Robert Motzer, MD, unpacks LITESPARK-011 results of belzutifan plus lenvatinib in advanced RCC

At the 2026 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium in San Francisco, California, Robert J. Motzer, MD, presented results from the phase 3 LITESPARK-011 trial (NCT04586231), evaluating the combination of belzutifan (Welireg) plus lenvantinib (Lenvima) vs cabozantinib (Cabometyx) in patients with previously treated advanced clear cell renal cell carcinoma (ccRCC).¹ Motzer, section head, Kidney Cancer, Genitourinary Oncology Service and the Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center in New York, New York, discussed the rationale for exploring this novel combination and its potential role after progression on immunotherapy-based regimens.

The treatment landscape for advanced RCC has changed substantially over the past decade with the introduction of immune checkpoint inhibitors such as nivolumab (Opdivo) and pembrolizumab (Keytruda), which are now commonly used in first-line combination regimens. However, as these front-line strategies have evolved, questions have emerged about optimal treatment sequencing after disease progression. Historically, agents such as cabozantinib, axitinib (Inlyta), and the combination of lenvatinib plus everolimus (Afinitor) have been used in later lines, though comparative evidence guiding these decisions has been limited.

Belzutifan, a first-in-class hypoxia-inducible factor–2 alpha (HIF-2α) inhibitor, targets a key pathway involved in RCC pathogenesis associated with alterations in the VHL gene. The LITESPARK-011 study investigated whether combining belzutifan with lenvatinib could improve outcomes compared with cabozantinib in patients whose disease progressed after prior immunotherapy.

In the following interview with Urology Times®, Motzer discusses the scientific rationale for the study, its design and key findings, and how this combination could potentially influence treatment strategies in the post–immunotherapy setting for patients with advanced ccRCC.

Urology Times: What was the background/rationale for conducting this trial?

Motzer: There have been recent changes in the paradigm for treatment of kidney cancer within the past 5 to 10 years, and it's largely been the introduction of checkpoint inhibitors, particularly nivolumab and pembrolizumab . Prior to that, the standard of care was a targeted drug called sunitinib [Sutent], which was given in first line. There really wasn't any kind of role for adjuvant therapy for RCC, and there were a number of different drugs that were compared in randomized trials and approved for patients who had progressed on sunitinib. These include cabozantinib, which is probably the one that's most commonly given, levatinib plus everolimus, axitinib, and tivozanib [Fotivda].

The checkpoint inhibitor nivolumab was approved in the second-line as well, and it prompted study of immunotherapy in the first line and in the adjuvant setting. So, there's been a change in the paradigm now where first-line therapy for advanced clear cell RCC consists of doublets with either immunotherapy and a combination of ipilimumab [Yervoy] plus nivolumab or a TKI plus checkpoint inhibitor. The 3 that are commonly given are lenvatinib/pembrolizumab, cabozantinib/nivolumab or axitinib/pembrolizumab. Even more recently, there's been established role for pembrolizumab given in the adjuvant setting. So, the front-line has changed, and this has resulted in a lack of evidence [about] what to do afterwards. Commonly, cabozantinib is given, but we didn't really have evidence for 1 vs another.

There is a new first-in-class medicine called belzutifan, which is a HIF-2α inhibitor. It inhibits a transcription factor that is involved right from the start with the VHL mutation. It's been approved as a single agent in heavily pretreated patients who have been through multiple lines of therapy. There's a strong rationale for combining tyrosine kinase inhibitors like lenvatinib with belzutifan. In this study, we assessed lenvatinib, a tyrosine kinase inhibitor that's approved in combination in first-line and second-line therapy, plus belzutifan, and compared that combination to cabozatinib, which is the drug that's most commonly given to patients who have progressed on immunotherapy.

Urology Times: How was this study designed? What were the key findings?

Motzer: The key eligibility for this trial is patients had to have clear cell RCC, which is the most common type of kidney cancer. They had to progress through 1 or 2 lines of immunotherapy, and no more than that. They could have been treated with a VEGF TKI as well in 1 of those first or second lines of therapy, and we also allowed patients who progressed following adjuvant pembrolizumab. The trial was 1:1 comparison between belzutifan plus lenvatinib vs cabozantinib. The primary end points were progression-free survival and overall survival. It was a large global phase 3; there was 184 sites that were involved. There were 747 patients that were randomized to 1 arm or the other.

