LITESPARK-011 Regimen: Potentially A New SOC in PD-1 Pretreated ccRCC?

In a Between the Lines program following the 2026 ASCO Genitourinary Cancers Symposium, experts convened to discuss findings from the LITESPARK-011 trial (NCT04586231), which evaluated belzutifan (Welireg) with lenvatinib (Lenvima) for the treatment of patients with advanced clear cell renal cell carcinoma (ccRCC).¹

Martin H. Voss, MD, and Matthew T. Campbell, MD, MS, began by providing a background of how the treatment landscape has evolved for this population over the past decade, and examined key clinical factors for treatment selection given multiple approved immunotherapy options in the first-line setting. Next, they weighed their approach in treating with immunotherapy-only or immunotherapy/tyrosine kinase inhibitor (TKI) combinations, considering multiple disease characteristics. Finally, they discussed goals of treatment, the state of the space surrounding transition from first-line to second-line therapy, and how treatment options following progression impact decisions regarding first-line treatment.

Voss, is the clinical director of Genitourinary Medical Oncology at Memorial Sloan Kettering Cancer Center; and Campbell, is an associate professor and associate medical director in the Department of Genitourinary Medical Oncology at the University of Texas MD Anderson Cancer Center.

Assessing Different Treatment Modalities

To begin, Campbell highlighted the state of ccRCC leading up to the presentation of the LITESPARK-011 data, punctuated by the establishment of his practice in 2015. He explained that within an area of study which initially only offered cytokine therapies, the development of more targeted options, aimed at the angiogenesis pathways with VEGFRTKIs, and mTOR therapy as a therapeutic option, creating options for patients and questions for clinicians about sequencing considerations.

“[S]tarting in 2016 we had the approval of nivolumab [Opdivo], which was the first immune checkpoint therapy that was approved after TKI therapy,” Campbell explained in the program. “[W]e also had 2 cornerstone TKI agents approved at that same time, which were lenvatinib [Lenvima] and cabozantinib [Cabometyx]. Since that time, we now have [observed] the emergence of all the dual immune checkpoint, or immune checkpoint plus TKI-based treatments that have become our frontline therapy.”

Next, he identified HIF-directed therapies as an emergent modality as one of many used for the treatment of advanced disease, pointing out the lack of clinical guidance on how to select and sequence therapies for patients.

Voss then touched upon the evolving use of immuno-oncology drugs within the advanced ccRCC space, initially assessed within the treatment-refractory space and eventually for use as frontline therapy for these patients. Highlighting the relative simplicity in sequencing in prior years, he expressed that the emergence of multiple therapies has since complicated the treatment paradigm.

He further highlighted the use of ipilimumab (Yervoy) with nivolumab, positing the question of how to determine when to use a TKI or further checkpoint blockade with a checkpoint inhibitor.

When to Choose Dual Checkpoint Inhibition vs TKI/Checkpoint Blockade

Campbell expressed that he takes the standpoint of considering what happens when therapy fails a patient, and when deciding between further checkpoint inhibition or a TKI. Except for patients with sarcomatoid differentiation in their tumors, a population which has shown a clear advantage with dual checkpoint blockade, he considers other key clinical characteristics when treating these patients.

“I’m looking at the sites of metastases and burden of disease and the patients that have bone metastases, liver metastases, brain metastases, malignant plural effusions, malignant ascites. [Those] are patients that I worry may only have 1 chance of capturing their disease and getting it under control, and that I will preferably give them an [immune checkpoint/TKI] based strategy,” Campbell stated. “Patients [who] have more indolent [disease], where I can potentially have a patient progress as best response, I will offer them [nivolumab/ipilimumab].”

Voss considers the probability of complications, a patient’s disease burden, and the flexibility of a longer upfront treatment to consider treatment durability when selecting treatment. He further explained that, given the emergence of options for these patients and the high numerical chance of disease recurrence, he might consider reserving a potentially more efficacious treatment option for second-line therapy in the event of therapy resistance.

