Findings presented at the 26th Annual Meeting of the Society of Urologic Oncology showed that the overall response rate (ORR) among all patients with RCC regardless of whether they received VHL-related surgery after starting belzutifan (n = 61) was 70% (95% CI, 57%-81%). This comprised a complete response (CR) rate of 11% and a partial response (PR) rate of 59%. Stable disease (SD) was achieved in 28% of patients, none experienced disease progression (PD), and 2% were not evaluable (NE). The estimated 48-month duration of response (DOR) rate was 76.2%, and the median time to response (TTR) was 8.5 months (range, 2.7-41.2)
Among patients who did undergo surgery (n = 16), the ORR was 38% (95% CI, 15%-65%) and comprised entirely of PRs. SD was achieved by 63% of patients and none experienced PD. Those who did not undergo surgery (n = 45%) experienced an ORR of 82% (95% CI, 68%-92%), including a CR rate of 16%, a PR rate of 67%, and a SD rate of 16%. One patient (2%) was NE.
Notably, among patients with VHL disease–associated neoplasms who underwent surgery (n = 16), the time from starting belzutifan to first surgery was a median of 37.0 months (range, 12-62) and the time of therapy after surgery was a median of 17.2 months (range, 1-40).
“Belzutifan is the only approved systemic treatment option for patients with VHL disease–associated RCC, pNETs, or CNS hemangioblastoma that does not necessitate immediate surgery,” W. Marston Linehan, MD, chief of the Urologic Oncology Branch, acting chief of the Surgical Oncology Program, and a senior investigator at the National Cancer Institute’s Center for Cancer Research in Bethesda, Maryland, and colleagues, wrote in a poster presentation of the data. “These results suggest that belzutifan may delay or reduce the need to undergo surgical procedures.”
What prior data have been reported with belzutifan in VHL disease–associated tumors?
On August 13, 2021, the hypoxia-inducible factor 2α inhibitor belzutifan received FDA approval for adult patients with VHL disease who require therapy for associated RCC, CNS hemangioblastomas, or pNET not requiring immediate surgery based on findings from LITESPARK-004.2
Results from LITESPARK-004 were previously published in Lancet Oncology in May 2025. At median follow-up of 49.9 months (IQR, 48.9-52.2), patients with RCC who received belzutifan (n = 61) achieved an ORR of 67% (95% CI, 54%-79%), with 11% achieving a CR and 56% achieving a PR.3 The median DOR was not reached (NR; 95% CI, 41.3-NR), and the median TTR of 11.1 months (IQR, 6.2-16.5).
Additional findings revealed that patients with CNS hemangioblastomas (n = 50) experienced an ORR of 48% (95% CI, 34%-63%) with a CR rate of 8%. The median DOR was NR (95% CI, NR-NR), and the median TTR was 5.5 months (IQR, 2.7-17.9).
What was the design of LITESPARK-004?
LITESPARK-004 was a single-arm study that enrolled patients with VHL disease who had a confirmed germline alteration and at least 1 measurable RCC tumor.1 Other key eligibility criteria included no evidence of metastatic disease, an ECOG performance status of 0 or 1, and no prior systemic anticancer therapy.
All 61 patients received oral belzutifan at 120 mg once daily until disease progression, unacceptable toxicity, or patient withdrawal. The efficacy-evaluable population included all patients who received 1 or more doses of belzutifan and had radiographically evaluable RCC; the safety-evaluable population comprised all patients who received at least 1 dose of belzutifan.
The study’s primary end point was ORR in VHL disease–associated RCC per RECIST 1.1 criteria as assessed by independent review committee (IRC). Secondary end points included ORR in CNS hemangioblastomas and pNETs per RECIST 1.1 criteria by IRC; DOR, TTR, progression-free survival per RECIST 1.1 criteria by IRC, time to surgery, improvement rate by qualitative assessment for patients with retinal hemangioblastomas, and safety.
At the April 1, 2024, data cutoff, all 61 patients had received belzutifan, 35 of whom remained on treatment at 60 months. Reasons for treatment discontinuation included patient’s decision (n = 12), PD for VHL disease–associated RCC (n = 7), adverse effects (AEs; n = 2), death (n = 2), pregnancy (n =1), and investigator’s discretion (n = 2). The median time from first dose to the database cutoff date was 61.8 months (range, 60.2-70.1)
What was the best overall response and DOR with belzutifan in patients with CNS hemangioblastoma and pNETs?