The trial met the primary end point of progression-free survival. The median [PFS] was 14.8 months for belzutifan plus lenvatinib, and it was 10.7 [months] for cabozantinib, with a hazard ratio of 0.70, and this was statistically significant [95% CI, 0.59 to 0.84; P = .00007]. The response rate was higher; it was 53% compared with 40% with cabozantinib. There were more complete responses in the combination arm. But I think the most striking finding was the fact that when patients did have a response, they were much more durable with the combination. The median duration of response to the combination was 23 months, compared with only 12.3 months with cabozantinib. The rate of ongoing, durable response at 2 years was 50% for belzutifan plus lenvatinib, compared with 25% with cabozantinib.

Overall survival was the other dual primary end point. We focused on the results of the second interim analysis. There was a trend in favor of a survival benefit for belzutifan plus lenvatinib, but it did not reach statistical significance at the interim analysis [HR, 0.85; 95% CI, 0.68 to 1.05; P = .06075]. This is going to be more formally tested at the final analysis for OS, which is upcoming.

Regarding the [adverse event] profile, all patients experience an adverse event on the trial, regardless of the arm. The number of high-grade events was similar between the 2 arms, as was the number of patients that had to have treatment discontinued for adverse events. That was about 11% for each arm. The [adverse] effects largely reflected the tyrosine kinase inhibitor chronic [adverse] effects that characterize lenvatinib and cabozantinib. There were some additional [adverse] effects with belzutifan, like anemia and hypoxia, that we normally see.

We did do a snapshot at 2 patient-reported outcome scales. They looked similar between the 2 arms, suggesting that the quality-of-life and the worsening of symptoms were the same between both arms. I do think that the results are considerable, and that it does provide the rationale for using this combination as a potential standard-of-care in this setting based on the progression-free survival benefit, the response duration, and the fact that the [adverse] effects both largely reflected the individual drugs.

Urology Times: This is the first phase 3 study of a HIF-2α inhibitor plus a VEGFR-TKI in ccRCC. What does this trial tell us about the evolving role of HIF-2α inhibition in kidney cancer?

Motzer: The HIF inhibitors are a relatively new class of drugs for RCC. There's a pathway that's affected that's considered to be pathogenesis in the development of RCC. It's via a mutation of the VHL gene, which interacts with HIF and other growth factors downfield, like VEGF and some others. It's felt that that’s primarily the driver in RCC. The tyrosine kinase inhibitors act downstream at the receptors for these growth factors. One of the benefits of the HIF inhibitors are that they are right at the very beginning of this pathway. In addition, they have a different toxicity profile than the VEGFR-TKIs, with less hypertension and diarrhea and so forth. For the most part, the ones that we look for are hypoxia and anemia.

It's a new class of compounds. They seem to be better positioned earlier in treatment and also in combination. This is 1 of 3 big phase 3 trials that are ongoing that look at this first-in-class belzutifan in combination with other drugs in various settings.

Urology Times: Pending further data from this trial and potential approval, how do you see this combination impacting the treatment landscape for patients who progress after first-line therapy?

Motzer: For patients who[se disease] progress[es] on first-line combinations—primarily ipilumimab/nivolumab, axitinib/pembrolizumab, or cabozantinib/nivolumab—I think that this would be a good choice. [Patients whose disease progresses after] lenvatinib/pembrolizumab, that's a first line program, may benefit from this program as well. I could see patients, if they're completing their 2 years of pembrolizumab, perhaps switching out the pembrolizumab and the belzutifan. It could be a good option for many patients.

You have to individualize treatment, and largely the individualization of treatment is around the site of progression, the clinical setting, or the patient's comorbidity. So, if a patient has severe anemia or if you're concerned about hypoxia, then this might not be the choice for that patient. That patient may benefit from either lenvatinib/everolimus or cabozatinib. On the other hand, for most fit patients who want to be aggressive and are looking for the most active program, this would be a good choice.

Urology Times: What are some of the next steps planned for this investigation, and what questions would you like to see answered?

Motzer: The report here was of the first interim and the second interim analysis. There will be a final analysis that will look specifically at overall survival. That will be important as well in terms of acceptance of the program. We did a snapshot of the patient-reported outcomes looking at quality of life, but there will be a much more comprehensive portfolio of patient-reported outcomes that will be reported as well.

It'd be very interesting if one could find a biomarker to help predict outcomes or duration of response. That's a little bit harder in a second- or third-line study, but I think it still would be interesting to look at some of the biomarker studies that are planned for this trial.

REFERENCE

1. Motzer RJ, Park SH, McDermott R, et al. Belzutifan (bel) plus lenvatinib (lenva) versus cabozantinib (cabo) for advanced renal cell carcinoma (RCC) after anti–PD-(L)1 therapy: Open-label phase 3 LITESPARK-011 study. J Clin Oncol. 2026;44(suppl 7; abstr LBA417)