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Welireg for cancers associated with von Hippel-Lindau disease. FDA approval

The Food and Drug Administration ( FDA ) has approved Welireg ( Belzutifan ), a hypoxia-inducible factor inhibitor for 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 ), not requiring immediate surgery.

Belzutifan was investigated in the ongoing Study 004, an open-label clinical trial in 61 patients with VHL-associated renal cell carcinoma ( VHL-RCC ) diagnosed based on a VHL germline alteration and with at least one measurable solid tumor localized to the kidney.
Enrolled patients had other Hippel-Lindau disease-associated tumors, including CNS hemangioblastomas and pancreatic neuroendocrine tumors.
Patients received Belzutifan 120 mg once daily until disease progression or unacceptable toxicity.

The primary efficacy endpoint was overall response rate ( ORR ) measured by radiology assessment, as assessed by an independent review committee using RECIST v1.1.
Additional efficacy endpoints included duration of response ( DoR ), and time-to-response ( TTR ).

An ORR of 49% ( 95% CI:36, 62 ) was reported in patients with Hippel-Lindau disease-associated renal cell carcinoma.
All patients with VHL-RCC with a response were followed for a minimum of 18 months from the start of treatment.
The median duration of response was not reached; 56% of responders had duration of response 12 months or more and a median time-to-response of 8 months.

In patients with other Hippel-Lindau disease-associated non-RCC tumors, 24 patients with measurable CNS hemangioblastomas had an overall response rate of 63% and 12 patients with measurable pNET had an overall response rate of 83%.
Median duration of response was not reached, with 73% and 50% of patients having response durations ≥ 12 months for CNS hemangioblastomas and pancreatic neuroendocrine tumors, respectively.

The most common adverse reactions, including laboratory abnormalities, reported in 20% or more of patients who received Belzutifan were decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea.
Anemia and hypoxia from Belzutifan use can be severe.
In Study 004, anemia occurred in 90% of patients and 7% had grade 3 anemia.
Patients should be transfused as clinically indicated.

The use of erythropoiesis stimulating agents for treatment of anemia is not recommended in patients treated with Belzutifan.
In Study 004, hypoxia occurred in 1.6% of patients.

Belzutifan can render some hormonal contraceptives ineffective, and Belzutifan exposure during pregnancy can cause embryo-fetal harm. ( Xagena )

Source: FDA, 2021