SUMMARY: The FDA on December 14, 2023, approved Belzutifan (WELIREG®) for patients with advanced Renal Cell Carcinoma (RCC) following a Programmed Death receptor-1 (PD-1) or Programmed Death-Ligand 1 (PD-L1) inhibitor and a Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor (VEGF-TKI). The American Cancer Society estimates that 81,800 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2023 and about 14,890 people will die from this disease. Clear cell Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer in adults. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five-year survival of patients with advanced RCC is about 14% and there is a significant need for improved therapies for this disease.
Patients with advanced RCC are often treated with immune checkpoint inhibitors and Vascular Endothelial Growth Factor Receptor (VEGFR) targeted Tyrosine Kinase Inhibitors, either in combination or sequentially. However upon progression on these therapies, there are limited treatment options and there is an unmet medical need.
The VHL (Von Hippel-Lindau) protein is a tumor suppressor gene located on the short arm of chromosome 3p. It is frequently mutated and inactivated in approximately 90% of clear cell Renal Cell Carcinomas (ccRCC). The VHL gene under normal conditions binds to Hypoxia-Inducible Factors (HIFs) and facilitates degradation of this factor. Under hypoxic conditions and in patients having biallelic loss of function and mutation of VHL genes, HIFs are not degraded. High HIF levels and subsequent overproduction of VEGF, PDGF and TGF-alpha, resulting in increased angiogenesis, increased tumor cell proliferation and survival, as well as metastasis.
Belzutifan (WELIREG®) is a a first-in-class, oral, HIF-2alfa inhibitor approved in the US 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. This approval was based on the Overall Response Rate (ORR) and Duration of Response (DOR) data from the Phase II LITESPARK-004 trial.
The present FDA approval was based on LITESPARK-005, which is a randomized, open-label, Phase III trial, in which Belzutifan was compared with Everolimus in pretreated advanced Renal Cell Carcinoma (RCC). In this study, 746 enrolled patients with metastatic clear cell RCC whose disease progressed after treatment with both an immune checkpoint inhibitor, such as a PD-1 or PD-L1 inhibitor, and VEGF-TKI, in sequence or in combination, were randomly assigned 1:1 to receive either Belzutifan 120 mg orally daily (N=374) or Everolimus 10 mg orally daily (N=372), until disease progression or unacceptable toxicity. The dual Primary endpoints were Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) and Overall Survival (OS). Secondary endpoints included Overall Response Rate (ORR) by BICR and Safety.
At the first pre-specified interim analysis at a median follow up of 18.4 months, Belzutifan significantly reduced the risk of disease progression or death by 25% compared to Everolimus (HR=0.75; P<0.001). The results at the second pre-specified interim analysis were consistent with first interim analysis. At a median follow-up of 25.7 months, Belzutifan significantly reduced the risk of disease progression or death by 26% compared to Everolimus (HR=0.74; P<0.001). The estimated 12-month PFS rate was 33.7% for patients who received Belzutifan versus 17.6% for patients who received Everolimus, and the estimated 18-month PFS rate was 22.5% and 9.0%, respectively. The Overall Survival data favored Belzutifan compared to Everolimus at both the first and second interim analysis, but did not reach statistical significance and will be tested at a subsequent analysis.
There was a statistically significant improvement in ORR at both the first and second interim analysis, and the ORR was 22.7% with a Complete Response rate 3.5% for patients who received Belzutifan versus an ORR of 3.5% with no patients achieving a Complete Response for patients who received Everolimus (P<0.00001). The time to response with Belzutifan was about three months. Quality of Life favored Belzutifan.
Treatment-related adverse events and in particular Grade 3 adverse events were similar in both treatment groups. Adverse events leading to treatment discontinuation occurred in 5.9% of patients who received Belzutifan and 14.7% among those who received Everolimus. The most common side effects associated with Belzutifan were anemia, fatigue, nausea, constipation, peripheral edema, dyspnea and arthralgia.
It was concluded that Belzutifan was associated with a statistically significant improvement in Progression Free Survival and Overall Response Rate compared to Everolimus in patients with advanced clear cell Renal Cell Carcinoma, after immune checkpoint and anti-angiogenic therapies. They added that this is the first Phase III trial to show positive results in advanced RCC following standard therapies and the first drug with a new mechanism of action to demonstrate efficacy in this group of patients.
Belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): Randomized open-label phase III LITESPARK-005 study. Albiges L, Rini BI, Peltola K, et al. DOI:https://doi.org/10.1016/j.annonc.2023.10.090. LBA88
