Ep. 2: VEGF TKIs in RCC: Toxicity and Tolerability

David Braun, MD, PhD Yale School of Medicine | Bradley McGregor, MD Dana-Farber Cancer Institute | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

December 8, 2025

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Key Points

  • The goal of treatment in second-line renal cell carcinoma (RCC) should be to maximize patient quality of life for as long as possible.

  • Anti-VEGF tyrosine kinase inhibitors (TKIs) approved for this population share common toxicities, though tivozanib has shown more promising tolerability in clinical trials.

  • Belzutifan is a non-TKI option for advanced RCC that carries its own distinct side effect profile.

Side Effects of Second-Line RCC Therapies

Cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, hosted a panel discussion with three medical oncologists to gather their clinical insights on treating patients with advanced RCC after first-line therapy. 

While first-line treatment for RCC can yield durable responses, second-line and later treatment is palliative in intent. The goal of therapy should be to provide patients with the highest quality of life for as long as possible. Therefore, managing treatment-related toxicities is critical, said Bradley McGregor, MD, of Dana-Farber Cancer Institute. 

Standard of care anti-VEGF TKIs used in advanced RCC share a side effect profile that includes hypertension, diarrhea, and hand-foot syndrome. Compared with other TKIs, tivozanib has been associated with lower rates of several shared toxicities and fewer dose reductions required due to toxicity. Hypertension is reported with tivozanib, but it can be controlled with early dose modifications and supportive medications to keep patients stable on the highest possible dose, Dr. McGregor said.

Belzutifan, a hypoxia-inducible factor-2α inhibitor, is the most recently approved agent for advanced RCC after first-line therapy, and it can be an alternative option for patients struggling with TKI-related toxicity. Though well tolerated, belzutifan commonly causes anemia and, more rarely, hypoxia.

Regardless of the treatment used, the doctors emphasized the need to educate patients on potential side effects so that, if they occur, they can be managed promptly without dose reductions.