59Real-World efficacy and safety of belzutifan in sporadic metastatic renal cell carcinoma: a multicenter study from the city of hope enterprise

Background Belzutifan is a novel HIF-2α inhibitor approved for use in Von Hippel-Lindau (VHL)-associated tumors and sporadic clear cell metastatic renal cell carcinoma (mRCC) following prior treatment with immune checkpoint inhibitor (IO) and tyrosine kinase inhibitor (TKI). However, real-world data on its efficacy and safety in patients with mRCC not represented in clinical trial remains limited. Methods We conducted a multicenter, retrospective study of patients with sporadic mRCC treated with belzutifan across the City of Hope Cancer Center enterprise in the United States. Clinical information and disease characteristics were abstracted from electronic medical records. Data were analyzed for objective response rate (ORR), disease control rate, progression-free survival (PFS), and overall survival (OS). Adverse events (AEs) were also recorded and graded per CTCAE v5.0. Results Between 2023 and 2025, 43 patients with sporadic mRCC received belzutifan. Among them, 26% were Hispanic and 70% identified as male. Median age at therapy initiation was 67 years (range 21-86). Clear cell histology was the most common (91%); one patient had mixed clear cell and papillary RCC; one patient had chromophobe histology with somatic VHL mutation; one patient had unclassified RCC. Sarcomatoid and rhabdoid features were present in 19% and 12%, respectively. At the start of therapy, baseline liver metastases and peritoneal disease were present in 33% and 19% of patients, respectively; 30% had bone metastases. The median number of prior lines of therapy in the metastatic setting was 3 (range 0-6), with the majority of whom received prior IO (95%) and prior TKI (88%). A total of 79% of patients previously had a nephrectomy, of whom 12% had prior adjuvant therapy. Among the 36 patients with available interval imaging after starting belzutifan, the ORR was 25% (9/36) with 9 patients having a partial response and no complete responses; 15 patients had stable disease and 13 had disease progression. The disease control rate was 64%. The median OS was 6.93 months (95% CI: 3.75-12.58). The median PFS was 3.09 months (95% CI 2.53-5.72). AEs of any grade were reported in 93% of patients. The most common all-grade AEs were anemia (79%), fatigue (30%), hypoxia (14%), and dyspnea (9%). Frequent grade 3-5 AEs included anemia (68%) and hypoxia (16%). Treatment interruption and dose reduction occurred in 16% and 26% of patients, respectively. Belzutifan discontinuation due to AEs occurred in 12%. Conclusions In this diverse and heavily pretreated cohort of patients with sporadic mRCC and higher frequency of visceral metastases, belzutifan had similar ORR but shorter OS and PFS compared to prior clinical trial observations. The safety profile remained consistent with previous reports. A key limitation of this study is that belzutifan was frequently initiated late in the disease course which may have limited observed efficacy.