Belzutifan Displays Robust Activity in VHL-Associated RCC

Belzutifan in VHL-associated RCC |

Image Credit: © Sebastian Kaulitzki

– stock.adobe.com

Treatment with belzutifan (Welireg) led to high response rates in patients with von Hippel-Lindau (VHL)–associated renal cell carcinoma (RCC) and other neoplasms, according to data from the phase 2 LITESPARK-004 trial (NCT03401788) published in Lancet Oncology.

At a median follow-up of 49.9 months (interquartile range [IQR], 48.9-52.2), patients with RCC who received the small-molecule HIF-2α inhibitor (n = 61) achieved an objective response rate (ORR) of 67% (95% CI, 54%-79%), with 11% achieving a complete response (CR) and 56% achieving a partial response. The median duration of response (DOR) was not reached (NR; 95% CI, 41.3-not reached [NR]), and the median time to response of 11.1 months (IQR, 6.2-16.5).

“Consistent with the primary analysis of the LITESPARK-004 study, after a minimum 48 months of follow-up, belzutifan continued to show durable antitumor activity in VHL-associated neoplasms,” the study authors wrote. “With more than 2 years of additional follow-up since the primary analysis, the proportion of participants with RCC who had an objective response increased from 49% in the previous analysis to 67% in the current analysis.”

Unpacking the LITESPARK-004 Design and Baseline Characteristics

LITESPARK-004 was a single-arm study that enrolled patients across 11 sites in Denmark, France, the United Kingdom, and the United States. Eligible patients needed to be at least 18 years old, have VHL disease based on the presence of a germline VHL alteration, have no evidence of metastatic disease, and an ECOG performance status of 0 or 1. Those with RCC tumors with a diameter larger than 3 cm, other tumors that required immediate surgery, or had previously received systemic anticancer therapy were excluded from the trial.

All patients received 120 mg of oral belzutifan once daily until disease progression, unacceptable toxicity, or patient withdrawal. Dose reduction to 80 mg once daily, then 40 mg once daily, was permitted. Treatment with belzutifan was discontinued if the 40-mg dose was intolerable.

The primary end point was ORR per RECIST 1.1 criteria as assessed by independent review committee. Secondary end points included DOR, time to response, progression-free survival (PFS), and time to surgery.

At baseline, the median age was 41.0 years (range, 29.0-51.0). Most patients were male (52%), White (90%), had an ECOG performance status of 0 (82%), and had VHL disease subtype 1 (84%). Non-RCC neoplasms consisted of pancreatic neuroendocrine tumors (n = 22), central nervous system (CNS) hemangioblastomas (n = 50), and retinal hemangioblastomas (n = 14). Ninety-seven percent of patients underwent at least 1 VHL disease-related surgical procedure.

Further Efficacy Data and Safety Results

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 time to response was 5.5 months (IQR, 2.7-17.9).

The ORR and CR among patients with pancreatic neuroendocrine tumors were 91% (95% CI, 71%-99%) and 50%, respectively. The median DOR was NR (95% CI, NR-NR) and the median time to response was 8.2 months (IQR, 5.5-10.9).

The median PFS in the overall population was 49.8 months (95% CI, 49.8-NR). The estimated 42-month PFS rate was 79% (95% CI, 65%-88%).

In terms of safety, 2 patients died; both deaths were deemed to be unrelated to treatment with belzutifan. The most common any-grade treatment-related adverse effects included anemia (89%), fatigue (66%), dizziness (25%), and nausea (25%). Grade 3 TRAEs consisted of anemia (11%), fatigue (5%), urinary tract infection (2%), blisters (2%), and hypoxia (2%). No grade 4 or 5 TRAEs were reported.

Interruption of treatment due to TRAEs occurred in 21% of patients. Dose reductions due to TRAEs occurred in 16% of patients. Furthermore, 25 patients discontinued treatment due to patient decision (n = 11), disease progression from VHL disease-associated RCC (n = 7), adverse effects (n = 2), death (n = 2), pregnancy (n = 1), or other reasons (n = 2). Thirty-six patients remained on treatment at the data cutoff.

“The extended follow-up results from this study show that antitumor responses with belzutifan are durable and improving across a range of VHL-associated neoplasms, which seems to translate into a delay or reduction [or both] in the need for surgical intervention for patients with this disease,” the study authors concluded. “Results from the LITESPARK-004 trial continue to provide support for the use of belzutifan as a systemic treatment in certain patients with VHL-associated RCCs, CNS hemangioblastomas, or pancreatic neuroendocrine tumors.”

Reference

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