Impact of belzutifan on anemia and hypoxia in sporadic and <i>VHL</i> -syndrome-associated renal cell carcinoma.

522 Background: Inactivation of the tumor suppressor von Hippel-Lindau ( VHL ) gene is associated with VHL -syndrome-associated renal cell carcinoma ( VHL- RCC) and sporadic renal cell carcinoma (spRCC). The inactivation of the VHL results in the accumulation of HIF-2a, promoting the expression of genes involved in angiogenesis and cycle-cell progression. Belzutifan, a HIF2α inhibitor, is approved for the treatment of VHL -RCC and spRCC patients (pts). Understanding the safety differences of belzutifan in these two populations can inform clinical management. Methods: This is a single-center, retrospective analysis of pts with spRCC and advanced VHL- RCC treated with belzutifan monotherapy between November 2018 and August 2024. The study population was separated into groups based on RCC type: spRCC and VHL- RCC. Demographic and clinical data were collected from medical records. The primary endpoints were the incidence of anemia and hypoxia. Continuous variables were reported as median with interquartile ranges (IQR) and compared using Wilcoxon rank-sum test. Categorical variables were presented as frequencies and percentage, with group comparisons performed using the Pearson Chi-Square test. Results: Pts with spRCC were older than those with VHL -RCC pts, with a median age of 67 y vs 41 y (p&lt; 0.001), and were predominantly male, (68% vs 36%, p = 0.035). Reduced glomerular filtration rate (defined as &lt; 50ml/min), was more prevalent in spRCC pts (36.5% vs 4.5%, p = 0.009). Baseline hemoglobin levels were similar between groups 13 g/dL (IQR: 10 – 14) vs.13 g/dL (IQR: 12.8 – 14.8). VHL- RCC pts received belzutifan for longer duration than spRCC pts (30.9 m vs 3.4 m, p &lt; 0.001). In terms of safety, any-grade and Grade 3 anemia were similar between groups, 82% vs 91% (ns) and 54% vs 36% (ns), respectively. However, anemia developed more rapidly in spRCC pts, 29 d vs. 82 d (p &lt;0.01) for any-grade, and 46 d vs. 104 d (p = 0.018) for grade 3 anemia. The need for blood transfusion was more frequent in spRCC patients (18% vs 0%, p &lt; 0.05) as was the use of erythropoietin-stimulating agents 2% vs 4.5%, p = 0.08). Any-grade hypoxia was more frequent in spRCC pts (59% vs 18%, p 0.005), and there was a trend towards more grade 3 hypoxia (54.5% vs 9%, p = 0.052). Grade 3 hypoxia developed faster in spRCC pts (29 d vs 225 d, p = 0.039), the need for oxygen was more frequent in this population (52.5% vs 9.5%, p =0.003). Treatment discontinuations were more frequent in spRCC pts than in the VHL -RCC pts, 36.4% vs 4.5% (p = 0.009), 75% of discontinuations in spRCC were due to toxicity. Conclusions: Our cohort demonstrates differences in the safety profile of belzutifan between spRCC and VHL -RCC patients. These findings underscore the importance for personalized monitoring and management for each patient population.