in this study who had progression as their best response. It is important to understand that clinically.

 

The duration of response. Again, this was the first signal and it was recognized. When I show you the LITESPARK-011 data, etc., we are seeing a pattern that belzutifan-containing regimens, be it monotherapy or combinations, have an element of durability to them and an element of tail of the curve. Again, that is just the nature of how belzutifan works as a HIF inhibitor.

 

You see that time to response of four months. That is probably the second scan on the study. That duration of response of 19 months is not that different than the IO/TKI regimens, which are 22, 24. It is a little less, but it is not remarkably less.

 

Belzutifan Any-Grade AEs: Time to First Onset and Duration

 

This is a composite table I made with the common AEs, anemia being the most common. Correct. Then time to onset and duration. You can see the time to onset is fairly early for all these drugs. So you know what you are in for with belzutifan. If you manage it right away, my favorite patients in clinic are on belzutifan 18 months later, totally cruising, barely any side effects. They might be on erythropoietin for anemia, but day to day they are doing great, much better than people on TKIs at 18 months.

 

I have not transfused a patient for belzutifan-induced anemia in a really long time, so I use erythroid-stimulating agents. I use them early and often. I will give them a few doses. Their hemoglobin climbs up and then I hold it and then it drifts down and I start it again. It is super easy. Patients can do it at home.

 

Hypoxia, as mentioned, is unique. It is not just in patients who have lung disease. It is a bit idiosyncratic. I tell people to just get a pulse ox. A lot of them have them from the COVID days or buy them on Amazon or whatever. As Brad said, they do not often have dyspnea. So they are not calling in because they are dyspneic. They are calling in because their pulse ox is 86% and they are freaking out.

 

You have to warn people that it is okay because when you have a quantitative number, patients cannot see their hemoglobin level. They just know they are tired. But when they see a low pulse ox, it can cause a fair amount of anxiety and then they are messaging over the weekend and we get the message Monday, etc.

 

You see that duration is especially short. You just stop the drug. Hypoxia gets better. You can restart at a dose reduction. My clinical experience is that if they get into trouble early on, if they are hypoxic on day four, even dose reduction is not going to work. I will be interested what you guys have seen.

 

Then you see the other ones. On the bottom is super interesting, this weight increase. This drug and this mechanism is being studied in cancer-induced cachexia because the weight increase, I do not think it is just from that their cancer is controlled. There is something else going on here and we definitely see it in patients.

 

ARC-20: Casdatifan PFS With 100 mg in Metastatic ccRCC

 

I mentioned casdatifan. Casdatifan is another HIF inhibitor. It is not yet FDA-approved but in trials. They have done a trial called ARC-20 that they have presented at multiple meetings. I am not sure there is data here, but it is a multi-cohort study. It was monotherapy in different doses and combinations, etc., etc.. There is now a frontline cohort. This is just some of the initial clinical data.

 

100 milligrams daily is now the phase III dose. This was data presented at ASCO GU. You see the confirmed objective response rate of 45%. Remember, belzutifan in this setting was 20%-ish. Maybe it was up to 29%, 30%. Again, a bit of apples and oranges. Different trials. I totally get it. That number jumps off the page a little bit.

 

The company will tell you there is better pharmacokinetics and pharmacodynamics with this drug. If that is true, that may be reflected in the response rate. They have done some really nice work that I do not think I have slides on, on biomarkers and drops in serum Epogen is a biomarker of response. This drug in this pathway is made for a biomarker, and we are actually going to get there. We are not there yet, but we are going to get there.

 

You see the median PFS of 15 months. In these refractory studies, those time to event endpoints are really hard to interpret. I know patients that I put on this study had been on multiple treatments. They tend to have long time to event endpoints, but the response rate is impressive.

 

You see here the PD rate of only 10%. Again, contrast that with belzutifan data of 34%. Again, a bit of apples and oranges. There is some early signals here that this may be a bit different than belzutifan.

 

PEAK-1: Casdatifan Plus Cabozantinib in Advanced or Metastatic ccRCC After Progression With Prior Anti–PD-1/PD-L1 IO

 

This is the registration trial. It is ongoing now. It is accruing. As I mentioned, they did a combination cohort in that ARC-20 with cabozantinib that I have not shown you, but decided on this as a registration study, refractory kidney cancer, cabozantinib monotherapy being a standard of care and looking at this combination. PFS, primary endpoint.

