LITESPARK-012: Lessons from a negative phase 3 trial in first-line RCC

Pembrolizumab (Keytruda) plus lenvatinib (Lenvima) is an established first-line option for patients with advanced clear cell renal cell carcinoma (ccRCC). The phase 3 LITESPARK-012 trial (NCT04736706) tested whether adding a third mechanism to this doublet could improve outcomes. Results were presented at the 2026 European Society for Medical Oncology (ESMO) Annual Congress in Madrid, Spain.¹

The trial randomly assigned 1688 patients across 3 arms. The investigational arms added either the hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan (Welireg) or MK-1308A, a coformulation of the anti–CTLA-4 antibody quavonlimab with pembrolizumab, to the doublet backbone. Neither triplet improved progression-free survival (PFS) or overall survival (OS), with median PFS of 20.8 and 20.7 in the investigational arms vs 23.7 months in the control arm (HR, 1.08 and 1.07, respectively). Median overall survival was 52.0 months with belzutifan and not reached in either the MK-1308A cohort or the control arm.

Brian I. Rini, MD, FASCO, chief of clinical trials at Vanderbilt-Ingram Cancer Center and Ingram professor of medicine at Vanderbilt University in Nashville, Tennessee, spoke with Urology Times® about the trial. He discussed its rationale and design, the survival and response findings, and what lessons clinicians can take away from negative trials.

Urology Times: Please describe the background/rationale for the LITESPARK-012 trial.

Rini: [The] standard of care in front-line advanced clear cell kidney cancer is an immune-based doublet, so an IO/TKI [immunotherapy/tyrosine kinase inhibitor] regimen. In this case, lenvatinib and pembrolizumab, which is a commonly used IO-based doublet, was the control arm, and then there were 2 experimental arms, which added a different third agent.

One of them added the HIF inhibitor belzutifan, which is approved as monotherapy in the advanced setting, and now also approved in combination with lenvatinib in the advanced setting and with pembrolizumab in the adjuvant setting. It’s approved in a number of settings, and [it’s] clearly active in those settings. The other arm added CTLA-4 inhibition with a drug called quavonlimab. It’s actually a co-formulated CTLA-4 and PD-1, so a third separate and distinct mechanism added to len/pembro as a base, if you will.

Urology Times: How was LITESPARK-012 designed?

Rini: [The trial was] very large. [We enrolled] over 1600 patients [with] untreated clear cell advanced kidney cancer randomized equally to the arms. The primary end points were progression-free and overall survival in all-comers in the belzutifan triplet. It was actually primarily intermediate- and poor-risk [patients] in the CTLA-4 triplet [arm] because of historic [ipilimumab/nivolumab] data, but generally similar across the arms.

[There were] very typical patient characteristics for frontline clear cell in terms of IMDC risk distribution, prior nephrectomy, sarcomatoid [features], all the things we look at. There was nothing unusual or unequal across the arms.

Urology Times: What did LITESPARK-012 show for progression-free and overall survival?

Rini: In both investigational arms, and we had already known this from a press release a few months ago, there was no advantage in progression-free or overall survival for either of the triplet arms compared to lenvatinib and pembrolizumab. In fact, the hazard ratios were above 1.

One of the take-homes from this trial is that len/pembro performed well. It’s clearly a standard of care. It has a high response rate, and the PFS was almost 2 years, so it performed exactly as it did in its registration trial, and maybe even a little better on some fronts. So that remains a standard of care—not the only one—but clearly a standard of care.

Another lesson here is about drug delivery. If you look at the number of cycles of, say, pembrolizumab that was delivered, it was significantly greater in the doublet arm than the triplet arms. I’m not exactly sure [why]; we’ll have to dive into details to know exactly why that happened. Because if you look at toxicity, it was expected added toxicity from when you would add the third drug, but I didn’t think it was anything that was too much. The study didn’t stop early. It accrued 500-plus patients per arm, so sometimes that’s the way the study is written.

Again, the CTLA-4 and PD-1 were co-formulated in that arm, so you couldn’t just hold one or the other. This is in contrast to when you give ipi/nivo, [where] you can hold the ipi and still give the nivo, but when obviously the drugs are co-formulated, you can’t do that.

Another potential reason, and I’m speculating here, is that when patients are on 3 drugs, you feel a little less bad about holding 1 drug than if they’re on 2. You may say, “Well, they’re on 3 drugs. I don’t mind holding 1, because they’re still getting 2 active drugs.” Again, this would only be true in the belzutifan arm. I don’t exactly know, and I think that’s going to take some more analysis.

This happened in the COSMIC[-313] study.² If you remember, that was ipi/nivo plus or minus cabo[zantinib]. So clearly, just giving 3 drugs to all patients is not as easy as perhaps we thought. We’re going to have to get more creative about how we deliver drugs to patients if we want to build on doublets.

