Behind the FDA approval of belzutifan plus lenvatinib in advanced ccRCC, with Robert Motzer, MD

The FDA approved belzutifan (Welireg) plus lenvatinib (Lenvima) for adults with advanced renal cell carcinoma (RCC) with a clear cell component following disease progression on a PD-1 or PD-L1 inhibitor in September 2026.¹ The decision adds a second-line option with phase 3 superiority data over cabozantinib (Cabometyx) after immunotherapy.

The approval is based on results from the phase 3 LITESPARK-011 trial (NCT04586231), which randomly assigned 747 patients to belzutifan 120 mg plus lenvatinib 20 mg daily or cabozantinib 60 mg daily.² At the second interim analysis, median progression-free survival was 14.6 months with the combination vs 10.6 months with cabozantinib (HR, 0.74; 95% CI, 0.61 to 0.89; 1-sided P = .00095).¹ Overall survival numerically favored the combination but did not reach statistical significance (HR, 0.85; 95% CI, 0.70 to 1.03).

Robert J. Motzer, MD, a genitourinary medical oncologist and the Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center, spoke with Urology Times® about the approval. Motzer, who is the lead author on the LITESPARK-011 trial, discussed the combination's significance, the trial population's relevance to routine practice, adverse event management, and the evolving role of HIF-2α inhibition in ccRCC.

Urology Times: What is the significance of the FDA approval of belzutifan plus lenvatinib for advanced ccRCC?

Motzer: There has been a change in paradigm for first-line treatment in metastatic clear cell RCC away from tyrosine kinase inhibitors to immunotherapy combinations. For the most part, the treatment paradigm was largely built on sunitinib or pazopanib as a first-line treatment, and when that changed, we've been left with a dearth of information in terms of what's the optimal treatment. There were a number of different studies that looked at immunotherapy in combination with a tyrosine kinase inhibitor for people who had progressed on prior immunotherapy combinations, which showed that they weren't helpful. We weren't able to establish what's the optimal second-line therapy. Cabozantinib has become the de facto standard of care in that situation.

Belzutifan was approved as a single agent in third-line therapy. That's probably not the optimal place to give belzutifan because the patients were heavily pretreated with anti-VEGF therapy to begin with. [LITESPARK-011] looked at moving that promising new HIF inhibitor, first in class, up to earlier-line therapy and combining it with lenvatinib, which is a potent and effective tyrosine kinase inhibitor that's approved in first-line therapy with pembrolizumab. It's also approved in second-line therapy combined with everolimus. It was a good partner for belzutifan. That study compared that combination, lenvatinib plus belzutifan, to what's been the de facto standard of care in the second line [setting].

Urology Times: What were the key efficacy and safety findings from the LITESPARK-011 trial?

Motzer: There was a strong benefit in progression-free survival, which was the primary end point, for lenvatinib plus belzutifan over cabozantinib. The hazard ratio was [0.74], which indicates there's about a [26%] less chance of progression any time over the course of the study with belzutifan plus lenvatinib compared [with] cabozantinib. The median progression-free survival was longer as well, and there was a higher response rate. One of the things that was most striking to people was that when the responses occurred, they were quite durable. The median duration of response was double with belzutifan plus lenvatinib compared [with] cabozantinib.

[Overall] survival is a [dual] primary end point. The data were relatively immature at the interim analysis [that was] reported in Lancet and [on which the approval was] based. There was a strong trend in terms of improved survival for belzutifan plus lenvatinib, but it didn't meet statistical significance. The final analysis, including the final survival analysis, will be reported at ESMO.

The safety profile was different for the 2 arms. Cabozantinib has a fair amount of toxicity, including skin toxicity and diarrhea, and so I think there was a bit of a trade-off in toxicity for the 2 programs. Belzutifan primarily causes anemia; that's its main [adverse event]. Some people develop dyspnea, and lenvatinib is primar[ily] hypertension and some diarrhea. So, the [safety] profiles were somewhat different for the 2 arms, but I can't tell you that one was particularly worse than the other.

The concern when you add additional agents [and] there's a benefit in progression-free survival and response, is that the trade-off is [a] worse [safety] profile, but it really wasn't clear from this that there was a worse [safety] profile. They were just different. We did report on some quality-of-life studies that suggested the patient-reported outcomes were similar between the arms. I see it as a gain in efficacy, and obviously the FDA looked at it the same way and granted regulatory approval for this combination.

Urology Times: Which aspects of the LITESPARK-011 population matter when applying the results to patients in routine practice?

Motzer: The eligibility was pretty wide open in terms of kidney function, liver function, and so forth. The one caveat is, given that belzutifan's main [adverse] effect is anemia, if a patient has refractory anemia that's fairly severe to begin with, it might not be the best choice for that patient. But other than that, it's hard to identify a particular patient population that wouldn't be suitable for this.

The only other issue that comes to mind is, what about first-line therapy? Obviously, this was lenvatinib [plus] belzutifan. What about patients who have [had] lenvatinib [plus] pembro[lizumab] in first line? That's been a question that's come up. I think there's a couple different choices. If a person is progressing on Lenvatinib/pembrolizumab in first line, and it's really clear progression, I would likely offer that patient cabozantinib in second line; [it’s a] different drug with a different mechanism of action.

