Katy Beckermann, MD, PhD, discusses LITESPARK trials and RCC’s evolving landscape

At the 2026 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, new data from the phase 3 LITESPARK-011 trial (NCT04586231) highlighted the potential of belzutifan (Welireg) plus lenvatinib (Lenvima) as a second-line option for patients with advanced renal cell carcinoma (RCC) whose disease progresses on anti–PD-1 therapy.^1,2 According to Katy Beckermann, MD, PhD, director of Genitourinary Cancer Research at Tennessee Oncology, the study addresses a major unmet need in the post–PD-1 setting, where clinicians have historically relied on sequential tyrosine kinase inhibitors (TKIs).

In LITESPARK-011 (NCT04586231), the combination of the HIF-2α inhibitor belzutifan with the multikinase inhibitor lenvatinib demonstrated a progression-free survival (PFS) benefit compared with cabozantinib (Cabometyx), with a hazard ratio of 0.70 and a roughly 4-month median PFS improvement. Objective response rates (ORRs) were also higher with the doublet, reaching 52.6%, which Beckermann noted aligns with response rates seen in other lenvatinib-based regimens in this setting. However, the most striking result was the durability of response: Patients receiving the combination experienced a median duration of response of approximately 23 months vs 12 months with cabozantinib.^1,2

Although overall survival (OS) has not reached statistical significance, the interim analysis showed a favorable trend (HR, 0.85; P = .06), with separation of survival curves emerging around 6 to 9 months. Beckermann said she considers the totality of evidence—including ORR, PFS, and response durability—to be sufficient to support the regimen as a new standard of care for many patients in the post-immune checkpoint inhibitor (ICI) setting, though comorbidities may limit its use in some individuals.

Biologically, the benefit may stem from combining vascular endothelial growth factor receptor (VEGFR) blockade with HIF-2α inhibition, particularly in tumors driven by angiogenic signaling. Subset analysis suggests that patients with good-risk disease by International Metastatic RCC Database Consortium (IMDC) criteria appeared to derive the greatest benefit across the IMDC categories.

Belzutifan-associated toxicities, including hypoxia and anemia, require proactive monitoring. Beckermann recommends patient education, frequent laboratory checks, and a home pulse oximetry journal to detect early trends in oxygen declines. Close monitoring for cardiac dysfunction is also warranted due to the combination with a TKI and potential for reduced ejection fraction.

In the adjuvant setting, LITESPARK-022 showed that adding belzutifan to pembrolizumab improved disease-free survival compared with pembrolizumab alone. Beckermann notes this is an early interval follow-up and hopes with maturation of the data that an OS signal will mature to help qualify if this will be a new standard of care, given the increased toxicity in a potentially cured population.^3,4

Urology Times: Let’s start with the recent LITESPARK-011 data from the ASCO GU Cancers Symposium. Given that no clear standard of care exists after progression on anti–PD-1 therapy, how do you interpret the magnitude of PFS benefit (HR, 0.70) and ORR improvement with belzutifan/lenvatinib compared with cabozantinib?

Beckermann: What we've come to see in the second-line setting post PD-1 progression, with several randomized phase 3 [trials such as] CONTACT-03 [NCT04338269], TiNIVO-2 [NCT04987203], that continuation of IO [immunotherapy] does not provide benefit and in fact may add to toxicity. Historically, we've seen clinical benefit to sequencing TKI in the refractory RCC setting. To understand how our current TKIs perform in a post-PD1 setting, there are 3 to 4 clinical trials where we see how sequencing of [TKIs] is going. [The cabozantinib] monotherapy arm in CONTACT-03 had an objective response rate of 40% and a median PFS of 10 months. That's exactly what we saw in LITESPARK-011. Cabozantinib was the control arm, and it performed consistently with what we had seen in these other randomized phase 3 trials. That was strong and gave us great data in that second-line setting, [as well as a] great response rate.

The investigational arm in LITESPARK-011 was taking lenvatinib, another broad [TKI] often used in the second-line setting, and adding belzutifan, a HIF-2α inhibitor that was approved in the third- and fourth-line setting. To me, the challenge about belzutifan as monotherapy in the third- and fourth-line setting is that a third of patients have progressive disease as best response. And so, although we were all so excited in the late-line setting, because it had a tail of the curve and this durable benefit, so many patients progressed that it was hard to use in a very refractory patient population. The question is, could we move it up and combine it with lenvatinib? Andrew [Hahn, MD], presented a trial called LenCabo [NCT05012371] where they looked also at post PD-1, and that gave us a sense of how lenvatinib performs. It was [lenvatinib plus everolimus (Afinitor)], but essentially, lenvatinib backbone, and that objective response rate reported out of ESMO [European Society for Medical Oncology Congress 2025], was 52.6%. I triple-checked the numbers, because the LITESPARK-011 objective response rate for lenvatinib and belzutifan was also exactly 52.6%. So I think the objective response rates are performing consistently how I would have expected them to based on these other clinical trials, and I think they're both clinically meaningful response rates in a post–PD-1 refractory setting; those are excellent.

As far as the PFS, what we saw here was that the lenvatinib and belzutifan arm, as you mentioned, had a statistically significant hazard ratio of 0.70, and the median PFS was a difference of about 4 months. And so again here, often, when progression can be symptomatic, that 4-month difference is clinically meaningful for patients. What really struck me the most from LITESPARK-011 was the duration of response. Patients who got a response in the lenvatinib/belzutifan arm, it nearly doubled. It was 23 months with the combination of lenvatinib and belzutifan vs 12 months with single agent TKI, in this case cabozantinib. That is just quite striking for a patient to hopefully be doing well on therapy, not having symptomatic progression. That is very clinically meaningful. And so although, again, the objective response rate and the PFS were exciting to see, the big highlight to me was that duration of response.

Urology Times: In your view, are the data from LITESPARK-011 sufficient to establish a new preferred regimen in the post-ICI setting, or does the lack of statistically significant OS at interim analysis temper that conclusion?

Beckermann: I do think that this is a new standard of care. The OS had a hazard ratio of 0.85. This was assessed at the second interim analysis, and there is still a final OS [analysis] to come. The P value on that hazard ratio of 0.85 was P = .06, and what you see is that both actually in the PFS and the OS, that at the beginning of the curves, there's overlap between the 2 arms. My hypothesis is that each arm equally treats patients with poor-risk biology, patients who, unfortunately, are progressing more quickly. But what we see in the OS curve, and similarly in the PFS, is that at about 6 months to 9 months, the curves start to separate, and the trend is the same in the OS. In kidney cancer, again, I'm always wanting OS, but we've only had 2 trials in the refractory setting. One was METEOR [NCT01865747], which tested cabozantinib vs sunitinib [Sutent], and then CheckMate 025 [NCT01668784], which tested nivolumab [Opdivo] vs everolimus [Afinitor] in the second-line setting. Those 2 trials that have proven OS benefit in the refractory setting. Again, it is clinically meaningful to have that durability of response. The OS is trending in the right direction, and I don't know that it's a standard of care for everyone, mostly because patients were excluded based on certain medical comorbidities. In the real world, those medical comorbidities will play a part in a certain patient selection, but otherwise, I do think with the ORR, the PFS, and the trending OS [that this is] a new standard of care.

Urology Times: The combination produced a 52.6% ORR, including 20 complete responses, with a median DOR of 23 months and some responses ongoing beyond 3 years. From a biologic standpoint, what do you believe is driving this depth and durability of response with HIF-2α inhibition plus VEGFR blockade? Are there patient subsets—IMDC risk groups, prior VEGFR-TKI exposure, or others—where you anticipate particularly meaningful long-term benefit?

Beckermann: It's so striking, and that’s exciting. I hope we'll continue to see some biomarker development. We haven't yet seen the biomarkers from, for example, LITESPARK-005 [NCT04195750], which was the first trial that got belzutifan, approved. When we look at the DFS [disease-free survival] subsets, almost everybody tended to benefit from the combination. Where you see the most striking pattern is within the IMDC subgroups that we commonly use to help us assess prognostication, and we categorize patients, based on clinical and laboratory factors, into good, intermediate, or poor-risk disease. The patients who did the best were those patients who had more of a good-risk disease. The hypothesis there is that maybe those are more angiogenically driven, more HIF dependent, perhaps less heterogeneity or clonal variation. But—and I think clinically many of us see this—patients who have a more indolent disease biology might be more responsive to belzutifan and have that durable benefit.

Urology Times: Hypoxia (15.4%, with 11.9% high grade) and anemia were notable class-specific toxicities with belzutifan, whereas overall grade 3 or higher adverse event (AE) rates were comparable between arms. In practical terms, how should urologists and multidisciplinary teams monitor and manage hypoxia risk, and do you foresee specific comorbid populations in whom you would hesitate to use this regimen?

