RCC refers to a diverse collection of malignancies that arise from renal tubular epithelial cells. Over the last two decades, significant breakthroughs in the histopathological and molecular characterization of RCC have resulted in major categorization modifications. The most frequent subtype of RCC is clear cell RCC, which accounts for the majority of kidney cancer mortality. RCC is heterogeneous, consisting of a variety of histological cell types with distinct genetics, biology, and behavior. Much of what we know about the molecular underpinnings of early sporadic RCC comes from the discovery of the genes that predispose us to inherited syndromes with RCC. Clear cell RCC (ccRCC) is the most common histologic entity resulting from morphologic heterogeneity in the proximal convoluted tubule and is made up of cells with clear or eosinophilic cytoplasm. Inactivation of the von Hippel Lindau (VHL) tumor suppressor gene causes these cancers.

Belzutifan (Welireg), a hypoxia-inducible factor-2 alpha (HIF-2) inhibitor, was approved by the FDA in August 2021 for adult patients with VHL disease who need treatment for pancreatic neuroendocrine tumors, renal cell carcinomas, or hemangioblastomas of the central nervous system that do not require immediate surgery. Since the agent's approval, this patient population segment has experienced a significant change. Belzutifan offers a novel approach to treat RCC, taking a different path than commonly used vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors. Belzutifan was approved based on the results of a Phase II study (NCT03401788) which enrolled 61 patients. The study found the agent not only effective but also to have a manageable safety profile.

 Cabozantinib, which is approved as monotherapy for advanced clear cell RCC, inhibits VEGF. Vascular endothelial growth factor receptor (VEGFR) TKI is used as the first line of therapy in advanced RCC as a result of advances in the understanding of the molecular biology underlying RCC.

As of the cutoff date in February 2022, the results of cohort 1 had patients of the treatment naïve group. In cohort 1, 35 patients enrolled in which the median age was 64 years and most of them were men. 57% of patients had a confirmed ORR and 37% has the best response to SD. Median DOR was 28.6 months (range, 1.7+ to 28.6); 13 patients remained in response for ≥6 months. Median PFS was 30.3 months; the estimated 12-month PFS rate was 67%. The anticipated 12-month OS rate was 96%; however, the median OS was not met. The ORR for each IMDC risk category was 62% for favorable risk in 21 points and 50% for intermediate/poor risk in 14 patients. Grade 3 treatment-related AEs occurred in 13 patients (37%), most commonly hypertension (n=4; 11%) and fatigue. There were no grade 4 or 5 treatment-related AEs. 

Belzutifan was first tested in patients who have had extensive pretreatment in early-phase studies, and good response and DCR rates were seen across risk groups. HIF-2 concentration is increased by anti-VEGF, which justifies combining the inhibitors. Although the exact cause of belzutifan hypoxia is unknown, it is thought that HIF-2 suppression may reduce the pulmonary artery vasoconstrictor response to ventilation/perfusion mismatch.

In clear cell RCC patients who have not received treatment, cabozantinib plus belzutifan displays encouraging activity, although prolonged follow-up is required for survival results. It will be too soon to comment on the safety of this combination, though it will be gripping to track down the details of this combination which, could possibly set a benchmark if approved.

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