LITESPARK-011 Raises Questions About RCC Treatment Sequencing

Treatment selection for patients with advanced renal cell carcinoma (RCC) following progression on first-line therapy can be challenging, particularly as treatment options and sequencing strategies continue to expand. In a virtual Case-Based Roundtable event, Neeraj Agarwal, MD, FASCO, medical oncologist and co-director of the Prostate Cancer Program at Dana-Farber Cancer Institute, moderated a discussion with oncologists in California on how newly published findings from the phase 3 LITESPARK-011 trial (NCT04586231) may influence treatment selection and sequencing for patients with advanced RCC.

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This is part 2 of a 2-part series. Read part 1.

EVENT RECAP

The group reviewed findings from the LITESPARK-011 trial, which randomized 747 patients with advanced clear cell RCC that progressed following anti–PD-(L)1 therapy to receive belzutifan (Welireg) plus lenvatinib or cabozantinib (Cabometyx).¹ At the second interim analysis, median progression-free survival (PFS) was 14.8 months with belzutifan plus lenvatinib vs 10.7 months with cabozantinib (HR, 0.70; 95% CI, 0.59-0.84; P < .0001).² Objective response rates were 52.6% and 40.2%, respectively. Overall survival (OS) favored the combination but had not reached statistical significance. Grade 3 or higher treatment-emergent adverse events occurred in 84.1% of patients receiving belzutifan plus lenvatinib and 82.7% receiving cabozantinib.

DISCUSSION QUESTIONS

• Considering the pending approval of LITESPARK-011, would you need to see an OS benefit before adopting it in practice?
• How would potential approval based on these data change your current approach?
• How would potential approval based on these data influence your first-line regimen choice?

Neeraj Agarwal, MD, FASCO: I'll make the first question simpler for our discussion. What do you think is going to be the role of belzutifan plus lenvatinib vs other combinations? The combination was compared with cabozantinib, not with lenvatinib [Lenvima]-everolimus [Afinitor], tivozanib [Fotivda], or axitinib [Inlyta]. Many times, many of us use cabozantinib in the first line, so it may not be the best comparison, but just for the sake of discussion, what do you think about the efficacy data of lenvatinib plus belzutifan vs cabozantinib? What role do you think the toxicity profile of belzutifan is going to play in your decision? And any other comments on this new trial? These are very new data.

Dawood Findakly, MD: I think anemia is one of the things that will be an issue with belzutifan and lenvatinib, depending on the baseline blood levels and patient [performance] status. Belzutifan tends to be more tolerable than lenvatinib, so I think it's mainly hypoxia and anemia, but it also depends on age. Older patients tend to not tolerate belzutifan too much. A lot of patients end up, as you mentioned, carrying oxygen, so we will not worry much if they are older patients. Younger patients have different [performance] statuses, so we’re usually more careful about that.

Agarwal: Thank you. And I do check vitamin B12, folate, and iron levels for all these patients. I just order anemia profile before starting belzutifan because we cannot risk something else confounding the adverse effects of belzutifan.

Sharmeen Mahmood, DO: I've had pretty good luck with belzutifan. It's been pretty well tolerated, but I only have a few patients on it, and I've not had that issue with hypoxia. The lenvatinib, though, I would dose-reduce. That's the one I think patients have a hard time with.

Agarwal: If you have not used cabozantinib in first line—say you have a patient with ipilimumab [Yervoy]-nivolumab [Opdivo] [who received] before—and then you are contemplating a second-line therapy, and you have 2 options, cabozantinib vs lenvatinib-belzutifan, would you sequence cabozantinib followed by lenvatinib-belzutifan, or would you use lenvatinib-belzutifan first? Are these data convincing enough to warrant a 2-drug regimen over 1?

Mahmood: For me, no, because I think cabozantinib is better tolerated, and for a few months' difference for PFS, I wouldn't do a 2-drug regimen.

Aditi Choudry, MD: If somebody has seen a [tyrosine kinase inhibitor (TKI)], so if they've been on nivolumab-cabozantinib in the first-line setting, I typically go with lenvatinib-everolimus, which is based on phase 2 data. So, I think compared to that, since this is phase 3, I would probably pick lenvatinib with belzutifan in the second line. I actually have a patient on it right now; I'm using it off label, so we'll see.

Agarwal: Very reasonable. Cabozantinib-nivolumab has failed the patient, and now you are looking for something else. I think lenvatinib-belzutifan is a very good combination. But just coming back to cabozantinib vs lenvatinib-belzutifan, anyone else? We have 2 opinions so far.

Findakly: I think just to answer this question, I would do cabozantinib first, just because of the amount of pills the patient will complain about taking. A lot of patients will not be willing to take too many pills; in addition, [there is the] adverse effect profile. So [I would pick] cabozantinib, mainly because of OS data; that could be different in the future.

Choudry: I have a question, Dr Agarwal. Going back to the trial’s baseline characteristics, how many of those patients were TKI-naive? If they're TKI-naive, I don't think these data are compelling because I think the toxicity is too much to use cabozantinib alone. So, in the trial, how many patients had immunotherapy [IO] vs IO-TKI in the front line? I guess that's what I'm trying to ask.

Agarwal: I think we have to go back to the trial…I know that many of the patients had only IO-IO regimen, but I'm not able to recall how many had IO-IO only. I think I would say 30% to 40% of patients had IO-IO.

Regardless, I wish we had those data separately reported because that would be very helpful, and I'm sure they will report those data once the primary paper is published. That's a great question; thank you. I don't have the answer right away on the efficacy of lenvatinib-belzutifan in patients who got only IO-IO vs who got TKI plus IO; I think they will report that down the line.

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DISCLOSURES: Agarwal previously disclosed receiving travel support from Pfizer, Exelixis, and Johnson & Johnson/Janssen.

REFERENCES

1. 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

2. Motzer RJ, Park SH, McDermott RS, 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. Jof ClinOncol. 2026;44(7_suppl). doi:10.1200/jco.2026.44.7_suppl.lba417