Belzutifan Receives European Approval in Localized/Advanced RCC Indications

LITESPARK-004 and LITESPARK-005 trial results support the approval of belzutifan in patients with associated localized or advanced clear cell RCC.

First, belzutifan was approved for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated, localized RCC; central nervous system (CNS) hemangioblastomas; or pancreatic neuroendocrine tumors (pNET) for whom localized treatments are unsuitable. Additionally, it received approval for adult patients with advanced clear cell RCC (ccRCC) that progressed following 2 or more lines of therapy including PD-1 or PD-L1 inhibition and at least 2 VEGF-targeted therapies.

Support for the EU approval in patients with VHL disease came from the phase 2 LITESPARK-004 trial (NCT03401788). For those with advanced RCC, supporting data came from the phase 3 LITESPARK-005 trial (NCT04195750).

“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 [ccRCC] that progressed following a PD-1 or PD-L1 inhibitor and at least 2 VEGF-targeted therapies,” Marjorie Green, MD, senior vice president and head of Oncology and Global Clinical Development at Merck Research Laboratories, said in the news release on the approval.¹ “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.”

Phase 2 LITESPARK-004 Trial

Data from the phase 2 LITESPARK-004 trial revealed that in patients with VHL disease who require therapy for associated RCC (n = 61), the overall response rate (ORR) was 49% (95% CI, 36%-62%), all of which were partial responses (PR). Additionally, the median duration of response (DOR) was not reached (NR), with responses ranging from 2.8+ to 22+ months. Furthermore, of treatment responders, 56% remained in response for a minimum of 12 months.

In patients with VHL disease-associated CNS hemangioblastomas, (n = 24), treatment with belzutifan elicited an ORR of 63% (95% CI, 41%-81%), with 1 complete response (CR; 4%) and a PR rate of 58%. Median DOR was NR, and ongoing responses ranged from 3.7+ months to 22+ months. Additionally, among responders in this subgroup, 73% remained in response for a minimum of 12 months.

Furthermore, in patients with VHL disease-associated pNET (n = 12), belzutifan exhibited an ORR of 83% (95% CI, 52%-98%), with 17% of patients attaining a CR and 67% attaining a PR. Median DOR was NR, and ongoing responses ranged from 11+ to 19+ months. Additionally, among responders, the 12-month response rate was 50%.

Investigators in the phase 2 LITESPARK-004 trial enrolled adult patients with VHL disease and at least 1 measurable RCC tumor to receive 120 mg of oral belzutifan daily across three 40 mg tablets.² Patients continued treatment until disease progression or unacceptable toxicity.

The primary end point of the trial was ORR. Secondary end points included DOR, time to response (TTR), progression-free survival (PFS), and safety.

Phase 3 LITESPARK-005 Trial

Data from the phase 3 LITESPARK-005 trial revealed that belzutifan reduced the risk of disease progression or death by 25% vs everolimus (Afinitor) in adult patients with advanced ccRCC (HR, 0.75; 95% CI, 0.63-0.90; P = .0008). Additionally, the median PFS was 5.6 months (95% CI, 3.9-7.0) vs 5.6 months (95% CI, 4.8-5.8) in the respective arms. The ORR was 22% (95% CI, 18%-27%) with belzutifan and 4% with everolimus (95% CI, 2%-6%), with CR rates of 3% and 0%, respectively, and PR rates of 19% and 4%.

Investigators in the phase 3 LITESPARK-005 trial enrolled adult patients with advanced RCC that progressed following prior PD-1–, PD-L1– or VEGF-targeted therapies to receive either 120 mg of oral belzutifan once daily or 10 mg of oral everolimus once daily.³

The primary end point was PFS per RECIST v1.1 criteria as assessed by blinded independent central review and OS. Secondary end points included ORR, DOR, and safety.

References

1. WELIREG® (belzutifan) receives first European Commission approval for two indications. News release. Merck. February 18, 2025. Accessed February 18, 2025. https://tinyurl.com/mw6572uv
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. Updated December 3, 2024. Accessed February 18, 2025. https://tinyurl.com/bp632f4d
3. A study of belzutifan (MK-6482) versus everolimus in participants with advanced renal cell carcinoma (MK-6482-005). ClinicalTrials.gov. Updated February 17, 2025. Accessed February 18, 2025. https://tinyurl.com/yzdrc4cd