 

LITESPARK-011: Belzutifan + Lenvatinib vs Cabozantinib for Advanced RCC

 

On to belzutifan-based combo. LITESPARK-011 was presented at ASCO GU. This was also refractory kidney cancer. This was the combination of lenvatinib standard 20 milligram daily dosing and belzutifan against again cabozantinib which has been the monotherapy standard of care in the refractory setting looking at PFS 750 patients.

 

LITESPARK-011: PFS and OS

 

What was demonstrated was a significant advantage in progression-free survival. You see a hazard ratio of 0.7 and a pretty big split of the curves. Again, you see at that 24-month mark, almost a doubling of the landmark PFS, 19 to 36, right? Again, there is just something about belzutifan that gives you that more elevated tail.

 

Now again these patients are probably on combo, not belzutifan monotherapy. We can talk about that as pluses and minuses of using belzutifan in this combination versus monotherapy, which I think is the clinical question.

 

OS was not yet significant. You can see the curves start to split at about maybe 15 months or so. Again, needs more follow up. I assume at a meeting coming up near you will see this follow up. This is important as well. It has been hard to show survival in the refractory kidney cancer space. Very few drugs have done it and they have mostly done it against everolimus. So we will see what these data turn out.

 

LITESPARK-011: DoR and ORR

 

Duration of response. Again, you see that nice tail of the curve, almost a 50% at 24 months, right? If I told you this was an immune drug, you would believe it, right? It is like, yes, you get some upfront progression, but you get durability, etc.. These are the numbers response rate. This was that the answer on one of the questions, 52.6%.

 

Cabozantinib did well in this trial. Cabozantinib performed exactly as you think it would. 40% response rate. PFS was about 10 months. We are seeing benefits. It was not that the control arm performed weekly. It was that this is clearly an active combination.

 

You see some CRs. Here, you see PD at only 6%. When you introduce a TKI in the regimen, your primary PD rate goes down. That would be the advantage of giving this combo is if you had that patient that we presented with more bulky disease and you need upfront disease control, belzutifan monotherapy with a 34% primary PD rate versus a combo with less than 6%.

 

LITESPARK-011: Any Grade Common TEAEs

 

These are the AEs. It was Katy Beckermann who did the discussion there and she showed this tornado plot and she had this cool graphic where it spun back and forth, and you could not tell which arm was which. I still do not know how she did that, but making the point.

 

I always tell patients, two drugs always have more toxicity than one. I still think that is true, but it was not as much worse. There really was not that much difference in the arms. You can read the numbers here. Actually cabozantinib monotherapy for instance with more diarrhea.

 

As you know, TKIs all have the same side effects, but they all have a unique profile. The numbers are the numbers in this large trial. I do not think it was quite as bad, especially with lenvatinib at 20. If any of you give lenvatinib/pembrolizumab with lenvatinib at 20, it is a tough drug at 20 milligrams. I would say it was surprisingly well tolerated in this trial.

 

Although in the box, you see the cardiac dysfunction 7% versus 1.1% and grade 3 basically 5% versus very little. They did not give more detail. We really need more detail on that because that is a pretty high number, right? 5% to 7%. I do not know if that was just numeric reductions in EF without clinical significance. I do not know what it is. I do not think they ever report it. So we will find out. That would be an important consideration.

 

Emerging Horizons: Cellular Therapy in Advanced RCC

 

Moving on. Last several slides are about just novel therapies. Kidney cancer, we need more therapies. We have been talking about VEGF and PD-1 for a really long time. We need novel mechanisms. These are just a smattering.

 

There is some CAR T-cell constructs. This CTX130 and the ALLO-316 are CAR T cells directed against CD70. We are starting to get little bits of data. You see in the bottom left there, the dose levels, one CR mostly stable disease. This drug has gone back. There is a second generation trial that is starting.

 

ALLO-316. This is out of the Memorial Group. They reported these data, I cannot quite remember, but at a recent meeting showing a fair amount of activity. Again, this is all refractory kidney cancer. We have not seen a lot of CAR T data in kidney cancer like many other diseases. Cellular therapy, broadly speaking is, in my opinion, probably the most promising at least area of kidney cancer.

 

On the right is bispecific T-cell engager, this xmAb. This is an ENPP3-directed therapy and some data presented at the EORTC meeting, which showed again some pretty impressive activity. There is a large trial going out now. It is also overexpressed in papillary kidney cancer. We have mostly developed drugs in clear cell and then we apply them to non-clear cell. This is an example where it is being developed in both at once.