Beckermann: That’s the challenge. Some of it is just that we're all gaining experience with this novel mechanism with HIF. The trial excluded patients who had underlying cardiac or pulmonary toxicities, and hemoglobin had to be 10 g/dL to enter on trial. My experience with HIF inhibitors is that many of these, as you just mentioned, they're on-target class side effects that we expect and can monitor for and support through, but it does require intensive monitoring. For example, with hypoxia, that can come on between 3-week patient visits, but if your patient is at home measuring their oxygen saturations with a pulse oximeter and writing it down, you can actually see this trend down. I ask my patients to get a pulse oximeter to monitor it twice daily, and if they see the trend dropping below 90%, to hold drug and call me. Certainly, we know holding drug is reversible, [and we can] supplement with oxygen, but that can be worrisome to a patient and can land them in the hospital—possibly even the ICU [intensive care unit], and we never want that if at all avoidable.

Similarly, for the anemia, when we block HIF, we block downstream EPO [erythropoietin] production. If we recognize that, and we recognize that it can happen early if we check labs frequent enough, many of us feel comfortable using ESAs [erythropoiesis-stimulating agents] and supplementing with essentially EPO and fix the underlying problem a little bit. [What I found to be] eye-opening on this trial that has changed my practice is the cardiac dysfunction that we saw, which I think makes sense. Again, we're combining a TKI, which has the known risk of decreasing ejection fraction, but seeing that that might be potentiated with the belzutifan has me monitoring a little bit more closely with routine echoes.

I was pleasantly surprised at the tornado plot. Looking at that plot, if you didn't know the name of the drugs or which arm was which, it wasn't so easy as to say, “This is the doublet arm. These are the higher toxicities.” But that being said, it is certainly a very different profile. And I think as physicians, pharmacists, or nurse practitioners—as we move it earlier in the lines of setting and we're using it more frequently—[it is important] that we're educating patients, that we're doing appropriate monitoring and appropriate support. And I think the trials often will list whether ESAs or blood transfusions were used. But in the community setting, it's not so easy as to send your patient down the hallway. Most of us don't have a blood bank attached, and so making our colleagues aware of the frequency and potential to manage anemia will go a long way. These are just small points that we'll have to put into our treatment algorithms to help support patients on therapy.

Urology Times: Switching to LITESPARK-022, adjuvant pembrolizumab became standard following KEYNOTE-564 (NCT03142334), yet recurrence rates remain substantial. With a DFS HR of 0.72 at 28 months of follow-up, how clinically meaningful do you consider this incremental benefit? Should we interpret this as practice-changing now, or do we need mature OS data before broadly adopting dual adjuvant therapy?

Beckermann: In the adjuvant setting, it is a slightly different bar to meet. These are patients who may have already been cured by their nephrectomy. We're trying to assess the risk of recurrence, but this trial, as much as we would love to have a ctDNA [circulating tumor DNA] or a KIM-1 or some type of biomarker to understand who's at highest risk, we're still using very classic methods such as T staging or tumor grade.

The combination has shown a clear DFS benefit. But for me right now, I will want to see that OS come through. The challenge is just that we recognize 50% of patients don't recur, and so when we go to intensify therapy further and we're adding more toxicities, it becomes a large discussion with the patient. These are often the longest conversations I have in clinic, recognizing that some of these patients may not even need treatment.

Urology Times: Most patients had intermediate-high or high-risk disease, and subgroup analyses generally favored the combination. Are there particular clinicopathologic features—tumor grade, M1 no evidence of disease (NED) status, PD-L1 status—that would most strongly influence your decision to escalate to combination adjuvant therapy vs pembrolizumab alone?

Beckermann: I’m going to take a step back and talk just briefly about some of the differences between LITESPARK-022 and KEYNOTE-564. The inclusion criteria were pretty similar. However, LITESPARK-022 enrolled almost twice as many patients with M1 disease because they allowed that enrollment to go from 24 months; in KEYNOTE-564, it was 12 months. LITESPARK-022 also included a patient population that had positive microscopic margins at time of surgery. The other difference is that KEYNOTE-564 stratified based on completely different [factors]. KEYNOTE-564 [included] ECOG performance status, geographic location, and M1 yes or no, whereas LITESPARK-022 [included] tumor grade and whether a patient was high-intermediate M1 NED, and high risk, that kind of variation.

