Belzutifan Earns Positive CHMP Opinion for VHL Disease–Associated Tumors, Advanced ccRCC

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending the conditional approval of belzutifan (Welireg) 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 tumors (pNETs), and for whom localized procedures are unsuitable; and the treatment of 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.1

The positive opinion was supported by data from the phase 2 LITESPARK-004 (NCT03401788), and phase 3 LITESPARK-005 (NCT04195750) trials, respectively.

If approved, belzutifan would become the first oral HIF-2α inhibitor available for this patient population in the European Union (EU). The recommendation for marketing authorization in the EU is now under review by the European Commission (EC); a final decision is anticipated for the first quarter of 2025.

“Today’s positive CHMP opinion brings us closer to offering belzutifan, a first-in-class HIF-2α inhibitor, to certain patients in the EU, in order to help address critical gaps in care for these patients,” Marjorie Green, MD, senior vice president and head of Late-Stage Oncology, Global Clinical Development, Merck Research Laboratories, stated in a news release. “We are committed to providing innovative treatment options that address serious unmet needs for patients globally and look forward to the EC’s decision.”

LITESPARK-004 Overview and Key Data

The single-arm, open-label LITESPARK-004 trial enrolled patients with VHL disease–associated RCC based on the presence of a germline VHL mutation with at least 1 measurable, solid RCC tumor; or other VHL-associated tumors, including CNS hemangioblastomas and pNET not requiring immediate surgery.1,2 Upon enrollment, patients received 120 mg of oral belzutifan daily until disease progression or unacceptable toxicity.

The primary end point of the study was objective response rate (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 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).1 The median DOR for these patients was not reached (NR; range, 2.8+ to 22+ months); 56% of responders (n = 30) maintained a response for at least 12 months.

Additional data showed patients with VHL-associated CNS hemangioblastomas (n = 24) experienced an ORR of 63% (95% CI, 41%-81%), with 4% achieving a complete response (CR) and 58% achieving a PR. The median DOR was NR (range, 3.7+ to 22+ months); 73% of responders (n = 15) maintained a response for at least 12 months.

In patients with VHL-associated pNET (n=12), the ORR was 83% (95% CI, 52%-98%), with CRs and PRs reported in 17% and 67% of patients, respectively. The median DOR was NR (range, 11+ to 19+ months); half of responders (n = 10) maintained a response for at least 12 months.

Serious adverse effects (AEs) associated with belzutifan occurred in 15% of patients, with common events including anemia, hypoxia, anaphylaxis, retinal detachment, and central retinal vein occlusion (n = 1 each). Permanent discontinuation of treatment due to AEs was reported in 3.3% of patients, with dizziness and opioid overdose each leading to discontinuation in 1.6% of patients. Adverse reactions led to dosage interruptions in 39% of patients. The most common causes of interruption reported in more than 2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness. Dose reductions occurred in 13% of patients, primarily due to fatigue (7%).

The most frequently reported AEs reported in at least 25% of patients, including laboratory abnormalities, were decreased hemoglobin (93%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%).

Findings from LITESPARK-004 also supported the FDA approval of belzutifan in August 2021 for adult patients with VHL disease who require therapy for associated RCC, CNS hemangioblastomas, or pNET who do not require immediate surgery.2

LITESPARK-005 Overview and Key Data

The open-label trial enrolled patients (n = 746) with unresectable locally advanced or metastatic ccRCC that had progressed after treatment with a PD-1 or PD-L1 inhibitor and a VEGF TKI.1,3 Upon enrollment, patients were randomly assigned to receive 120 mg of belzutifan or 10 mg of everolimus once daily. Randomization was stratified by International Metastatic RCC Database Consortium risk category and number of prior VEGF TKIs.

The study’s coprimary end points were progression-free survival (PFS) assessed by blinded independent central review and overall survival (OS).

In LITESPARK-005, belzutifan demonstrated a 25% reduction in the risk of disease progression or death compared 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) for belzutifan and 5.6 months (95% CI, 4.8-5.8) for everolimus. The ORR with belzutifan was 22% (95% CI, 18%-27%), including a CR rate of 3% and PR rate of 19%. In comparison, the ORR with everolimus was 4% (95% CI, 2%-6%) with no CRs and a PR rate of 4%.

Serious AEs occurred in 38% of patients treated with belzutifan, including hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%), and pleural effusion (2.2%).1 Fatal reactions (3.2%) included sepsis and hemorrhage (0.5% each). Treatment was permanently discontinued in 6% of patients, primarily due to hypoxia (1.1%) and hemorrhage (0.5%).

Dosage interruptions were reported in 39% of patients treated with belzutifan, more frequently in those 65 years of age or older (48% vs 34%). Common reasons for dose interruption included anemia (8%), hypoxia (5%), and fatigue (3.2%). Dose reductions were reported in 13% of patients, with hypoxia (5%) and anemia (3.2%) being the primary causes.

The most common AEs reported in at least 25% of patients in the experimental arm included decreased hemoglobin (88%), fatigue (43%), musculoskeletal pain (33%), increased creatinine levels (34%), decreased lymphocyte counts (34%), increased alanine aminotransferase levels (32%), decreased sodium levels (31%), increased potassium levels (29%), and increased aspartate aminotransferase levels (27%).

Based on these results, belzutifan was approved by the FDA in December 2023 for the treatment of adults with advanced RCC following a PD-1 or PD-L1 inhibitor and a VEGF-TKI.3

References

1. Merck receives positive EU CHMP opinion for WELIREG® (belzutifan) as treatment for adult patients with certain types of von Hippel-Lindau disease-associated tumors and for certain previously treated adult patients with advanced renal cell carcinoma. Merck. December 13, 2024. Accessed December 13, 2024. https://www.merck.com/news/merck-receives-positive-eu-chmp-opinion-for-welireg-belzutifan-as-treatment-for-adult-patients-with-certain-types-of-von-hippel-lindau-disease-associated-tumors-and-for-certain-previously-trea
2. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. FDA. February 1, 2022. Accessed December 13, 2024. 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 December 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma