Belzutifan-Containing Combinations Are Reshaping Treatment Sequencing Discussions in RCC

Positive data supporting the use of belzutifan (Welireg)-based regimens in the adjuvant and relapsed/refractory settings could reshape the treatment landscape in renal cell carcinoma (RCC), as the agent’s unique mechanism of action and efficacy when integrated with existing treatment approaches offer a clear clinical advantage, according to expert panelists who participated in a recent OncLive® Peer Exchange.

During the discussion, filmed at the 2026 Genitourinary Cancers Symposium (ASCO GU), an expert panel unpacked updated RCC data presented at the meeting and how they affect treatment sequencing in advanced RCC, as well as emerging data in the field.

How could new data from the LITESPARK studies inform treatment sequencing?

The panelists began their conversation by highlighting some of the most notable data in RCC that were presented during ASCO GU, namely findings from the phase 3 LITESPARK-022 (NCT05239728) and LITESPARK-011 (NCT04586231) trials. Both studies evaluated combinations containing the selective HIF-2α inhibitor belzutifan in patients with clear cell RCC (ccRCC). LITESPARK-022 examined belzutifan plus pembrolizumab (Keytruda) as adjuvant therapy in patients at an increased risk of recurrence post nephrectomy, and LITESPARK-011 examined the agent in combination with lenvatinib (Lenvima) after immune checkpoint inhibitor therapy.^1,2

LITESPARK-022 enrolled patients with histologically confirmed ccRCC who did not receive prior systemic therapy, had undergone surgery within 12 weeks prior to random assignment, and had an ECOG performance status of 0 or 1.¹ The primary end point was investigator-assessed disease-free survival (DFS). Overall survival (OS) and safety were assessed as secondary end points.

“LITESPARK-022 was one of the big [trials] at ASCO GU,” Monty Pal, MD, FASCO, said. “This trial looked at the current standard of care in the adjuvant setting, pembrolizumab, with or without belzutifan. [Findings from] the study demonstrated a meaningful benefit pertaining to DFS.”

Findings from the first interim analysis of LITESPARK-022 presented during ASCO GU revealed that the median investigator-assessed DFS among patients in the combination (n = 921) and pembrolizumab monotherapy (n = 920) arms was not reached (NR; 95% CI, 36.9-NR) and NR (95% CI, NR-NR), respectively (HR, 0.72; 95% CI, 0.59-0.87; P = .0003). The 12-, 24-, and 30-month DFS rates in the combination arm were 91.9%, 80.7%, and 75.8%, respectively; these respective rates were 85.2%, 73.7%, and 68.6% in the monotherapy arm.

OS data did not reach statistical significance at the time of the presentation; the median value in both arms was NR (95% CI, NR-NR), although a trend toward the investigational arm was observed (HR, 0.78; 95% CI, 0.51-1.19; P = .1220). In the combination arm, the respective 12-, 24-, and 30-month OS rates were 98.3%, 96.2%, and 95.6%; these rates were 98.6%, 95.7%, and 93.8%, respectively, in the active comparator arm.

“[These data] tell us that there is a benefit for many patients to intensifying adjuvant therapy, but just like before, when we were considering when and how to give adjuvant pembrolizumab, I believe there's the right treatment for the right patient and the right risk profile,” Vincent Xu, MD, commented. “Even though the relative benefit may be what it is in the trial, the absolute benefit is going to vary from patient to patient. You have to see what's going on in the patient’s life, how big their absolute risk reduction is, and what other competing comorbidities exist for them.”

The findings from LITESPARK-022 presented during ASCO GU supported the February 2026 supplemental new drug applications (sNDAs) seeking the approval of belzutifan plus pembrolizumab or berahyaluronidase alfa-pmph (Keytruda Qlex) for the adjuvant treatment of adult patients with RCC with a clear cell component at an increased risk of recurrence following nephrectomy.³ These sNDAs are under priority review by the FDA.

“[There needs to be] a long discussion [with patients] about the pros and cons of early toxicity risk that at times can be life-changing, [as well as] their potential impact on later therapy,” Matthew Campbell, MD, added. “If a patient has comorbidities where we’d worry about future TKI [tyrosine kinase inhibitor] tolerance issues, those patients may be great fits for starting treatment earlier [vs] potentially waiting. That may be their best shot to get therapy. It's become an extremely complex discussion. My average length of time in these discussions is around an hour per patient.”

LITESPARK-011 enrolled patients with unresectable, locally advanced, or metastatic ccRCC who experienced disease progression on or after treatment with an anti–PD-L1 monoclonal antibody in the first- or second-line setting or less than 6 months after the last dose of an adjuvant anti–PD-L1 monoclonal antibody.² Patients were also required to have a Karnofsky performance status score of 70% or higher and have received a maximum of 2 prior systemic regimens; prior treatment with a VEGFR-TKI was allowed. The dual primary end points were progression-free survival (PFS) per RECIST 1.1 criteria as assessed by blinded independent central review (BICR) and OS; overall response rate (ORR) per BICR was the key secondary end point.

Findings from LITESPARK-011 presented during ASCO GU demonstrated that the median PFS among patients who received belzutifan plus lenvatinib (n = 371) was 14.8 months (95% CI, 11.2-16.6) compared with 10.7 months (95% CI, 9.2-11.1) among patients treated with cabozantinib (Cabometyx; n = 376; HR, 0.70; 95% CI, 0.59-0.84; 1-sided P = .00007). The 12-month PFS rates were 55.0% and 41.0%, respectively, and the 24-month PFS rates were 35.6% and 19.1%, respectively.

“These are very exciting data [that show] that this combination is highly active in the refractory setting,” Xu said. “It’s outstanding that we now have options that are not just active, but really active; the PFS was superior to cabozantinib, which is a very strong control arm. This is great news for patients, but I would take away [from the data] that in exchange for more activity, you're going to have more toxicity. It's clear that 2 drugs are going to be more toxic than the one, especially because you have this added mechanism of belzutifan, which has nonoverlapping toxicities with the VEGFR-TKIs. [Patients] can have some more fatigue, but also anemia and sometimes hypoxia.”

Although the OS data did not reach statistical significance at the time of the presentation, a trend in favor of the combination arm emerged (HR, 0.85; 95% CI, 0.68-1.05; 1-sided P = .06075). The 12- and 24-month OS rates in the combination arm were 79.7% and 62.8%, respectively; the corresponding rates in the control arm were 77.7% and 55.4%, respectively. The ORR in the combination arm was 52.6% (95% CI, 47.3%-57.7%) compared with 40.2% (95% CI, 35.2%-45.3%) in the control arm, representing an estimated difference of 12.4% (95% CI, 5.3%-19.3%). The respective complete response rates were 5.4% and 1.1%.

“If a patient has just failed an immuno-oncology [IO] doublet and you want to try to overcome resistance [or] if they had a high bulk of disease, I might start with another doublet because if you look across all solid tumors, so many patients don't even get to second- or third-line therapy,” Alan Tan, MD, commented. “But if a patient started with an IO-TKI [doublet], they're probably already pretty beaten up from that continuous [exposure to a] TKI. A discussion with the patient [would be necessary], but most likely a patient would want to have a break in toxicity instead of [receiving] a strong doublet like [the LITESPARK-011 regimen], because we know that across the lenvatinib trials the problem [has been] the discontinuation rate.”

Findings from LITESPARK-011 supported the February 2026 FDA acceptance of an sNDA seeking the approval of belzutifan plus lenvatinib for the treatment of adult patients with RCC with a clear cell component following treatment with a PD-1 or PD-L1 inhibitor.⁴

Where do other agents fit into the RCC treatment paradigm in light of these new belzutifan data?

After reviewing the new data presented during ASCO GU, the panelists discussed how these updates may affect their use of other established agents, such as cabozantinib. Xu noted that cabozantinib remains an important treatment option in the frontline and relapsed/refractory settings due to its multitargeted design, which allows the agent to show activity even after prior treatment with other TKIs. He added that cabozantinib can be especially useful in patients who are able to tolerate a TKI and who do not need immediate combination therapy.