[LITESPARK-022] was a huge trial, 1841 patients. It was the largest randomized phase 3 trial we've ever done, and it's the first adjuvant trial to have an active control arm. I emphasize that because I do think it's a different patient population. This trial excluded patients for anemia, and they couldn't have underlying pulmonary toxicities. So although we are drawing cross-trial comparisons with KEYNOTE-564, I just want to highlight that there are key differences. We can even emphasize these differences by noting that the pembrolizumab monotherapy arm in each study performed slightly differently at the 2-year DFS landmark.

All that being said, if you look at the subsets of these trials, what we'd seen in KEYNOTE-564 was that it was a really nice story. Patients who had higher-risk disease, patients who were M1 NED in KEYNOTE-564 with pembrolizumab, tended to benefit the most from pembrolizumab. That was nice; you could go and see the patient you felt was high risk and feel better about treating that patient.

Unfortunately, the same was not the case in LITESPARK-022. [In that trial], all the hazard ratios tended to favor the combination arm. But if you looked at that risk of recurrence, the group that tended to do the best on pembrolizumab plus belzutifan was that more intermediate-high rather than the M1 NED, the high risk. Here, my hypothesis would be that it's because maybe belzutifan targets a more indolent, more HIF-2–dependent patient population. That’s the reason I really want to see the OS—is that going to affect the OS signal? I don't know, but there just wasn't a really clear DFS subset that said to me, this is the patient population that if a patient came in to me tomorrow having a DFS-only benefit, that I should treat. The things that were striking to me on that DFS curve, though, was that there seems to be something going on, and I'm hopeful it will relate to an OS benefit, because the DFS curve separated early, and the absolute magnitude of the benefit stayed separated after 12 months, suggesting that maybe we are seeing some CR [complete response], some getting rid of the clones that would ultimately go on to cause recurrence. We know that'll take us probably still another 3 or 4 years before we get that OS data.

Urology Times: Grade 3 or higher treatment-related AEs increased from 17.9% with pembrolizumab alone to 42.2% with the addition of belzutifan, with high rates of anemia (84% overall; 12.1% grade ≥3) and some grade 3 or higher hypoxia. In a potentially cured population, how do you balance DFS benefit against this increased toxicity burden, and what infrastructure is needed in routine practice to safely deliver prolonged HIF-2α inhibition in the adjuvant setting?

Beckermann: This very much goes back to a lot of the things that we think about doing in the metastatic setting: close monitoring of oxygen levels, the ability to give ESAs [and do] intense monitoring in those first 3 months, because that's when we know those belzutifan on-target toxicities happen, or dose reductions or dose holds as needed. It’s not an unmanageable regimen, but certainly we're more than doubling the grade 3 [AEs] in a patient population who might otherwise already be cured. Again, I hope that it will show OS benefit, and I also hope we continue to try to develop MRD [minimal residual disease]-type biomarkers so that we can better predict who it is that needs intensification of therapy.

Urology Times: How would you characterize the current first-line systemic therapy landscape for metastatic clear-cell RCC, and what has changed most dramatically in the past 3 to 5 years?

Beckermann: I think what's changed most is that, to me, there are 2 great options. We have a pure IO regimen with PD-1 and CTLA-4, and we have 3 regimens of IO-TKI. I think the majority of us would say we would choose our regimen based on what each individual patient needs when they come in. If a patient is very symptomatic and needs a quick response, they’re in visceral crisis, we are going to double our mechanisms. We're going to use an IO and TKI to make sure that we're capturing all the biology we can to get the highest ORR right up front. What’s changed in the past 3 to 5 years as we've had longer and longer follow-up—and I think now, 10 years, if I'm right, on CheckMate 214 [NCT02231749]—is just to see the durability that comes with that pure IO backbone. I don't know that it necessarily always allows us to pick that medicine, because, again, we have so many patients who unfortunately do come in metastatic who need a quick response up front. But I think knowing the durability of CheckMate 214 with ipilimumab and nivolumab makes it a strong front-line option.

Urology Times: When you first meet a newly diagnosed patient with metastatic RCC, what clinical features immediately shape your treatment strategy?

Beckermann: I go through the IMDC criteria. That helps me prognosticate and understand how their biology is behaving. The biggest thing to me is, how quick do I need a response? Am I worried that if I started a pure IO treatment up front that we wouldn't have a chance to get to a second-line therapy? That’s probably the biggest question in my mind.