Urology Times: What do the response rate findings suggest about intensifying first-line treatment with HIF-2α inhibition or CTLA-4 blockade?

Rini: There wasn’t much difference in response rate or complete response rate. The results were consistent across the board [in terms of] duration of response or anything we might look at. So whether that was a lack of drug delivery in the triplet arms, or some other issue[, is an open question].

Clearly CTLA-4 inhibition is active in kidney cancer. [There’s] a little bit of debate about that, but it’s active. Belzutifan, HIF inhibition, is definitely active. It’s approved in multiple settings and as monotherapy. So I think it’s a watershed moment for the field to step back and say, “Well, why didn’t we see anything? Is it just drug delivery? Is there something else going on here?”

It wasn’t that the hazard ratios were 0.80 and just missed significance—they were 1. In fact, they were above 1. We can’t use the excuse that there was activity, but it just barely missed. It’s a huge, well-conducted trial, and it’s flatly negative. I think it’s an important moment for the field. We need to learn from our failures as well as our successes and how to move this forward.

Urology Times: What are the most important unanswered questions for future first-line advanced RCC trials?

Rini: We need to figure out how [to] deliver multiple mechanisms to patients. We can do it with 2, but we’ve not been able to do it with 3. Do we need some sort of adaptive approach, a staggered approach? [There are] bispecifics, which are antibodies that have 2 targets, like PD-1 and VEGF, which are being tested widely in kidney cancer in early phase trials. That might be a way to inhibit 2 targets with 1 drug. I’m hypothesizing here, but it might be more tolerable, and a way to add on a third mechanism that we haven’t been able to do based on this trial and COSMIC[-313]. That’s a fundamental question: Can we do it? How can we do it? Do we need a novel way to do it, i.e. these bispecifics or some other mechanism?

Secondly, obviously, we need double mechanisms in kidney cancer. We’ve been beating up the VEGF and IO and now HIF axis for some time now, and have moved the needle a little, but I wouldn’t say a lot in recent years. Whether that’s cell therapy or other targets, I don’t know. But we need new targets to go after because the current mechanisms clearly aren’t helping all patients.

Urology Times: Is there anything else you’d like readers to take away from LITESPARK-012?

Rini: When you have negative trials, they can be negative but informative. We talk about positive and negative trials, and that’s usually based on the P value and the primary end point, appropriately. But there’s a lot to learn from this 1600-patient trial. This is a huge effort. We put a lot of patients through therapy. There’s obviously a lot of resources expended on trials like this.

Biomarker efforts are important. Those take sometimes many years to unfold. [And] looking at specifics of why couldn’t we deliver drugs? Why did patients stop? Was it patient motivated, doctor motivated, toxicity? There’s a lot of things to dig into, but clearly you need to be able to give active drugs for an adequate period of time to see an effect. I think we just assumed that we’d put them together, all the drugs are active, and so we’d see a benefit.

One last thing to mention: There was a prior randomized phase 2 [KEYMAKER-U03 substudy 03A] presented at ESMO last year by Cristina Suárez.³ At least for the belzutifan-based triplet, [it] showed a significant PFS advantage, and this was about 60 or 80 patients per arm compared with len/pembro. I remember sitting in the audience and thinking, “Wow, this looks really good. At least that arm of the phase 3 is going to be positive.”

But it just shows you that you never know until you do the trial, and phase 3s are what I call the great equalizer. You get all sorts of patients from around the globe, and it’s a real test of a regimen, which makes positive phase 3s more impressive, but also is humbling. We need to take phase 2s for what they’re worth, which are preliminary but not definitive.

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REFERENCES

1. Choueiri TK, Powles TB, Voss MH, et al. First-line pembrolizumab + lenvatinib + belzutifan or MK-1308A + lenvatinib in advanced RCC: Randomized open-label phase 3 LITESPARK-012 study. Presented at: 2026 European Society for Medical Oncology Congress. October 23-27, 2026. Madrid, Spain. Abstract 3586O. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2026_abstracts/3586O.html.pdf

2. Motzer RJ, Albiges L, Treviño Aguirre SA, et al. Cabozantinib plus nivolumab and ipilimumab in previously untreated, advanced renal cell carcinoma: final results and biomarker analyses from the phase III COSMIC-313 study. Ann Oncol. 2026 Jun;37(6):861-871. doi:10.1016/j.annonc.2026.02.011

3. Suarez C, Rojas C, Shin SJ, et al. Novel pembrolizumab-based treatments as first-line therapy in advanced clear-cell renal cell carcinoma: substudy 03A of the open-label, umbrella platform, phase I/II KEYMAKER-U03 trial. Ann Oncol. 2026;37(2):229-240. doi:10.1016/j.annonc.2025.10.01