Merck's Welireg gains positive EU CHMP opinion for VHL, RCC tumors

Merck, known as MSD outside of the United States and Canada, announced that the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending the conditional approval of Welireg (belzutifan), Merck’s oral hypoxia-inducible factor-2 alpha (HIF-2a) inhibitor, as monotherapy for: The treatment of 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 tumours (pNET), and for whom localized procedures are unsuitable; The treatment of adult patients with advanced clear cell renal cell carcinoma (RCC) that progressed following two or more lines of therapy that included a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and at least two vascular endothelial growth factor (VEGF) targeted therapies.

The CHMP’s recommendation will now be reviewed by the European Commission for marketing authorization in the European Union (EU), and a final decision is expected in the first quarter of 2025.

“Today’s positive CHMP opinion brings us closer to offering Welireg, a first-in-class HIF-2a inhibitor, to certain patients in the European Union, in order to help address critical gaps in care for these patients,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “We are committed to providing innovative treatment options that address serious unmet needs for patients globally and look forward to the European Commission’s decision.”

The CHMP recommendation in VHL disease-associated tumours is based on objective response rate (ORR) and duration of response (DOR) results from the LITESPARK-004 trial. If approved, Welireg would be the first and only systemic treatment for patients with VHL disease-associated tumours in the EU.

In August 2021, Welireg was approved in the US for the treatment of adult patients with VHL disease who require therapy for associated RCC, CNS hemangioblastomas or pNET not requiring immediate surgery based on the results from LITESPARK-004, an open-label clinical trial in 61 patients with VHL-associated RCC. In the LITESPARK-004 trial, Welireg showed an ORR of 49% (95% CI, 36-62) in patients with VHL-associated RCC (n=30/61); all responses were partial responses (PR). Median DOR for these patients was not reached, with ongoing responses ranging from 2.8+ to 22+ months; among responders, 56% (n=17/30) maintained a response for at least 12 months.

Patients enrolled in LITESPARK-004 had other VHL-associated tumours, including CNS hemangioblastomas and pNET. In patients with VHL-associated CNS hemangioblastomas (n=24) in this trial, Welireg showed an ORR of 63% (95% CI, 41-81) (n=15/24), with a complete response (CR) rate of 4% (n=1/24) and a PR rate of 58% (n=14/24). Median DOR for these patients was not reached, with ongoing responses ranging from 3.7+ to 22+ months; among responders, 73% (n=11/15) maintained a response for at least 12 months. In patients with VHL-associated pNET (n=12) in this trial, Welireg showed an ORR of 83% (95% CI, 52-98) (n=10/12), with a CR rate of 17% (n=2/12) and a PR rate of 67% (n=8/12). Median DOR for these patients was not reached, with ongoing responses ranging from 11+ to 19+ months; among responders, 50% (n=5/10) maintained a response for at least 12 months.

The CHMP recommendation in advanced clear cell RCC that progressed following two or more lines of therapy that included a PD-(L)1 inhibitor and at least two VEGF targeted therapies, is based on PFS and ORR results from the LITESPARK-005 trial, the first positive Phase 3 trial in these patients.

In December 2023, Welireg was approved in the US for the treatment of adult patients with advanced RCC following a PD-1 or PD-L1 inhibitor and a VEGF-TKI based on the results from LITESPARK-005, an open-label clinical trial in 746 patients with unresectable, locally advanced or metastatic clear cell RCC that progressed following PD-1 or PD-L1 checkpoint inhibitor and VEGF receptor targeted therapies either in sequence or in combination. In the trial, WELIREG reduced the risk of disease progression or death by 25% (HR=0.75 [95% CI, 0.63-0.90]; p=0.0008) versus everolimus in these patients. Median PFS was 5.6 months (95% CI, 3.9-7.0) for Welireg versus 5.6 months (95% CI, 4.8-5.8) for everolimus. The ORR for Welireg was 22% (n=82) (95% CI, 18-27), with a CR rate of 3% (n=10) and a PR rate of 19% (n=72), and the ORR for everolimus was 4% (n=13) (95% CI, 2-6), with no patients achieving a CR and a PR rate of 4% (n=13).

Von Hippel-Lindau disease is a rare genetic disease, which impacts an estimated 200,000 people worldwide and an estimated 10,000 to 15,000 people in Europe. Patients with VHL are at risk for recurrent, benign blood vessel tumours as well as some cancerous ones. The most commonly occurring tumour is RCC, a form of kidney cancer, which occurs in about 70% of patients with VHL disease.

Renal cell carcinoma is by far the most common type of kidney cancer. In 2020, more than 130,000 new cases of RCC were diagnosed in Europe. Renal cell carcinoma is about twice as common in men than in women. Approximately 30% of patients with kidney cancer are diagnosed at an advanced stage.

Indications in the US: Certain von Hippel-Lindau (VHL) disease-associated tumours; Welireg (belzutifan) is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumours (pNET), not requiring immediate surgery.

Welireg is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI).

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