 

TRAVERSE: ALLO-316 in Advanced or Metastatic ccRCC

 

This is just the schema for that ALLO-316. Again, we are going back to fludarabine/cyclophosphamide and lymphodepletion. It takes me back to my fellowship transplant days. There is a lot to learn. It is a bit embarrassing to me that a lot of our cellular therapy is behind prostate cancer. We are the immune responsive disease, right? We should have developed this. I am not really sure why. Honestly, I have not been personally involved in a lot of this, but it is an area that needs to move forward, and it finally is starting to move forward a bit.

 

Phase I Trial of NeoVax, a Personalized Neoantigen Cancer Vaccine, + Ipilimumab in Advanced RCC

 

This is NeoVax. It is a neoantigen cancer vaccine, as the slide says. Vaccines have been around for a really long time in kidney cancer since I started doing it. They have never really made much of an impact here. Whether this will? Obviously, we now have drugs like ipilimumab and ipilimumab/nivolumab that are certainly more potent immune stimulators than we had in the past.

 

We are going to start to see more of these personalized cancer vaccines enter into the clinic. This is an open-label, phase I trial. Again, there is not big data. There is not phase IIs. There is not randomized data. Of course, we are just starting to get some of the initial trials, I should say.

 

Emerging Horizons: PD-1/PD-L1 x VEGF Bispecific Antibodies

 

The other most exciting area I would say is bispecific. This is a table of several different PD-1/PD-L1 VEGF bispecifics combining the obvious two mechanisms in kidney cancer. They all have different formats and binding arms, and I would not read all that to you, but there is different molecular biochemical characteristics that may make a difference. Certainly some are PD-1 and some are PD-L1. That will probably make a big difference.

 

There is trials going on. There is a multi-cohort trial that just started combining it with ipilimumab, axitinib and maybe a HIF inhibitor. I have a slide.

 

IVORY: Ivonescimab in Patients With Advanced ccRCC Following ICI

 

Ivonescimab. Ivonescimab has this trial at MD Anderson looking at two different cohorts of post-ipilimumab/nivolumab, post-IO/TKI. There is plenary data in lung cancer that is being presented. Let us go back a slide.

 

Emerging Horizons: PD-1/PD-L1 x VEGF Bispecific Antibodies

 

Then you see a number of other compounds. They are pretty much almost every of the major companies either has a bispecific or has in-licensed it from a Chinese company where a lot of these have originated. You are about to see probably starting maybe in a year from now, some of the phase I, phase II data with these bispecifics.

 

The big question is, are they going to be any different than just giving IO/TKI? I do not know the answer to that. If they are not different efficacy-wise, maybe they are going to be safer and easier to combine because we have not successfully done triplets yet in kidney cancer. So maybe this allows us to attack two targets with one drug. That will be the way to move triplets forward. But all remains to be seen.

 

Poll 4

 

Poll four. Which innovation do you predict will most impact care by 2028? Two years. I am not sure how we picked that year, but two years, or let us just say into the future.

 

1. CAR T;
2. HIF-2-alpha inhibition;
3. Vaccines; or
4. Something else.

 

If you vote for something else, we are going to ask you.

 

Yes. It is impacting it now. We probably should have put something else there. I agree. It is hard to argue with that because there is already FDA approved drugs and clinical data and other phase IIIs ongoing. CAR T-cell therapy, I would probably just broaden that and say cellular therapy. Then maybe bispecifics. I am going to ask you guys, what do you think? You do not have to go by the answer.

 

Dr. Tawagi: Bispecific. I am going to say bispecifics.

 

Dr. Rini: You are going to say bispecific.

 

Dr. McGregor: Yes, I am going to say bispecific.

 

Dr. Rini: Okay.

 

Dr. McGregor: The vaccine story is interesting. That is really interesting. We have the NeoVax trial we presented. We had reported like 10 patients. No one relapsed at four years of follow-up with just the vaccine alone without any immunotherapy. We have the personalized mRNA vaccine. That is really potentially a development in the perioperative space that is going to build upon pembrolizumab and hopefully do better as well.

 

Dr. Tawagi: Is it the same agent that is the squamous lung, do you know? The bispecific.

 

Dr. McGregor: Yes.

 

Dr. Tawagi: Yes. It is the same one. Yes.

 

Dr. McGregor: Yes. 

 

Notable 2026 ASCO Abstracts in RCC

 

Here is some abstracts. Rana presented the RADICAL study today. This was cabozantinib plus/minus radium in RCC patients with bone metastases. If you take care of patients, these are terrible morbidity from bone metastases. We desperately need therapies. The TKIs do not work well. None of our treatments work well in patients, not like with one bone met that can be radiated. But multifocal disease, those patients do well.

 

This did not show a difference in skeletal-related events, which was the primary endpoint. Good effort, organ-targeted therapy but did not show a difference in this study.

 

There is some belzutifan-based. This HC-7366 I think is a stress response pathway inhibitor. We are starting to see a belzutifan-based combos. Why it is active. The second reason is very combinable. A whole lot easier to combine with belzutifan than a TKI. This is an example. Ben Garmezy at Sarah Cannon down the street from me. But there is going to be a lot of these.

 

That middle one is an imaging study. We have not really talked about imaging, but there are CA IX-directed imaging agents now. Obviously you can attach therapeutic moieties to them. That is another area that I would not talk about.

 

A lot of belzutifan-based abstracts here. I do not know these data. I am not sure I have seen them, but again, there is more biomarker works starting to come out now with belzutifan, casdatifan and HIF. We are doing a much better job of developing biomarkers of HIF inhibition than we did with TKIs or IO. There is another oral HIF inhibitor.

 

Also put in a plug Clinical Science Symposium tomorrow morning where RAMPART is being presented and the decision regret analysis from Elizabeth now, which is fascinating data, by the way. So get up early and be there.

 

Faculty Debate Integrating Agents in Post-progression Settings

 

Maybe I will ask you guys, both of you. I am going to sit down, but I will ask both of you how you have integrated belzutifan in your practice? Where are you using it? Early, late? Let us assume lenvatinib/belzutifan gets approved. Will you give everybody combo, or if not, who would you still give belzutifan monotherapy to? Whoever wants to start.

 

Dr. McGregor: We have been using HIF-2 inhibitors for a while on trial, and so I feel comfortable with it. To your point, those patients where it works, it can work really well with a great quality of life. I have been using it in patients without underlying lung disease, with more indolent disease, and I will use it.

 

Dr. Rini: Which line of therapy are you…

 

Dr. McGregor: I will use it like second or third. I find usually using it earlier just have better reserves and they can tolerate that PD maybe a little bit better.

 

Dr. Rini: Yes. Fair enough.

 

Dr. McGregor: I have used lenvatinib/belzutifan technically off-label and patients right at that point where they are really progressing rapidly. I am never going to give them a chance to get belzutifan.

 

Dr. Rini: If both are approved, you preferentially give belzutifan monotherapy and use lenvatinib/belzutifan in high volume?

 

Dr. McGregor: I would give lenvatinib/belzutifan if I had a situation where I do not think they are going to tolerate that 35%.

 

Dr. Rini: But you would not necessarily give it to everybody?

 

Dr. McGregor: I do not think so. Because like you said, patients who are on belzutifan and works, they love it. They are like, this is the best life ever. So I do not want to lose that.

 

Dr. Rini: Karine, what do you think?

 

Dr. Tawagi: No, I would agree. I would use belzutifan/lenvatinib in select high-volume cases, but otherwise thinking about, again, you are already have the toxicity of continuous TKI for someone with palliative intent treatment. So balancing quality of life for somebody in that situation.

 

Dr. Rini: What if there is a survival benefit?

 

Dr. Tawagi: That will be very compelling. I do not know. I still feel that in the real-world, the toxicity will be a bit different than the tornado plot that we saw.

 

Dr. Rini: Yes, I agree.

 

Dr. McGregor: I would be curious if there is a survival benefit, how many patients on the cabozantinib arm got belzutifan after cabozantinib? Is that just an effect of getting belzutifan at some point in time versus not?

 

Dr. Rini: Yes. I do not think they have presented data yet on subsequent therapy.

 

Dr. McGregor: Based on when the trial was.

 

Dr. Rini: Karine, where do you tend to use belzutifan did you say?

 

Dr. Tawagi: Post IO/TKI, probably second-line.

 

Dr. Rini: Second. Okay.

 

Dr. Tawagi: Yes, otherwise third-line if I have used the ipilimumab/nivolumab frontline.

 

Q&A

 

There is actually a couple of audience questions. This is along the points, how would you sequence belzutifan/lenvatinib if approved second-line and you use lenvatinib/pembrolizumab upfront, is that going to change your first-line option?

 

Dr. Rini: I do not choose frontline based on what I am going to do later because I do not know what is going to happen. The patient could progress in three months or be on for three years. There is so many different things that can happen that I just do it one at a time. I tend to give a lot of lenvatinib/pembrolizumab upfront, so I probably would not be giving lenvatinib/belzutifan later. I will be giving belzutifan monotherapy, which I think I would like to do anyway for all the reasons we have talked about, if that is the question. Yes, absolutely.

