Dr Gopal on the Advantages and Potential Benefit of Belzutifan in RCC

Nikhil A. Gopal, MD, assistant professor, urology, assistant professor, College of Medicine - Memphis, Department of Urology, The University of Tennessee Health Science Center, discusses the benefit of belzutifan (Welireg) for patients with renal cell carcinoma (RCC), as well as its potential use in the frontline setting.

The highly selective HIF2α inhibitor belzutifan has demonstrated efficacy in the treatment of patients with clear cell RCC (ccRCC), particularly in those who have progressed on prior therapy, Gopal begins. The phase 3 LITESPARK-005 trial (NCT04195750) demonstrated the superior efficacy of belzutifan over everolimus (Afinitor) and led to improved patient-reported quality of life (QOL) outcomes in this setting, Gopal details. Ongoing phase 2 trials are also investigating the efficacy of belzutifan in combination with cabozantinib (Cabometyx) for treatment-naive patients, he adds.

One notable advantage of belzutifan is its selectivity in targeting the HIF2α pathway, which is upregulated in most ccRCC cases due to loss of the von Hippel-Lindau gene, Gopal details. The resulting upregulation of HIF2α leads to increased transcription of angiogenesis factors such as VEGF, contributing to tumor growth and progression. By specifically targeting HIF2α, belzutifan blocks the angiogenesis pathway without affecting other pathways targeted by agents such as sunitinib (Sutent) or immunotherapy, Gopal explains.

On December 14, 2023, the FDA granted approval to belzutifan for the treatment of patients with advanced RCC who have undergone treatment with a PD-1 or PD-L1 inhibitor and a VEGF TKI based on data from LITESPARK-005. The safety profile of belzutifan in this trial appears favorable, with the main adverse effect (AE) being anemia, Gopal says. This approval indicates the tolerability of belzutifan even in patients with early-stage disease who are often high functioning, he emphasizes. Notably, most patients on the trial continued on belzutifan therapy for over 2 years with minimal treatment discontinuation, suggesting the agent's tolerability and efficacy. This ability to provide effective therapy with minimal AEs is particularly exciting for patients who can maintain a good QOL during treatment, according to Gopal.

Overall, belzutifan represents a promising treatment option for ccRCC, offering selective targeting of the HIF2α pathway and demonstrating efficacy in both refractory and treatment-naive settings with a favorable safety profile. Further research and clinical trials will continue to explore the potential of belzutifan in improving outcomes for patients with ccRCC.