FDA Approval Positions Belzutifan Plus Pembrolizumab as a New Adjuvant Standard in ccRCC

The June 2026 FDA approval of adjuvant belzutifan (Welireg) plus pembrolizumab (Keytruda) in patients with clear cell renal cell carcinoma (ccRCC) represents a major improvement in outcomes for patients by bolstering the efficacy to standard-of-care (SOC) pembrolizumab without significantly compromising safety, according to Toni Choueiri, MD.¹

The approval, which also included belzutifan plus berahyaluronidase alfa-pmph (Keytruda Qlex), was supported by data from the phase 3 LITESPARK-022 trial (NCT05239728).^1,2 Data from LITESPARK-022 demonstrated that patients who received belzutifan plus pembrolizumab experienced a significant disease-free survival (DFS) benefit compared with those who received placebo plus pembrolizumab (HR, 0.72; 95% CI, 0.59-0.87; P = .0003). The median DFS was not reached in either arm. Overall survival (OS) data were not mature at the protocol pre-specified interim analysis.

“[This is] a major approval. It’s a win for patients on top of the pembrolizumab in adjuvant RCC, a SOC that we waited 5 decades for,” Choueiri, the director of the Lank Center for Genitourinary Oncology and the medical director of International Strategic Initiatives at Dana-Farber Cancer Institute, as well as the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School, both in Boston, Massachusetts, said in an interview with OncLive®. “Only a few years after the initial approval [of pembrolizumab in ccRCC] in 2021…LITESPARK-022 added belzutifan [plus] pembrolizumab [as] the new SOC. The study at the first interim analysis is positive for the primary end point of DFS. This is an important milestone for patients.”

In the interview, Choueiri discussed the place of adjuvant belzutifan plus pembrolizumab in the ccRCC treatment landscape, detailed key data from LITESPARK-022, and outlined the potential next steps for belzutifan.

OncLive: In light of this approval, how should adjuvant belzutifan plus pembrolizumab be integrated into clinical practice?

Choueiri: [When considering the use of this regimen, we should always have] a multidisciplinary discussion with the patient about the risks and benefits. In my practice, I will only offer it in those patients that met the eligibility criteria of the study, meaning they have to have ccRCC, an intermediate- to high-risk of recurrence, high-risk [disease], or resected metastatic disease without any evidence of residual disease on [imaging] within a year [of resection].

How was LITESPARK-022 designed?

The study enrolled patients with intermediate-high-risk ccRCC, high-risk ccRCC, or M1 ccRCC [with no evidence of disease] who had undergone surgery within the previous 3 months. Patients were randomly assigned 1:1 to receive standard pembrolizumab plus placebo or pembrolizumab plus the belzutifan.

The primary end point was investigator-assessed DFS. Secondary end points included OS and safety. [A total of 1841] patients were randomly assigned. Most patients had a good performance status, and more than 80% had intermediate-high-risk disease. Approximately two-thirds of patients had grade 3 or 4 tumors, while approximately one-third had grade 1 or 2 tumors.

What were the notable findings from LITESPARK-022 that supported the approval?

Overall, the study met its primary end point of DFS with a HR of 0.72, representing a 28% reduction in the risk of recurrence or death after a median follow-up of 28 months, which I would consider relatively short.

It was encouraging to see the Kaplan-Meier curves begin separating as early as 3 months and continue to separate beyond 1 year, which is important because adjuvant treatment ends after 1 year. Even after treatment stopped, the curves continued to diverge.

When we evaluated the prespecified subgroups, there were no surprises. Benefit [with the belzutifan regimen] was observed regardless of tumor grade, sex, age, or ECOG performance status.

OS [data] remain immature. At this first interim analysis, only 87 deaths had occurred among [1841] randomly assigned patients, representing approximately 29% of expected events. Many patients who experienced recurrence were successfully treated with local therapy for oligometastatic disease or systemic therapy. Therefore, longer follow-up is needed to determine the OS benefit.

In summary, LITESPARK-022 is the first adjuvant trial to demonstrate a significant benefit for a combination regimen compared with an active control. This was not a comparison with placebo or observation. Pembrolizumab was the active control, and it has already demonstrated an OS benefit compared with observation in a patient population that was very similar to that enrolled in [the phase 3] KEYNOTE-564 [trial (NCT03142334)].

Are there any safety concerns with adjuvant belzutifan in combination with pembrolizumab?

There were no unexpected safety findings. As expected, combining 2 drugs resulted in more all-grade and grade 3 adverse effects [AEs] than pembrolizumab alone, and slightly more patients discontinued treatment because of AEs.

For example, treatment-related AEs leading to discontinuation of all study treatment occurred in 10.2% of patients receiving pembrolizumab plus belzutifan compared with 7.3% of those receiving pembrolizumab alone. While that difference was numerically higher, I would not consider it substantial.

The additional AEs reflected the known safety profile of belzutifan, including anemia, fatigue, and hypoxia, most of which were grade 1 or 2. Overall, these toxicities were manageable because we have gained experience using belzutifan in advanced disease and understand how to manage anemia and select appropriate patients.

What does the future hold for belzutifan following this approval?

We still overtreat and undertreat, meaning there are patients who receive 2 drugs and experience recurrence, and there are patients who do not receive any drug and, at least at 28 months, do not experience recurrence. It will be important to know who’s who. That [will require] biomarkers, so the work continues. Hopefully we’ll [be able to] find the right patients for the right combination.

At the 2026 ASCO Annual Meeting, we presented circulating tumor DNA [ctDNA] data in patients with RCC treated with pembrolizumab. The results were encouraging in terms of specificity. The sensitivity was extremely low, but the problem here is not so much a study design issue as it is a technology issue. ctDNA minimal residual disease testing is evolving very fast, the sensitivity is getting better, and the tests are improving. I think we’ll get there one day.Top of Form

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References

1. FDA approves belzutifan with pembrolizumab for adjuvant treatment of renal cell carcinoma. FDA. June 12, 2026. Accessed July 1, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-pembrolizumab-adjuvant-treatment-renal-cell-carcinoma
2. 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