The FDA has approved belzutifan for the treatment of adult patients with von Hippel-Lindau disease who require therapy for associated renal cell carcinoma, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors that do not require immediate surgery.
The FDA has approved belzutifan (Welireg) 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 tumors (pNET) that do not require immediate surgery.1
The approval was based on findings from the ongoing, open-label, single-arm phase 1 Study 004 (NCT03401788), which demonstrated that belzutifan elicited an objective response rate (ORR) of 49% (95% CI, 36%-62%) in patients with VHL-associated RCC (n = 61). All responses were partial responses (PRs) and 56% of patients maintained a response lasting at least 12 months (n = 17/30). The median duration of response was not reached.
Data from a subgroup analysis showed that patients with pNETs (n = 12) had an ORR of 83% (95% CI, 52%-98%) comprising a complete response rate of 17% and a PR rate of 67%. For those with CNS hemangioblastoma (n = 24), the ORR was 63% (95% CI, 41%-81%) with a 4% complete response rate and a 58% PR rate. The median duration of response was not reached in either subgroup. Among responders, 50% (n = 5/10) of patients with pNETs and 73% (n = 11/15) in those with CNS hemangioblastoma had a response lasting at least 12 months.
For the phase 1 study, investigators set out to examine the safety and efficacy of belzutifan as a treatment in patients with VHL disease–associated RCC and other VHL neoplasms.
To be eligible for enrollment, patients needed to have a diagnosis of VHL disease based on germline alteration, have at least 1 measurable RCC tumor, and an ECOG performance status of 0 or 1. Patients could not have previously received systemic anticancer therapy and they could not have metastatic disease.
A total of 61 patients were given oral belzutifan at a once-daily dose of 120 mg. The primary end point of the trial was ORR in VHL disease–associated RCC per RECIST v1.1 criteria and independent radiology committee. Key secondary end points comprised ORR in non-RCC neoplasms, duration of response (DOR) in RCC and non-RCC neoplasms, and safety.
The median age of study participants is 41 years (range, 19-66), 52.5% are male, 82.0% had an ECOG performance status of 0, and the number of previous tumor reduction procedures reported per patient was 4 (range, 0-15). All patients had pancreatic lesions, 36.2% had pNET, 82.0% had CNS hemangioblastoma, and 26.2% had retinal lesions.
Additional findings from the trial showed that 91.8% of patients (n = 56/61) experienced a reduction in target lesion size.
The 12-month progression-free survival rate in those with VHL disease–associated RCC who received the agent was 98.3%; the 24-month rate was 96.5%.
All patients with retinal hemangioblastoma experienced improved and stable responses with belzutifan; 68.8% experienced a best response of improved and 31.1% experienced a best response of stable.
The most frequent adverse effects, including laboratory abnormalities, that were experienced by 20% or more of patients who were given belzutifan on the trial included decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Anemia and hypoxia with the agent can be severe, according to the FDA.
Data from Study 004 showed that anemia was experienced by 90% of patients; in 7% of patients, this effect was grade 3 in severity. According to the FDA, patients should be transfused as clinically indicated. Notably, the regulatory agency does not recommend the use of erythropoiesis-stimulating agents for the treatment of this effect.
Moreover, hypoxia was reported in 1.6% of patients on the trial. The agent is known to be able to render some hormonal contraceptives ineffective, and exposure exposure to belzutifan during pregnancy can cause embryo-fetal harm.