The other treatment choice that I've been using in patients who are on lenvatinib/pembrolizumab, if they're having a mild degree of progression or they've completed the pembrolizumab, is just switching in the belzutifan. I continue them on the lenvatinib, and then I switch in the belzutifan in place of pembrolizumab.

That population obviously wasn't captured on the trial. On the trial, patients could not have had prior lenvatinib,³ but I think in real-life treatment, certainly if patients have had ipi/nivo [ipilimumab plus nivolumab], if they've had cabo/nivo [cabozantinib plus nivolumab], axi/pembro [axitinib plus pembrolizumab], and even some selected patients with lenvatinib/pembro, [they] would be good candidates for this combination.

Urology Times: How do you monitor and manage adverse effects when starting belzutifan plus lenvatinib?

Motzer: The side effects that characterized this program were mostly based on the tyrosine kinase inhibitor, and [in] both arms, the tyrosine kinase inhibitor [adverse events] dominated treatment.

Hypertension is an [adverse event] we see fairly often with lenvatinib. It needs to be monitored closely at home by patients with a cuff. It needs a nursing follow-up or follow-up from the office with the patient to make sure their blood pressure is safe. If a person has underlying hypertension, I oftentimes refer them to a nephrologist right from the beginning to help manage the blood pressure.

Occasionally, with some patients that have [elevated] blood pressure, I'll start out with part of the dose to make sure that they're tolerating it, and then I add the additional pills to raise the dose once I know the patient's safe. So, for a dose of 20 mg, if a person has a blood pressure I'm concerned about, I may start them out on 10 mg, and then add the additional 10 mg when I know that it's safe.

The other [adverse] effects for lenvatinib are proteinuria, so we generally make recommendations that proteinuria is monitored periodically. In my own practice, I generally keep an eye on the patient's serum albumin, and certainly if it looks like that's dropping, then I'm much more diligent with checking the urine protein.

For belzutifan, the [adverse] effects are anemia, dyspnea, or hypoxia. Anemia is by far the most common, so I generally track the hemoglobin quite frequently at first—every couple weeks. There are different philosophies in terms of how to manage anemia from belzutifan, and I think it's highly individualized. It can be withholding the dose and restarting it again in a week or so if it's mild. It can be reducing the dose. It can be giving transfusions periodically. Or there's a lot of interest in terms of giving erythropoietin-stimulating agents to maintain the hemoglobin for patients with belzutifan.

In my own practice, I've largely used dose reduction and occasional transfusion, but I think erythropoietin-stimulating agents [are] another viable alternative for managing the anemia, particularly if you want to maintain the dose. As we get more experience with that, there'll probably be more [use] of those agents to help maintain the higher dose with belzutifan.

As far as dyspnea, which is another class effect for belzutifan, [it's] unusual; [it] does not occur with TKIs or other agents we see with RCC, so it's kind of a new toxicity. We usually have the patient take their pulse ox daily at home. It’s pretty uncommon to see that, but certainly when it occurs in my own practice, then I hold it and drop the dose.

Urology Times: What does LITESPARK-011 suggest about the role of HIF-2α inhibition across ccRCC treatment?

Motzer: Belzutifan was originally studied in heavily pretreated patients, and [in] LITESPARK-005[, it was] compared with everolimus. It showed activity in that heavily pretreated patient group, which is a high bar to reach. Based on its unique toxicity profile and lack of many of the other [adverse events] we may see with some of these other drugs, the efforts have been to move it up front.

In LITESPARK-011, it was primarily a second-line treatment. I think that's where it belongs, as a second-line treatment, and it's also been recently studied and approved with pembrolizumab in the adjuvant setting. Those are 2 big trials that successfully have combined belzutifan [with] earlier-line therapy and are now both standard of care.

Urology Times: Is there anything else you would like readers to take away about belzutifan plus lenvatinib?

Motzer: I'm very excited about this combination. In the trial, I treated quite a few patients; I think we were one of the lead enrollers worldwide, and I really had a good experience with this particular program. Two patients that I treated achieved complete remissions and remain in complete remission at this time. I do think it is a leap forward in our management of metastatic RCC in the second-line space, and I encourage clinicians to try it and to use it in their patients who meet the criteria.

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REFERENCES

1. FDA approves belzutifan in combination with lenvatinib for advanced renal cell carcinoma with a clear cell component. News release. US Food & Drug Adminstration. September 24, 2026. Accessed September 30, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-combination-lenvatinib-advanced-renal-cell-carcinoma-clear-cell-component

2. Motzer RJ, McDermott R, Park SH, et al. Belzutifan plus lenvatinib versus cabozantinib in patients with previously treated advanced renal cell carcinoma (LITESPARK-011): an open-label, randomised, controlled, phase 3 trial. Lancet. 2026;408(10557):808-820. doi:10.1016/S0140-6736(26)01089-5

3. A Study of Belzutifan (MK-6482) in Combination With Lenvatinib Versus Cabozantinib for Treatment of Renal Cell Carcinoma (MK-6482-011). ClinicalTrials.gov. Last updated May 5, 2026. Accessed September 30, 2026. https://clinicaltrials.gov/study/NCT04586231