Belzutifan approved in EU for renal cell carcinoma

The European Commission has granted a conditional approval to belzutifan (Welireg), a HIF-2α inhibitor, for 2 indications, Merck announced in a news release.¹

The approvals are backed by data from the LITESPARK-004 and LITESPARK-005 trials.

Specifically, belzutifan was approved in the EU for the treatment of patients with von-Hippel Lindau (VHL) disease who require therapy for certain associated tumors, including localized renal cell carcinoma (RCC), as well as for patients with advanced clear cell RCC who progressed following at least 2 lines of prior therapy that included a PD-1 or PD-L1 inhibitor and at least 2 VEGF-targeted therapies.

This decision is valid across all 27 EU members states, as well as Iceland, Liechtenstein, and Norway.

The conditional approval of belzutifan is valid for 1 year. The decision is subject to yearly renewal pending data from the LITESPARK-004 trial (NCT03401788) and another ongoing phase 2 trial of belzutifan in certain VHL disease-associated tumors.

“The approval of WELIREG 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,” said Marjorie Green, MD, senior vice president and head of oncology, global clinical development at Merck Research Laboratories, in the news release.¹ “This is an important moment, and we are pleased that WELIREG, a first-in-class HIF-2α inhibitor, can now potentially help these patients in need.”

The approvals in VHL disease-associated tumors and advanced clear cell RCC are supported by data from the phase 2 LITESPARK-004 trial and the phase 3 LITESPARK-005 trial (NCT04195750), respectively.

LITESPARK-004

In the LITESPARK-004 trial, belzutifan led to an objective response rate (ORR) of 49% in patients with VHL-associated RCC. All response were partial responses. The median duration of response has not yet been reached; 56% of respondents have maintained a response for 12 months or longer. According to Merck, “ongoing responses rang[e] from 2.8+ to 22+ months” among the respondents.

Overall, the open-label, phase 2 LITESPARK-004 trial enrolled 61 patients with VHL disease with at least 1 measurable solid tumor localized to the kidney and who did not require immediate surgery. Those enrolled in the trial received 120 mg belzutifan orally once daily until disease progression or unacceptable toxicity. The primary end point is ORR, and the secondary end points include duration of response, time to response, progression-free survival (PFS), time to surgery, and safety.

According to Merck, “This study evaluated response rates in other common VHL disease-associated tumors including pNET and CNS hemangioblastomas” as well.

Final completion of the trial is expected in March 2026.²

LITESPARK-005

The approval in certain patients with previously treated advanced clear cell RCC is supported by data from the LITESPARK-005 trial, for which data were recently published in The New England Journal of Medicine.³

Overall, belzutifan demonstrated superior PFS vs everolimus (Afinitor) in patients with advanced RCC whose tumors had progressed following treatment. Specifically, 24% of patients in the belzutifan arm vs 8.3% of patients in the everolimus arm were alive and free from progression at 18-month follow-up (P = .002). This translated to a 25% reduction in the risk of disease progression or death with belzutifan (HR, 0.75; 95% CI, 0.63-0.90; P = .0008). The median PFS was 5.6 months in both groups.

Additionally, the ORR was 21.9% (95% CI, 18-27) among patients who received belzutifan compared with 3.5% (95% CI, 2-6) among patients who received everolimus (P < .001). In the belzutifan arm, the ORR consisted of a complete response rate of 3% (n = 10) and a partial response rate of 19% (n = 72). No patients achieved a complete response in the everolimus arm, and the partial response rate was 4% (n = 13).

At a median follow-up of 25.7 months, the median overall survival was 21.4 months in the belzutifan cohort and 18.1 months in the everolimus cohort. At 18 months, 55.2% of patients in the belzutifan group vs 50.6% of patients in the everolimus arm were alive (HR, 0.88; 95% CI, 0.73 to 1.07; P = .20).

Regarding safety, 61.8% of patients in the belzutifan arm and 62.5% of patients in the everolimus arm experienced a grade 3 or higher adverse event (AE). Additionally, 5.9% of patients in the belzutifan cohort and 14.7% of patients in the everolimus cohort discontinued treatment due to AEs.

In total, the randomized, open-label, active-controlled phase 3 LITESPARK-005 trial enrolled 746 patients with unresectable, locally advanced, or metastatic RCC. Participants were randomly assigned 1:1 to receive 120 mg of belzutifan orally once daily (n = 374) or 10 mg of everolimus orally once daily (n = 372) until disease progression or unacceptable toxicity.

The primary end point was PFS, as determined by blinded independent central review per RECISTv1.1, and overall survival. Key secondary end points included ORR, duration of response, and safety/tolerability.⁴

REFERENCES

1. WELIREG (belzutifan) receives first European Commission approval for two indications. News release. Merck. Published online and accessed February 18, 2025. https://www.merck.com/news/welireg-belzutifan-receives-first-european-commission-approval-for-two-indications/

2. A phase 2 study of belzutifan (PT2977, MK-6482) for the treatment of Von Hippel Lindau (VHL) disease-associated renal cell carcinoma (RCC) (MK-6482-004). ClinicalTrials.gov. Last updated December 3, 2024. Accessed February 18, 2025. https://clinicaltrials.gov/study/NCT03401788

3. Choueiri TK, Powles T, Peltola K, et al. Belzutifan versus everolimus for advanced renal-cell carcinoma. N Engl J Med. 2024;391(8):710-721. doi:10.1056/NEJMoa2313906

4. A study of belzutifan (MK-6482) versus everolimus in participants with advanced renal cell carcinoma (MK-6482-005). ClinicalTrials.gov. Last updated February 17, 2025. Accessed February 18, 2025. https://clinicaltrials.gov/study/NCT04195750