1. Median PFS (5.6 months vs 5.6 months) and median OS (21.4 months vs 18.1 months) were similar in both arms.

2. Treatment-related adverse events grade 3-5 occurred in 38.7% of the belzutifan group and 39.4% of the everolimus group.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Antiangiogenic and immune checkpoint therapies have improved outcomes for patients with advanced clear-cell renal-cell carcinoma, and after disease progression, options are limited and have limited improvements in overall survival. VHL mutations, which occur in more than 90% of clear-cell renal-cell carcinoma, cause HIF-2α accumulation, leading to tumour growth. Belzutifan, a HIF-2α inhibitor, targets the dysregulated HIF pathway, and this phase 3 trial evaluated its efficacy and safety compared to everolimus. The primary endpoints included disease-free survival (DFS) and overall survival (OS), and secondary endpoints included objective response rate (ORR), duration of response (DoR), safety, and participant-reported outcomes. Median PFS was 5.6 months in the belzutifan group and 5.6 months in the everolimus group. PFS at 12 months and 18 months were 33.4% and 24.0% in the belzutifan group, and 17.1% and 8.3% in the everolimus group (significant). Median OS was 21.4 months in the belzutifan group and 18.1 months in the everolimus group with an HR of 0.88 (non-significant). OS at 12 months and 18 months were 67.9% and 55.2% in the belzutifan group, and 65.8% and 50.6% in the everolimus group. ORR was 21.9% in the belzutifan group and 3.5% in the everolimus group (significant). Median DoR was 19.5 months with belzutifan and 13.7 months with everolimus. With regards to safety, treatment-related adverse events grade 3-5 occurred in 38.7% in the belzutifan group and 39.4% in the everolimus group, with the most common events being anemia (32.5% vs 18.1%) and hypoxia (10.5% vs 1.1%). The median time to worsening of disease-related symptoms was not reached with belzutifan and was 11.99 months with everolimus, with HR 0.53 (significant). The Median time to confirmed deterioration in quality of life was 19.35 months and 10.19 months, respectively, with HR 0.75 (significant). The strengths of this study included its methodology and the limitation included limited follow-up time. Overall, belzutifan was shown to have limited improved outcome measures when compared to everolimus as a treatment option in advanced renal-cell carcinoma after both immune checkpoint and antiangiogenic therapies.

Click to read the study in NEJM

Relevant Reading: Belzutifan for Renal Cell Carcinoma in von Hippel–Lindau Disease

In-Depth [randomized controlled trial]: This phase 3, multicenter, open-label trial enrolled adults with stage IV clear-cell renal-cell carcinoma who had disease progression after treatment with immunotherapy and a VEGFR-TKI and randomized them (1:1) to belzutifan (n=374) or everolimus (n=372). Median follow-up time was 18.4 months for the first interim analysis and 25.7 months for the second interim analysis. Median PFS was 5.6 months (95%CI, 3.9-7.0) in the belzutifan group and 5.6 months (95%CI, 4.8-5.8) in the everolimus group. PFS at 12 months and 18 months were 33.4% (95%CI, 28.4-38.5) and 24.0% (95%CI, 19.0-29.4) in the belzutifan group and 17.1% (95%CI, 12.7-22.1), and 8.3% (95%CI, 4.9-12.7) in the everolimus group (p=0.002). Median OS was 21.4 months (95%CI, 18.2-24.3) in the belzutifan group and 18.1 months (95%CI, 15.8-21.8) in the everolimus group with an HR 0.88 (95%CI, 0.73-1.07, p=0.20). OS at 12 months and 18 months were 67.9% (95%CI, 62.9-72.4) and 55.2% (95%CI, 50.0-60.1) in the belzutifan group and 65.8% (95%CI, 60.7-70.3) and 50.6% (95%CI, 45.3-55.5) in the everolimus group.  ORR was 21.9% (95%CI, 17.8-26.5) in the belzutifan group and 3.5% (95%CI, 1.9-5.9) in the everolimus group (p<0.001). Median DoR was 19.5 months (1.9 to 31.6) with belzutifan and 13.7 months (3.8 to 21.2) with everolimus. With regards to safety, treatment-related adverse events grade 3-5 occurred in 38.7% in the belzutifan group and 39.4% in the everolimus group, with the most common events being anemia (32.5% vs 18.1%) and hypoxia (10.5% vs 1.1%). Median time to worsening of disease-related symptoms was not reached (95%CI, 21.26 months-NA) with belzutifan and was 11.99 months (95%CI, 5.55-15.38) with everolimus, with HR 0.53 (95%CI, 0.41-0.69). The median time to confirmed deterioration in the quality of life was 19.35 months (95%CI, 11.89-NA) and 10.19 months (95%CI, 6.47 to 12.98), respectively, with HR 0.75 (95%CI, 0.58-0.96). Overall, belzutifan was shown to have limited improved outcome measures when compared to everolimus as a treatment option in advanced renal-cell carcinoma after both immune checkpoint and antiangiogenic therapies.

Image: PD

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