Efficacy and safety of belzutifan in patients with metastatic clear cell renal cell carcinoma (mccRCC): Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

Abstract

479 Background: Belzutifan, a hypoxia-inducible factor 2α inhibitor (HIF2i), has been recently approved for the management of patients with advanced RCC following treatment with a PD-1 or PD-L1 inhibitor and a VEGF tyrosine kinase inhibitor. We sought to assess the efficacy and safety of belzutifan in patients with mccRCC using the IMDC dataset. Methods: Patients with mccRCC treated with belzutifan monotherapy in the second-line setting or beyond were included. Cases were stratified by line of therapy (2-3L vers 4L+). Baseline demographic and clinical characteristics, as well as efficacy parameters and adverse events from belzutifan treatment were collected. Clinical outcomes included overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and overall survival (OS). TTF and OS were estimated using the Kaplan-Meier method. Results: Overall, 74 patients with mccRCC treated with belzutifan monotherapy were included, of whom 44 and 31 were treated in the 2-3L and 4L+ setting, respectively. Baseline characteristics were similar across subgroups stratified by line of therapy (Table 1). Median follow-up was 13.7 months. ORR was 10.7% (95% CI: 5.0-21.4%). In the 2-3L subgroup, ORR was 13.8%, while in the 4L+ subgroup it was 7.4%. DCR was 60.7% (95%CI: 47.6-72.4%) in the overall study population, with similar rates across line of therapy subgroups (i.e., 2-3L: 62.1% and 4L+: 59.3%). Median TTF was 7.72 months (95%CI: 4.17-12.0 months) in the overall population, reaching 10.81 (95%CI: 7.72-NR) and 3.68 (95%CI: 2.30-8.67) months in the 2-3L and 4L+ subgroups, respectively. The 12-month OS rate was 64.4% (2-3L subgroup: 80.8% and 4L+ subgroup: 40.3%). Among patients with available date for safety parameters (n=47), 38.2% experienced adverse events requiring belzutifan dose reduction, most commonly due to anemia or symptomatic hypoxia. Conclusions: In this retrospective analysis, belzutifan demonstrated lower efficacy compared to clinical trials, with poorer clinical outcomes identified towards later lines of therapy. However, higher rates of dose reduction (38.2%) suggest a need for proactive monitoring and management of adverse events. Larger studies with longer follow-up remain essential to identify optimal therapy sequencing schemes and help optimize the use of belzutifan in clinical practice. Summary of baseline characteristics in the study population, stratified by line of therapy subgroups. Total(n=74) 2-3L(n=44) 4L+(n=31) Age, median (IQR) 56.5 (51.0-63.9) 57 (49.9-64) 55.8 (52-63.7) Favorable IMDC Risk Group, n (%) 14 (25.4%) 7 (23%) 7 (28%) Intermediate IMDC Risk Group, n(%) 29 (52.8%) 17 (57%) 12 (48%) Poor IMDC Risk Group, n (%) 12 (21.8%) 6 (20%) 6 (24%) IQR: interquartile range.