“A question that I see…is whether the growing number of options that we have in the second line…weighs into what option one chooses in the front line,” Voss said. “If you have a favored second-line regimen, is that something that you would want to keep in your back pocket and not use up front…is that something that would make anyone less likely to choose a lenvatinib-based frontline regimen, specifically lenvatinib/pembrolizumab [Keytruda].”

Sequencing Considerations for Approved ccRCC Options

Campbell explained that for most patients who are fit, he uses the lenvatinib/pembrolizumab combination, citing concerns about the toxicity of cabozantinib. Additionally, he highlighted that for clinicians on the fence between reduced dose lenvatinib or cabozantinib, using cabozantinib earlier in the treatment sequence could potentially save the lenvatinib-based combination for a later line of therapy.

Voss further iterated that beyond TKI use, he strives for a strategy that minimizes failure and maximizes the possibility of response in early lines of treatment. Particularly with pembrolizumab he might consider its use in patients where clinical benefit may be urgent. In contrast, for patients with higher vulnerability or frailty, he may consider a reduced dose regimen of cabozantinib and nivolumab based on the phase 3 CheckMate 9ER data (NCT03141177).²

Outlining the LITESPARK-011 Trial Design

Contextualized by the wide array of options in the metastatic frontline setting, Voss highlighted that no positive randomized phase 3 trial met their primary end point in the later line, post–PD-1 setting. Identifying studies such as the CONTACT-03 study (NCT04338269) evaluating atezolizumab (Tecentriq) and cabozantinib and the TiNivo-2 trial (NCT04987203) evaluating tivozanib (Fotivda) and nivolumab, he underscored that TKI monotherapies remained the standard of care at the publication of the LITESPARK-011 data.^3,4

Prior to examining the data of LITESPARK-011, Campbell outlined the mechanism of action of the belzutifan/lenvatinib regimen. He began in explaining that a vast majority of patients with ccRCC have impaired Von Hippel-Lindau (VHL) pathways, in which a lack of oxygen suppresses prolyl hydroxylases to activate HIF-α, which acts as a transcription factor for gene upregulation. Specifically, the addition of belzutifan could help reduce oncogene transcription while lenvatinib targets multiple receptors, including VEGFR, to suppress angiogenesis.

Next, Campbell outlined the statistical plan and end points of the trial, highlighting a “fairness” applied to the comparator arm, cabozantinib, which displayed an improvement in OS in the phase 3 METEOR trial (NCT01865747) vs everolimus (Afinitor) in an advanced RCC population.⁵ Additionally, he highlighted a key point in considering geographic region in assessing OS data.

“Geographic region is critical, because of access to therapy. North America is a bit murky, because [it includes] the US, but it can include Canada, and Central American countries as well that may not have a lot of access to later line therapy options,” Campbell stated. “[In] Western Europe, the access is hugely variable across countries and then rest of world, where it tends to be more limited in terms of what is available later.”

They next highlighted the dual primary end points of progression-free survival (PFS) per blinded independent central review (BICR) and OS, a key secondary end point of ORR per BICR, and duration of response (DOR) and safety as secondary end points. Additionally, they touched upon the timeline for each analysis, explaining that the first data cutoff occurred June 2024 and was events-driven, primarily for response data; the second interim analysis, which was the subject of the program, occurred approximately a year later after PFS data matured. A third, final OS analysis will be presented once that data matures.

Examining the LITESPARK-011 Data

Next, Voss examined the Kaplan-Meier estimates for the investigational and comparator arms, highlighting a PFS advantage with the belzutifan-based regimen at 14.8 months (95% CI, 11.2-16.6) vs 10.7 months (95% CI, 9.2-11.1) with cabozantinib (HR, 0.70; 95% CI, 0.59-0.84; P = .00007) in the second interim analysis. He pointed to a trend towards significance with median OS, which displayed an HR of 0.90 (95% CI, 0.70-1.15; P = .19322) vs 0.85 (95% CI, 0.68-1.05; P = .06075) in the first and second analysis, respectively; the respective values for median OS in each arm during the second analysis were 34.9 months (95% CI, 27.5-not reached [NR]) and 27.6 months (95% CI, 24.0-31.4).

