European Commission approves bestivan for treatment of VHL disease-related tumors, advanced ccRCC

The European Commission has approved the oralHIF-2α inhibitor bezutifan as monotherapy for the following indications:

Adult patients with von Hippel-Lindau (VHL) disease who require treatment for associated localized renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastoma, or pancreatic neuroendocrine tumors (pNETs) and for whom local surgery is not appropriate; and

Adult patients with advanced clear cell renal cell carcinoma (ccRCC) whose disease has progressed after 2 or more therapies, including a PD-(L)1 inhibitor and at least 2 VEGF-targeted therapies.

The drug had previously received conditional approval from the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) in December 2024.

Data from the Phase 2 and 3 trials of LITESPARK-004 (NCT03401788) and LITESTARK-005 (NCT04195750) support these regulatory decisions, which represent the first approval of besetivan in the European Union (EU). In LITESPRAK-004, besotivan produced an ORR of 49% (95% CI, 36%-62%) in patients with VHL-related RCC (n=61), all of which were partial responses (PR). Additionally, patients with VHL-related CNS hemangioblastoma (n=24) had an ORR of 63% (95% CI, 41%-81%), 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%), and the CR and PR rates were 17% and 67%, respectively.

Among patients who received bezantivan in LITESPRAK-005, the risk of disease progression or death was reduced by 25% compared with patients treated with everolimus (Afinitor; HR, 0.75; 95% CI, 0.63-0.90; P=0.0008). The median progression-free survival with bezotivan is The median progression-free survival with everolimus was also 5.6 months (95% CI, 3.9-7.0). The ORR of bezotivan was 22% (95% CI, 18%-27%), of which CR and PR were 3% and 19% respectively. The ORR of everolimus was 4% (95% CI, 2%-6%), consisting entirely of PR.

Notably, the drug's conditional approval is valid for 1 year, with annual updates based on additional clinical data from LITESPARK-004 and the ongoing evaluation of the Phase 2 trial of bezutivan in certain VHL-related tumors.

Additional efficacy data from LITESPRAK-004 showed that the median DOR for bezutin was not reached (NR) across all VHL-related tumor types. Among patients with VHL-associated RCC (n=61), 56% maintained response for at least 12 months (range, 2.8+ to 22+). Among patients with central nervous system hemangioblastoma (n=24), 73% maintained a response for at least 12 months (range, 3.7+ to 22+), and among patients with pNETs (n=12), 50% maintained a response for at least 12 months (range, 11+ to 19+).

Regarding safety,15% of patients experienced serious adverse reactions (SAEs). These included anemia, hypoxia, allergic reaction, retinal detachment, and central retinal vein occlusion (1 case each). 3.3% of patients permanently discontinued treatment due to adverse events. Thirty-nine percent of patients required dose interruptions, most commonly for fatigue, anemia, and nausea. Thirteen percent of patients required dose reduction, primarily due to fatigue. The most common adverse events observed in this trial were decreased hemoglobin, fatigue, increased creatinine, and headache.

InLITESPRAK-005, 38% of patients experienced serious adverse events, the most common of which were hypoxia, anemia, and pneumonia. Fatal adverse events, including sepsis and bleeding, occurred in 3.2% of patients. Six percent of patients permanently discontinued treatment with Aes, primarily due to hypoxia and bleeding. Dose interruptions occurred in 39% of patients, with higher rates among patients 65 years of age or older than those under 65 years of age. The most common reasons for dose interruption include anemia and hypoxia. Dose reduction occurred in 13% of patients, mainly due to hypoxia and anemia. The most common adverse events observed in this trial were decreased hemoglobin, fatigue, musculoskeletal pain, and increased creatinine.

Reference materials:https://www.onclive.com/view/european-commission-approves-belzutifan-for-vhl-disease-associated-tumors-advanced-ccrcc