Reference Detail

Ref Type

Journal Article

PMID

(38344974)

Authors

Chan KH, Li N, Lador R, Amsbaugh M, Gonzalez A, Cen P

Title

Belzutifan, HIF-2α Inhibitor, and Clear Cell Renal Cell Carcinoma With Somatic Von-Hippel-Lindau Loss-of-Function Mutation.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of investigative medicine high impact case reports	12		2024 Jan-Dec	23247096241231641	J Investig Med High Impact Case Rep

URL

Abstract Text

The Von-Hippel-Lindau (VHL) gene, acting as a tumor suppressor, plays a crucial role in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). Approximately 90% of individuals with advanced ccRCC exhibit somatic mutations in the VHL gene. Belzutifan, orally administered small-molecule inhibitor of hypoxia-induced factor-2α, has demonstrated promising efficacy in solid tumors associated with germline loss-of-function mutations in VHL, including ccRCC. However, its impact on cases with somatic or sporadic VHL mutations remains unclear. Here, we present 2 cases where belzutifan monotherapy was employed in patients with advanced ccRCC and somatic loss-of-function mutations in VHL. Both patients exhibited a swift and sustained response, underscoring the potential role of belzutifan as a viable option in second or subsequent lines of therapy for individuals with somatic VHL mutations. Despite both patients experiencing a pulmonary crisis with respiratory compromise, their rapid response to belzutifan further emphasizes its potential utility in cases involving pulmonary or visceral crises. This report contributes valuable insights into the treatment landscape for advanced ccRCC with somatic VHL mutations.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
VHL	N78K	missense	unknown	VHL N78K does not lie within any known functional domains of the Vhl protein (UniProt.org). N78K has been identified in sequencing studies (PMID: 23434146, PMID: 11921283, PMID: 38344974), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Jun 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
VHL N78K	clear cell renal cell carcinoma	predicted - sensitive	Belzutifan	Case Reports/Case Series	Actionable	In a clinical case study, a patient with metastatic clear cell renal cell carcinoma harboring VHL N78K responded to treatment with Welireg (belzutifan) as a second-line therapy (PMID: 38344974).	38344974
VHL T133fs	clear cell renal cell carcinoma	predicted - sensitive	Belzutifan	Case Reports/Case Series	Actionable	In a clinical case study, Welireg (belzutifan) treatment resulted in a durable response lasting at least 1.5 years in a heavily-pretreated clear cell renal cell carcinoma patient harboring VHL T133fs (PMID: 38344974).	38344974