Overall, patients with CNS hemangioblastoma who received belzutifan (n = 50) achieved an ORR of 50% (95% CI, 36%-64%), including a CR rate of 12%, PR rate of 38%, SD rate of 40%. Three patients (6%) experienced PD and 2 (4%) were NE. ORRs in those who did (n = 12) vs did not undergo surgery (n = 38) after starting belzutifan were 25% (95% CI, 6%-57%) and 58% (95% CI, 41%-74%), respectively. The estimated 48-month DOR rate was 81.5%, and the median TTR was 7.9 months (range, 2.3-52.3).
In patients with pNETs who received belzutifan (n = 20), the ORR was 90% (95% CI, 68%-99%), including a CR rate of 65%, PR rate of 25%, SD rate of 10%. No patients experienced PD. ORRs in those who did (n = 5) vs did not undergo surgery (n = 15) after starting belzutifan were 100% (95% CI, 48%-100%) and 87% (95% CI, 60%-98%), respectively. The estimated DOR rate at 48 months was 94.1%, and the median TTR was 10.8 months (range, 5.4-22.0).
How did responses differ according to the number and size of RCC lesions, as well as VHL subgroup?
The ORR was highest in patients with 2 or fewer tumors that were no more than 3 cm in size (n = 36; 81%), followed by patients with 1 or fewer tumors less than 2 cm in size (n = 15; 60%), and those with 1 or more tumors greater than 3 cm (n = 10; 59%). The respective CR rates for these groups were 33.3% (n = 5), 2.7% (n = 1), and 10% (n = 1).
Assessment of response rates according to VHL subgroup showed that patients RCC displaying VHL exon deletions (n = 18) had an ORR of 61% vs 74% in those with VHL mutations (n = 43). In CNS hemangioblastoma, the ORRs were 60% for those with VHL deletions (n = 15) and 46% in those with VHL mutations (n = 35). For the pNET subgroup, the ORRs in patients with VHL deletions (n = 5) vs mutations (n = 15) were 100% vs 87%, respectively.
Did responses improve in patients with retinal hemangioblastomas?
All patients with retinal hemangioblastomas at baseline (n = 14) and those whose eyes were assessed at baseline (n = 18) experienced an improvement. The ORRs with belzutifan in these respective populations were 100% (95% CI, 77%-100%) and 100%( 95% CI, 82%-100%).
In the retinal hemangioblasoma group, the median TTR was 2.8 months (range, 2.5-10.8) and the median DOR was NR (range, 8.5-61.0+)
What should be known about the safety profile of belzutifan according to this analysis?
Investigators shared that no new safety signals were observed with additional follow-up. All patients experienced any-grade AEs. The most common any-grade AEs associated with belzutifan included anemia (93%), fatigue (77%), headache (49%), dizziness (46%), nausea (39%), myalgia (31%), arthralgia (28%), constipation (26%), dyspnea (26%), COVID-19 (25%), abdominal pain (23%), increased alanine aminotransferase levels (21%), and blurred vision (21%). Of note, grade 4 embolism, retinal detachment, and retinal vein occlusion occurred in 1 patient each.
References
- Linehan WM, Jonasch E, Iliopoulos O, et al. LITESPARK-004: 5-year follow-up of the hypoxia-inducible factor 2α inhibitor belzutifan in von Hippel-Lindau disease–associated neoplasms. Presented at: 26th Annual Meeting of the Society of Urologic Oncology. December 2-5, 2025; Phoenix, Arizona. Abstract 172.
- FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. News release. FDA. Updated February 1, 2022. Accessed December 5, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-cancers-associated-von-hippel-lindau-disease
- Srinivasan R, Iliopoulos O, Beckermann KE, et al. Belzutifan for von Hippel-Lindau disease-associated renal cell carcinoma and other neoplasms (LITESPARK-004): 50 months follow-up from a single-arm, phase 2 study. Lancet Oncol. 2025;26(5):571-582. doi:10.1016/S1470-2045(25)00099-3
