From Bench to Bedside: HIF-2α Inhibition in RCC

In 2024, kidney cancer is projected to be one of the top 10 cancers in terms of incidence rate in the United States, with an estimated 81,610 new diagnoses.¹ with an estimated 81,610 new diagnoses. Renal cell carcinoma (RCC) accounts for approximately 80% to 90% of all kidney cancer cases, with the predominant subtype being clear cell RCC (ccRCC).²

Fortunately, we have been witnessing remarkable advancements in the treatment of patients with RCC with the advent of angiogenesis and immune checkpoint inhibitors.³ Loss of function in the VHL gene is a hallmark of ccRCC pathogenesis.⁴ Aberrations in the VHL protein (pVHL) increase the activity of hypoxia-inducible factor-2 (HIF-2), which plays a crucial role in carcinogenesis.⁵ Understanding the roles of pVHL and HIF-2α not only reveals how mammalian cells sense and respond to oxygen in normal cellular processes but also elucidates the underlying mechanisms involved in cancer development. For their research in this area, William G. Kaelin Jr., MD; Sir Peter J. Ratcliffe, MD, FRS, FMedSci; and Gregg L. Semenza, MD, PhD, were awarded the Nobel Prize in Physiology or Medicine in 2019.⁶

Biology and Drug Information

As a tumor suppressor gene, VHL is part of the E3 ubiquitin ligase complex degrading HIFs under normal oxygen levels.⁷ HIF-2α, also known as endothelial PAS domain protein 1, is a transcription factor that plays a role in the cellular response to hypoxia.⁸ Under hypoxic conditions, HIF-2α binds to an aryl hydrocarbon receptor nuclear translocator, also known as HIF-1β, and becomes an active transcription complex, inducing the expression of proteins active in angiogenesis, proliferation, and migration.⁹ In ccRCC, accumulation of HIF-2α is due to the loss of the VHL protein, leading to a state of pseudohypoxia.^5,10

Belzutifan (Welireg) is a second-generation and more potent inhibitor of HIF-2α than the previously developed MK-3795.11 The agent binds to the inner pocket of HIF-2α and inhibits the formation of the HIF-2α and HIF-1β complex. Thus, it blocks abnormal protein expression caused by the abnormal accumulation of HIF-2α (Figure).

As a result of this mechanism of action, in the first-in-human phase 1 LITESPARK-001 study (NCT02974738), anemia was among the most common grade 3 or higher adverse effects (AEs) due to decreased levels of erythropoietin, a down-stream HIF-2 inducible gene.^11,12 Reduction in erythropoietin levels usually occurs early in the treatment course and is closely associated with the plasma level of belzutifan.¹¹ Therefore, packed ed blood cell transfusions and/or erythropoiesis-stimulating agents can be used to manage significant anemia. Hypoxia is another potential AE.¹¹ The precise cause of hypoxia is not fully understood; however, it is considered multifactorial, potentially involving impaired hypoxia sensing in various body parts responsible for ventilation.¹³ To manage hypoxia, close monitoring with a pulse oximeter and dose adjustments should be made when hypoxic conditions are detected (SpO2 < 88% at rest).

Clinical Trial Data

LITESPARK-001 marked the transition of HIF-2α inhibitors to the clinical setting. Investigators evaluated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, and anticancer activity of belzutifan in 55 patients with refractory ccRCC.¹¹ The most recent data update, published in January 2024, showed that, at a median follow-up of 41.2 months (range, 38.2-47.7), the objective response rate (ORR) was 25%.¹⁴

Accounting for the underlying biology, the safety and efficacy of belzutifan were investigated in patients with von Hippel-Lindau disease,
a rare autosomal dominant disorder that results from a germline variant in VHL.¹⁵ The corresponding phase 2 LITESPARK-004 study (NCT03401788) demonstrated initial significant activity in patients with RCC with an ORR of 49% (95% CI, 36%-62%) and other non-RCC neoplasms associated with
von Hippel-Lindau disease (n = 61), such as retinal hemangioblastomas.¹⁶ The findings supported the FDA approval of belzutifan for this distinct patient population in August 2021.¹⁷

Another phase 2 study, LITESPARK-003 (NCT03634540), assessed the effects of combining the HIF-2α–targeting approach with the multitargeted tyrosine kinase inhibitor cabozantinib (Cabometyx). Cohort 2 (n = 52), which consisted of patients in their second or third line of treatment after previous immunotherapy, achieved an ORR of 31% (95% CI, 19%-45%). Cohort 1 (n = 50), which included treatment-naive patients with RCC, experienced an ORR of 70%.¹⁸

Focusing on the optimal dosage, the phase 2 LITESPARK-013 study (NCT04489771) compared the efficacy and safety profile of belzutifan at daily doses of 120 mg vs 200 mg. With similar efficacy in both arms, this trial supported using the conventional 120-mg daily dose. The incidence of treatment-related AEs was consistent with previous studies and was slightly higher in the 200-mg arm.¹⁹

The phase 3 LITESPARK-005 study (NCT04195750) was the last major step before belzutifan’s milestone FDA approval for patients with advanced RCC in December 2023.²⁰ The trial included 746 pretreated patients with 1 to 3 prior lines of systemic therapy. Participants were randomly assigned 1:1 to receive the mTOR-inhibitor everolimus (Afinitor) or belzutifan. Treatment with belzutifan resulted in a 25% risk reduction for progression or death (HR, 0.75; 95% CI, 0.63-0.90; P < .001). Despite that, OS data did not reach statistical significance. The ORR was 21.9% (95% CI, 17.8%-26.5%) vs 3.5% (95% CI, 1.9%-5.9%) with belzutifan compared with everolimus, respectively. Notably, in this heavily pretreated population, time to deterioration of cancer symptoms also favored belzutifan.²¹

Due to extensive research and clinical advancements, HIF-2α inhibition has emerged as a valid and promising therapeutic option for the treatment of patients with kidney cancer. Ongoing studies and accumulating evidence, especially in combination regimens and earlier lines of therapy, continue to bolster the potential of HIF-2α inhibitors (Table).^22-29