Regarding the findings, Campbell aired his thoughts as he witnessed the read out at the conference.

“I was happy to see a positive phase 3 study in terms of [PFS}. That is an important milestone with a combination as compared with an active comparator,” Campbell explained. “I was curious, based on what we have learned about belzutifan since the approval and as we watched its development. If we’re going to see a belzutifan kick that may be a bit later for patients…was this going to be something that we’d see very early on with a significant increase in response rate than what we were anticipating or was this going to be something that was going to mature a little later?”

Voss concurred, and added that at the very least, the combination of belzutifan with lenvatinib conferred additive effects in terms of efficacy, including higher response rates, but questioned whether there would be emergent drug synergy as well.

“Is there going to be a synergism to this where we start to see a strong signal that goes beyond what one might expect by planning on mechanisms and one drug makes the other more effective,” Voss pondered. “Or…is it possible that with these late effects that we sometimes see with belzutifan, that this combination enables patients to be on [treatment] long enough to benefit from its mechanism at a greater proportion of patients?”

Comparing the Treatment Tolerability of Belzutifan-Based Regimens in ccRCC

Then, Voss and Campbell touched upon the toxicity profile of the belzutifan regimen. Voss began by stating that the combination was well-tolerated, but brought up a couple of points for consideration:

• A numerically higher incidence of high grade/serious adverse effects (AEs) in the combination arm, which was to be expected with the addition of HIF-2α inhibition
• Despite similar discontinuation rates of all study drugs, numerically higher discontinuations of belzutifan and lenvatinib individually

Voss further identified a trend where dose reductions were more common in the comparator arm despite higher individual drug discontinuations in the combination arm, which introduces the question of rationale for dose de-escalation with the investigational regimen.

Campbell further expanded upon this circumstance, expressing an interest in when lenvatinib might have been discontinued and why, primarily considering its proclivity to induce proteinuria. Furthermore, he explained that severe anemia is a common AE related to belzutifan administration, underscoring his institute’s use of erythropoietin stimulating agents to help combat anemia.

After further discussion, Campbell expressed that no “unpleasant” AEs appeared to occur at an alarmingly high rate in the belzutifan arm, highlighting patient discomfort with mucositis, dysquesia, and hand-foot syndrome, and concerns about proteinuria, but that they compared similarly to prior clinical trials. Voss’s key takeaway from the safety data was that it did not appear to be more challenging to be on either regimen.

Could Belzutifan/Lenvatinib Become a New Standard of Care in Advanced ccRCC Following PD-(L)1 Therapy?

When asked whether or not Campbell would be compelled to use this regimen given the current data available, he expressed a willingness to use it for select patients with ccRCC:

“In the right setting, I will use this regimen. I’m still trying to tease out who the perfect patients are. We clearly saw that the patients that were most ill, while it is worth potentially considering, may still not benefit more than what benefits them with cabozantinib. We still need to figure out that group of patients with kind of the most aggressive biology,” Campbell concluded.

Voss concluded in dispelling a common misconception regarding therapy selection.

“[I]t's a real challenge, because gut feeling one would always consider more aggressive therapy for more aggressive cancer, but the data doesn’t necessarily suggest that principle always applies. Is it really then the more indolent progressors that we consider for this, and if it were those, are these really the patients that we want to expose to more toxicities?”

References

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):417. doi:10.1200/JCO.2026.44.7_suppl417
2. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982
3. Pal SK, Albiges L, Tomczak P, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2023;402(10397):185-195. doi:10.1016/S0140-6736(23)00922-4
4. Choueiri TK, Albiges L, Barthélémy P, et al. Tivozanib plus nivolumab versus tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 Study. Lancet. 2024;404(10460):1309-1320. doi:10.1016/S0140-6736(24)01758-6
5. Chouieri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814-1823. doi:10.1056/NEJMoa1510016