“If you're using the belzutifan and lenvatinib combination, then I would imagine that you have a patient who has very aggressive disease with liver [and/or] bone metastases and is symptomatic with very dire sites that are involved,” Ulka N. Vaishampayan, MD, FASCO, asserted. “I don't know that you're thinking a whole lot about the future because you may not have a whole lot of options after that. I would usually prefer cabozantinib, because it's a multitargeted TKI with evidence of robust efficacy in pretreated RCC.”

Tan noted that he has often preferred the combination of cabozantinib and nivolumab (Opdivo) due to his experience managing its associated toxicities in the phase 3 CheckMate 9ER (NCT03141177) and COSMIC-313 (NCT03937219) studies. These trials evaluated nivolumab plus cabozantinib and nivolumab plus cabozantinib and ipilimumab (Yervoy), respectively, in patients with previously untreated advanced or metastatic RCC.^5,6

“Retrospective data from [the phase 3] CheckMate 214 trial [NCT02231749] and COSMIC 313 studies [showed that,] in the ipilimumab-nivolumab arms of both studies, the 3-week KIM-1 ratio was a very good long-term biomarker [for] durable [responses with] ipilimumab plus nivolumab,” Xu said. “We are currently proposing a trial through the Alliance Cooperative Group in which we [will enroll] patients with suboptimal [expression of this] 3-week biomarker. Instead of trying to push [them] through 3 more cycles of ipilimumab plus nivolumab, which might hurt the patient, we will try to pivot and randomly assign them to receive an IO plus a TKI.”

Sumanta “Monty” Kumar Pal, MD, FASCO, is codirector of the Kidney Cancer Program, as well as a professor and vice chair of academic affairs in the Department of Medical Oncology & Therapeutics Research, at City of Hope Comprehensive Cancer Center in Duarte, California.

Ulka N. Vaishampayan, MD, FASCO, is a professor of internal medicine, the director of the phase 1 program, and coleader of the Translational and Clinical Research Program at the University of Michigan Rogel Cancer Center in Ann Arbor, Michigan.

Wenxin “Vincent” Xu, MD, is a physician at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts.

Alan Tan, MD, is a genitourinary oncology and melanoma specialist at Vanderbilt-Ingram Cancer Center and an assistant professor of medicine in the Division of Hematology and Oncology at Vanderbilt University Medical Center in Nashville, Tennessee.

Matthew T. Campbell, MD, MS, is the associate medical director of the Department of Genitourinary Medical Oncology and an associate professor in the Department of Genitourinary Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston.

References

1. Choueiri TK, Motzer RJ, Karam JA, et al. Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): the randomized phase 3 LITESPARK-022 study. J Clin Oncol. 2026;44(suppl 7):LBA418. doi:10.1200/JCO.2026.44.7_suppl.LBA418
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. J Clin Oncol. 2026;44(suppl 7):LBA417. doi:10.1200/JCO.2026.44.7_suppl417
3. Keytruda (pembrolizumab) plus Welireg (belzutifan) given as adjuvant therapy reduced the risk of disease recurrence or death by 28% compared to Keytruda monotherapy in certain patients with earlier-stage renal cell carcinoma (RCC). News release. Merck. February 28, 2026. Accessed March 4, 2026. https://www.merck.com/news/keytruda-pembrolizumab-plus-welireg-belzutifan-given-as-adjuvant-therapy-reduced-the-risk-of-disease-recurrence-or-death-by-28-compared-to-keytruda-monotherapy-in-certain-patients-with/
4. Welireg (belzutifan) plus Lenvima (lenvatinib) reduced the risk of disease progression or death by 30% compared to cabozantinib in certain previously treated patients with advanced renal cell carcinoma (RCC). News release. Merck. February 28, 2026. Accessed March 4, 2026. https://www.merck.com/news/welireg-belzutifan-plus-lenvima-lenvatinib-reduced-the-risk-of-disease-progression-or-death-by-30-compared-to-cabozantinib-in-certain-previously-treated-patients-with-advanced-renal-ce/
5. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982
6. Choueiri TK, Powles T, Albiges L, et al; COSMIC-313 Investigators. Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. N Engl J Med. 2023;388(19):1767-1778. doi:10.1056/NEJMoa2212851