 

Dr. Tawagi: Are there upcoming or promising biomarkers that could predict treatment response for patients with RCC?

 

Dr. Rini: Just a simple question. We have struggled to develop clinically actionable biomarkers in kidney cancer. I alluded to but did not show data. The folks have done a really nice job of biomarker development alongside the drug. Usually, it is developed the drug, get it approved, and then we will do biomarkers later. That is usually how it goes. I give them a ton of credit for doing so.

 

There is nothing clinically actionable now that I use in my clinic. In, I do not know what it is going to be, one to three years, we will have some viable biomarkers for HIF-based treatment. We do a lot of biomarker work, so I am hopeful. But realistically TKI has been around for 25 years. Right?

 

Dr. Tawagi: Right.

 

Dr. Rini: If we have not developed them now, it is unlikely in immune therapy maybe somewhere in the middle. We are doing a better job of studying it and consenting patients, and obviously the technologies and RNA-seq and stuff, we can do all that stuff easily. When it comes down to seeing a patient in clinic, we are still struggling.

 

Dr. Tawagi: Absolutely.

 

Dr. McGregor: I would add to the HIF-2 story, as much as you do not have a biomarker yet, it is also important to know that we do not have a biomarker, which you should not give someone casdatifan or belzutifan. If you have a patient who you get NGS on a clear cell, you may not see a beta mutation. Right now what we know, that does not mean that patient should not be offered a HIF-2 inhibitor, like this is approved for clear cell renal cell carcinoma, independent of any.

 

Dr. Rini: It is a good point. It has nothing to do with VHL.

 

Dr. McGregor: Yes, we do not withhold. Should not withhold belzutifan because they are on VHL mutation on NGS panel that you get clear cell.

 

Dr. Tawagi: Then speaking of biomarkers, why are not we using KIM to screen for RCC?

 

Dr. McGregor: The KIM-1 story is certainly evolving. It is very interesting, but it is not simply a positive or negative test or high or low, like what tests you use, what is the cut off, all those different factors. There is just a lot more to learn. There is that nice data to look at that prospective analysis of its elevated years before the diagnosis.

 

Again, when you have the CLIA-certified lab, and you need to really get those cut-offs. Even right now, if you look at the different tests that have been used in the IMmotion assay versus HIF-2 and 4 assays, the cut-offs to use for KIM-1 for high versus low is not exactly the same. It is an early biomarker. It is a very interesting biomarker, especially looking at changes in KIM-1 as a way of assessing response, independent imaging. More to come.

 

Dr. Tawagi: Another question on, if you were to start lenvatinib/belzutifan, and someone has fatigue, how to figure out what to dose reduce?

 

Dr. Rini: The lenvatinib. Yes. Obviously when you are giving two drugs and we have talked about this with IO/TKIs, you do not know. 20 lenvatinib is tough. Even lenvatinib/pembrolizumab not many of my patients stay at 20. That would be my first. Again, for me, my own practice patterns, I will be giving more belzutifan monotherapy.

 

You could envision and this is not how it is going to be approved with the label, giving just lenvatinib induction for those patients who need a little response and then just dropping it and keeping them on belzutifan monotherapy.

 

We actually approached the company about doing that study. Not shockingly, they do not want to do it. In clinical practice, again, it is not curative therapy, right? You are just controlling disease with the least amount of drug, not the most amount of drug. It will be interesting to see how it develops in practice. I feel like that may not be an uncommon scenario where people just they start and they dose reduce and they go to 14 and then 10 and they are just, now, let us just drop it.

 

Dr. Tawagi: I guess final question is, based on what we heard about ctDNA today, are any of you checking ctDNA in practice, or are you more compelled to after today?

 

Dr. Rini: I am not. The current assays are not sensitive enough. We are going to get there. Martin Voss did a nice discussion about where we are going assay-wise. When we are sitting here in, I do not know, again, two, three years, will be where a lot of solid tumors are, where we have sensitive tumor informed or other non-tumor informed assays.

 

We desperately need it because we are wildly overtreating people. But I would not do it and make clinical decisions.

 

Dr. McGregor: That is the hard part, right? If you have, again, less than 10% of patients are positive. If you have a positive ctDNA following nephrectomy, that is a bad sign, although even that you notice there are some patients who are converted to negative without any treatment. At the same time, a lot of patients who are negative repeatedly still relapse. You cannot use it to decide who to offer therapy, not with the current assays. So we just need better tools.

 

Dr. Rini: Yes.

 

Dr. Tawagi: Yes, absolutely.