European Commission Approves Belzutifan for VHL Disease–Associated Tumors, Advanced ccRCC

The European Commission has approved the oral HIF-2α inhibitor belzutifan (Welireg) as monotherapy for the following indications:1

• Adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated, localized renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNETs), and for whom localized procedures are unsuitable; and
• Adult patients with advanced clear cell RCC (ccRCC) whose disease has progressed following 2 or more lines of therapy, including a PD-(L)1 inhibitor and at least 2 VEGF-targeted therapies.

The agent had previously received a positive opinion for conditional approval from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) in December 2024.

Data from the phase 2 LITESPARK-004 (NCT03401788) and phase 3 LITESPARK-005 (NCT04195750) trials supported these regulatory decisions, which represent the first approvals for belzutifan in the European Union (EU).

In LITESPARK-004, belzutifan produced an ORR of 49% (95% CI, 36%-62%) in patients with VHL-associated RCC (n = 61), all of which were partial responses (PR). Furthermore, patients with VHL-associated CNS hemangioblastomas (n = 24) experienced an ORR of 63% (95% CI, 41%-81%) with a complete response (CR) rate of 4% and a PR rate of 58%. In patients with VHL-associated pNET (n = 12), the ORR was 83% (95% CI, 52%-98%) with CR and PR rates of 17% and 67%, respectively.

Among patients in LITESPARK-005 who received belzutifan, the risk of disease progression or death was reduced by 25% vs those treated with everolimus (Afinitor; HR, 0.75; 95% CI, 0.63-0.90; P = 0.0008).1 The median PFS was 5.6 months (95% CI, 3.9-7.0) with belzutifan and 5.6 months (95% CI, 4.8-5.8) with everolimus. The ORR with belzutifan was 22% (95% CI, 18%-27%), 3% and 19% of which were CRs and PRs, respectively. The ORR with everolimus was 4% (95% CI, 2%-6%) and was entirely comprised of PRs.

“The approval of belzutifan in the EU introduces the first and only systemic treatment option for adult patients with certain VHL disease-associated tumors for whom localized procedures are unsuitable, and offers a new option for adult patients with advanced clear cell renal cell carcinoma that progressed following a PD-1 or PD-L1 inhibitor and at least 2 VEGF-targeted therapies,” Marjorie Green, MD, MPH, senior vice president and head of oncology, global clinical development, at Merck Research Laboratories, stated in a news release. “This is an important moment, and we are pleased that belzutifan, a first-in-class HIF-2α inhibitor, can now potentially help these patients in need.”

Notably, the agent's conditional approval will be valid for 1 year and is subject to annual renewal based on the emergence of additional clinical data from LITESPARK-004 and an ongoing phase 2 trial evaluating belzutifan in certain VHL-associated tumors.

Overview of LITESPARK-004 and -005

LITESPARK-004 was a single-arm, open-label trial enrolling 161 patients with VHL disease–associated RCC and other tumors. Patients were required to have a germline VHL mutation with at least 1 measurable solid RCC tumor, or other VHL-associated tumors, including CNS hemangioblastomas and pNETs not requiring immediate surgery. Treatment consisted of 120 mg of oral belzutifan daily and was administered until disease progression or unacceptable toxicity. The primary end point of the study was ORR by RECIST 1.1 criteria per independent review committee assessment. Duration of response (DOR) and time to response served as additional efficacy end points.

In contrast, the open-label LITESPARK-005 trial enrolled 746 patients with unresectable locally advanced or metastatic ccRCC that had progressed following treatment with a PD-1 or PD-L1 inhibitor and a VEGF TKI. Patients were randomly assigned to receive either 120 mg of belzutifan or 10 mg of everolimus once daily, and they were stratified by both International Metastatic RCC Database Consortium risk category and the number of prior VEGF TKIs. The study’s coprimary end points were PFS assessed by blinded independent central review and overall survival (OS).

In August 2021, the FDA approved belzutifan for the treatment of adult patients with VHL disease who require therapy for associated RCC, CNS hemangioblastomas, or pNET who do not require immediate surgery, based on data from LITESPARK-004.2

The agent also received FDA approval in December 2023 for adults with advanced RCC following a PD-1 or PD-L1 inhibitor and a VEGF TKI, based on data from LITESPARK-005.3

Additional Efficacy and Safety Data

Additional efficacy data from LITESPARK-004 showed that the median DOR with belzutifan was not reached (NR) across VHL-associated tumor types.1 Among patients with VHL-associated RCC (n = 61), 56% maintained a response for at least 12 months (range, 2.8+ to 22+). In those with CNS hemangioblastomas (n = 24), 73% maintained a response for at least 12 months (range, 3.7+ to 22+), and in patients with pNETs (n = 12), 50% maintained a response for at least 12 months (range, 11+ to 19+).

Regarding safety, serious adverse effects (SAEs) occurred in 15% of patients. These included anemia, hypoxia, anaphylaxis, retinal detachment, and central retinal vein occlusion (1 patient each). Permanent discontinuation due to AEs occurred in 3.3% of patients. Dose interruptions were required for 39% of patients, most commonly for fatigue, anemia, and nausea. Dose reductions were necessary for 13% of patients, primarily due to fatigue (7%). The most common AEs observed in this trial were decreased hemoglobin (93%), fatigue (64%), increased creatinine (64%), and headache (39%).

In LITESPARK-005, SAEs occurred in 38% of patients, the most common of which were hypoxia (7%), anemia (5%), and pneumonia (3.5%). Fatal AEs occurred in 3.2% of patients, including sepsis (0.5%) and hemorrhage (0.5%). Permanent discontinuation due to Aes occurred in 6% of patients, primarily due to hypoxia (1.1%) and hemorrhage (0.5%). Dosage interruptions occurred in 39% of patients, with a higher rate in those 65 years or older (48%) vs younger than 65 (34%). The most common causes of dose interruption included anemia (8%) and hypoxia (5%). Dose reductions occurred in 13% of patients, primarily for hypoxia (5%) and anemia (3.2%). The most common AEs observed in this trial were decreased hemoglobin (88%), fatigue (43%), musculoskeletal pain (33%), and increased creatinine (34%).

References

1. Welireg® (belzutifan) receives first European Commission approval for two indications. Merck. News Release. February 18, 2025. Accessed February 18, 2025. https://www.merck.com/news/welireg-belzutifan-receives-first-european-commission-approval-for-two-indications/
2. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. FDA. February 1, 2022. Accessed February 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-cancers-associated-von-hippel-lindau-disease
3. FDA approves belzutifan for advanced renal cell carcinoma. FDA. December 14, 2023. Accessed February 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma