Belzutifan for Renal Cell Carcinoma in von Hippel–Lindau Disease

Jonasch, Eric; Donskov, Frede; Iliopoulos, Othon; Rathmell, W. Kimryn; Narayan, Vivek; Maughan, Benjamin L.; Oudard, Stéphane; Else, Tobias; Maranchie, Jodi K.; Welsh, Sarah J.; Thamake, Sanjay; Park, Eric K; Perini, Rodolfo F.; Linehan, W. Marston; Srinivasan, Ramaprasad

doi:10.1056/nejmoa2103425

Cited by 355 publications

(275 citation statements)

References 23 publications

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“…Belzutifan (PT2977, MK-6482), a 2nd generation small molecule HIF-2α inhibitor that showed increased potency and an improved pharmacokinetic profile, was evaluated in a phase 1 trial [ 103 ]. Recently, a phase 2 study evaluated the efficacy and safety of belzutifan in pre-treated patients with RCC with VHL disease [ 104 ]. Belzutifan showed promising results with a 49% ORR.…”

Section: Potential Candidates For Systemic Treatment and Ongoing Phas...mentioning

confidence: 99%

The Frontline Immunotherapy-Based Treatment of Advanced Clear Cell Renal Cell Carcinoma: Current Evidence and Clinical Perspective

Kim

2022

Biomedicines

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Approximately 400,000 patients are diagnosed with kidney cancer annually worldwide, leading to approximately 170,000 deaths. Renal cell carcinoma (RCC) accounts for more than 90% of kidney cancers. The most common histological subtype is clear cell RCC, which is found in approximately 85% of metastatic RCC cases. The VHL-HIF-VEGF axis is well known; therefore, targeting VEGF has been the mainstay for managing advanced clear cell RCC. Recently, the treatment landscape for advanced clear cell RCC has changed extensively. In particular, immune checkpoint inhibitor-based treatment showed promising results in front-line treatment and became the standard of care. Herein, we review the current evidence on front-line treatment options and discuss the clinical and future perspective.

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Section: Potential Candidates For Systemic Treatment and Ongoing Phas...mentioning

confidence: 99%

The Frontline Immunotherapy-Based Treatment of Advanced Clear Cell Renal Cell Carcinoma: Current Evidence and Clinical Perspective

Kim

2022

Biomedicines

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“…Belzutifan is an oral HIF-2-alpha inhibitor studied at a dose of 120 mg daily in a phase-2, open-label, single-group, multicentric trial, enrolling 61 patients. [ 5 ] Patients were 18 years and older with germline VHL mutation and at least one measurable RCC 1–3 cm with no metastatic disease with ECOG of 0 or 1. The primary end-point was objective response measured according to RECIST v1.1, with 49% showing partial response and 49% having stable disease.…”

Section: Belzutifan: a Novel Oral Drug For Renal Cancer In Von Hippel Lindau Diseasementioning

confidence: 99%

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Mandal

2022

Indian J Urol

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“…The most promising of these combinations seems to be that of BYL719 and everolimus: the combined effects of these drugs include shrinkage or collapse of tumor cell spheroids, in addition to GSK3 inhibition, cyclinD1/D3 downregulation in PCC cell lines [ 130 ]. The HIF1 inhibitor, belzutifan, has recently been shown to be useful in VHL disease [ 131 ] and Pacak-Zhuang disease [ 132 ] and we understand that clinical trials of this drug are in progress in PPGL.…”

Section: Model Systemsmentioning

confidence: 99%

Model systems in SDHx-related pheochromocytoma/paraganglioma

Takács‐Vellai

Farkas

Ősz

et al. 2021

Cancer Metastasis Rev

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Pheochromocytoma (PHEO) and paraganglioma (PGL) (together PPGL) are tumors with poor outcomes that arise from neuroendocrine cells in the adrenal gland, and sympathetic and parasympathetic ganglia outside the adrenal gland, respectively. Many follow germline mutations in genes coding for subunits of succinate dehydrogenase (SDH), a tetrameric enzyme in the tricarboxylic acid (TCA) cycle that both converts succinate to fumarate and participates in electron transport. Germline SDH subunit B (SDHB) mutations have a high metastatic potential. Herein, we review the spectrum of model organisms that have contributed hugely to our understanding of SDH dysfunction. In Saccharomyces cerevisiae (yeast), succinate accumulation inhibits alpha-ketoglutarate-dependent dioxygenase enzymes leading to DNA demethylation. In the worm Caenorhabditis elegans, mutated SDH creates developmental abnormalities, metabolic rewiring, an energy deficit and oxygen hypersensitivity (the latter is also found in Drosophila melanogaster). In the zebrafish Danio rerio, sdhb mutants display a shorter lifespan with defective energy metabolism. Recently, SDHB-deficient pheochromocytoma has been cultivated in xenografts and has generated cell lines, which can be traced back to a heterozygous SDHB-deficient rat. We propose that a combination of such models can be efficiently and effectively used in both pathophysiological studies and drug-screening projects in order to find novel strategies in PPGL treatment.

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Belzutifan for Renal Cell Carcinoma in von Hippel–Lindau Disease

Cited by 355 publications

References 23 publications

The Frontline Immunotherapy-Based Treatment of Advanced Clear Cell Renal Cell Carcinoma: Current Evidence and Clinical Perspective

The Frontline Immunotherapy-Based Treatment of Advanced Clear Cell Renal Cell Carcinoma: Current Evidence and Clinical Perspective

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Model systems in SDHx-related pheochromocytoma/paraganglioma

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