After trying triplet therapy in the frontline with Cosmic-313 where there were challenges from toxicity perspective in delivering all the drugs, then at ESMO last fall, we saw early phase data from other triplet combinations such that I think now in the coming 1 to 2 years, we'll be starting to see additional triplets of immunotherapy plus TKI, PD-1, TKI/HIF, and so I think perhaps some of these current clinical decision points that I have will ultimately not be the decision point. Maybe we'll have triplets that will address both upfront response rate and durability of the curve. That would be the hope.

Urology Times: What practical differences have you observed between clinical trial outcomes and real-world patient responses to IO-TKI combinations?

Beckermann: Certainly, we recognize with real-world evidence that many of our patients don't fit into the same categories and the same performance status, different medical comorbidities that make tolerating these drugs different, require additional dose reductions. That is something we have to be mindful about [and consider] how we can best support a patient so that they can get multiple lines of therapy and adjust to each individual person based on the [adverse] effect profile that they can tolerate, but still getting in the most efficacious dose that we can.

Urology Times: Which ongoing clinical trials or emerging agents are you most excited about, and why?

Beckermann: I’m always excited about novel mechanisms. I’m certainly thrilled to be seeing that we're doing different combinations; for example, LITESPARK-011 is a huge step and will be a benefit to patients. Some of it is finding the best combination, the best line of treatment for how we sequence patients. But then also, I think we're not at a place yet where we've figured out how to attack the broad biology of kidney cancer, and we still have, unfortunately, a selection of patients who have more aggressive poor-risk disease that we can't always treat as aggressively as I wish we could.

There are lots of mechanisms out there that I've seen, [such as] CAR T [chimeric antigen receptor T-cell therapy] and bispecifics. I've seen an oral checkpoint therapy that looks promising in a post–PD-1 setting, which is quite exciting. [There are] farnesyltransferase [inhibitors] that might relieve TKI resistance. There is a PERK inhibitor, similarly thought to maybe decrease or get around some of the resistance mechanisms that we see when we sequence TKIs. There are lots of exciting early-phase monotherapy or combination trials.

REFERENCES

1. Motzer RJ, Park SH, McDermott RS, et al. Belzutifan (bel) plus lenvatinib (lenva) versus cabozantinib (cabo) for advanced renal cell carcinoma after anti-PD-(L)1 therapy: open-label phase 3 LITESPARK-011 study. Presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium. February 26-28, 2026. San Francisco, CA. Abstract LBA417. https://meetings.asco.org/meetings/2026-asco-genitourinary-cancers-symposium/334/16925?presentation=256659

2. Welireg (belzutifan) plus Lenvima (lenvatinib) reduced the risk of disease progression or death by 30% compared to cabozantinib in certain previously treated patients with advanced renal cell carcinoma (RCC). News release. Merck. February 28, 2026. Accessed March 13, 2026. https://www.businesswire.com/news/home/20260228417897/en/WELIREG-belzutifan-Plus-LENVIMA-lenvatinib-Reduced-the-Risk-of-Disease-Progression-or-Death-by-30-Compared-to-Cabozantinib-in-Certain-Previously-Treated-Patients-With-Advanced-Renal-Cell-Carcinoma-RCC

3. Choueiri TK, Motzer RJ, Karam JA, et al. Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): the randomized phase 3 LITESPARK-022 study. Presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium. February 26-28, 2026. San Francisco, CA. Abstract LBA418. https://meetings.asco.org/meetings/2026-asco-genitourinary-cancers-symposium/334/16925?presentation=256660

4. Keytruda (pembrolizumab) plus Welireg (belzutifan) given as adjuvant therapy reduced the risk of disease recurrence or death by 28% compared to Keytruda monotherapy in certain patients with earlier-stage renal cell carcinoma (RCC). News release. Merck. February 28, 2026. Accessed March 13, 2026. https://www.businesswire.com/news/home/20260228025853/en/KEYTRUDA-pembrolizumab-Plus-WELIREG-belzutifan-Given-as-Adjuvant-Therapy-Reduced-the-Risk-of-Disease-Recurrence-or-Death-by-28-Compared-to-KEYTRUDA-Monotherapy-in-Certain-Patients-With-Earlier-Stage-Renal-Cell-Carcinoma-RCC