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Selective HIF2A Inhibitors, What Started as a Von Hippel-Lindau Niche Is Now Gearing up for the Big Stage

Von Hippel-Lindau (VHL) loss is a near critical event for clear cell renal cell carcinoma, the most predominant histologic subtype of kidney cancers. The actual VHL genetic syndrome is an autosomal dominant inherited disorder resulting from a deletion or mutation in the VHL gene, which is located on the short arm of chromosome 3. The clinical phenotype manifests with the development of clear cell renal cell carcinomas, pheochromocytomas, pancreatic neuroendocrine tumors, and hemangioblastomas.1 However, the inherited syndrome is not mandatory for clear cell renal cell carcinoma development, as the 3p chromosomal region is lost in 91% of these tumors.2 Subsequent loss of heterozygosity generally occurs through mutation or hypermethylation, resulting in biallelic inactivation of the VHL tumor suppressor gene.3

The primary effector of VHL-mediated tumorigenesis is through the hypoxia-inducible factors (HIF1A and HIF2A), which are ubiquitinated by VHL in normoxic conditions, tagging them for degradation in the proteasome.4 In hypoxic conditions, HIF1A and HIF2A are not hydroxylated, a circumstance where VHL is unable to bind. This leads to the stabilization of HIF1A and HIF2A and the resultant translocation to the nucleus of these transcription factors to modulate the expression of hypoxia response genes. Many of these target genes lead to angiogenesis (e.g. vascular endothelial growth factor) and cellular proliferation, important for hypoxic conditions.5 Interestingly, this is mostly driven by HIF2A, as HIF1A is often deleted in clear cell renal cell carcinoma. Deletion of HIF1A leads to an increased proliferative state, confirming HIF1A as a tumor suppressor gene in this situation.6 In a tumor lacking VHL, the constitutive activation of HIF2A has unfortunate consequences.

As HIF2A is a transcription factor, this was originally felt to be one of the “undruggable” targets. Generally, it had been felt that proteins without easy binding pockets that interact directly with other proteins or DNA are difficult to target with therapeutic agents. However, a PAS protein-protein interaction domain on HIF2A has led to the development of allosteric inhibitors that bind specifically to that pocket, inhibiting heterodimerization with ARNT, a key event necessary for HIF2A to bind its DNA targets.7

Belzutifan, a second generation HIF2A inhibitor, was approved by the United States Food and Drug Administration on August 13, 2021, for patients with VHL disease. As surgical resection is the foundation of VHL syndrome tumor management, the approval of Belzutifan is for patients who do not require immediate surgery but who require therapy for associated renal cell carcinoma, central nervous system hemangioblastomas, and/or pancreatic neuroendocrine tumors.8

For clear cell renal cell carcinoma, PT2385 was the first HIF2A agent studied in clinical trials, however, it has become evident that Belzutifan has much higher potency. At the European Society of Medical Oncology in Madrid, Spain, just a few weeks ago, we saw data presented from some key trials with Belzutifan. The LITESPARK-005 trial, confirmed progression-free survival benefit (HR 0.74, 0.63-0.88) of Belzutifan (median 5.6 months) over Everolimus (median 5.6 months) for patients who received previous anti-PD-(L)1 antibody therapy and vascular endothelial factor tyrosine kinase inhibition.9 The patient population consisted of patients receiving 2nd, 3rd, or 4th line therapy for metastatic clear cell renal cell carcinoma, however, approximately 86% of the patient population enrolled to receive 3rd or 4th line therapy. The trial included mostly IMDC intermediate and poor risk patients, with only around 22% favorable risk patients. Although the median progression-free survival was the same in both arms, the Kaplan-Meier curves separated at the median and widened in favor of Belzutifan. The objective response rates were 21.9% and 3.5% for Belzutifan over Everolimus, respectively.

While we wait to see what regulators will recommend, we have multiple clinical trials using Belzutifan in combination with various other active agents in various clinical settings. Additionally, there are other HIF2A inhibitors being developed that are worth exploring in clinical trials with patients who harbor clear cell renal cell carcinoma.

Select Trials with HIF2A Inhibitors for Renal Cell Cancers

  • LITESPARK-024 - Belzutifan with Palbociclib vs. Belzutifan monotherapy for advanced renal cell carcinoma (NCT05468697)
  • Abemaciclib with or without Belzutifan for advanced refractory clear cell renal cell carcinoma (NCT04627064)
  • Pembrolizumab, Lenvatinib and Belzutifan or Pembrolizumab, Lenvatinib, and Quavonlimab vs. Pembrolizumab and Lenvatinib for advanced clear cell renal cell carcinoma (NCT04736706)
  • Adjuvant Belzutifan plus pembrolizumab vs. placebo plus pembrolizumab for clear cell renal cell carcinoma post nephrectomy (NCT05239728)
  • NKT2152 in patients with clear cell metastatic renal cell carcinoma who have exhausted other therapies (NCT05119335)
  • Phase 2 combination of NKT2152 with palbociclib and sasanlimab in metastatic clear cell renal cell carcinoma (NCT05935748)
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Suarez C, et al. Selective HIF2A Inhibitors in the Management of Clear Cell Renal Cancer and Von Hippel–Lindau-Disease-Associated Tumors. Med Sci 2023; 11:46.
  2. Creighton CJ, et al. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013; 499:43-9.
  3. Razafinjatovo C, et al. Characterization of VHL missense mutations in sporadic clear cell renal cell carcinoma: hotspots, affected binding domains, functional impact on pVHL and therapeutic relevance. BMC Cancer 2016; 16:638.
  4. Gossage L, Eisen T, Maher ER. VHL, the story of a tumour suppressor gene. Nat Rev Cancer 2015; 15:55-64.
  5. Choudhry H, Harris AL. Advances in Hypoxia-Inducible Factor Biology. Cell Metab 2018; 27:381-98.
  6. Gordan JD, et al. HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 2008; 14:435-46.
  7. Scheuermann TH, et al. Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat Chem Biol 2013; 9:271-6.
  8. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-cancers-associated-von-hippel-lindau-disease
  9. Albiges L, et al. Belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): Randomized open-label phase III LITESPARK-005 study. Presented at: European Society of Medical Oncology 2023 Congress. European Society of Medical Oncology 2023; LBA88.