RCC / GU Oncology 12/09/2025

Ep. 3: Balancing Patient Goals and Efficacy in Second-Line RCC Therapy

Professional male doctor in formal attire with a red bow tie, emphasizing oncology and cancer research. David Braun, MD, PhD 1. Female oncologist in white coat, healthcare professional specializing in cancer treatment, at Karmanos Cancer Institute, Wayne State University. Ulka Vaishampayan, MBBS 1. Expert oncologist smiling in professional attire, emphasizing cancer treatment insights and medical expertise for OncUpdates. Bradley McGregor, MD Smiling man with beard wearing a white shirt, professional headshot, suitable for oncology or cancer research content, emphasizing healthcare and medical expertise. Rahul Gosain, MD, MBA Oncologist smiling in white coat, highlighting cancer research and treatment expertise, with a bow tie, in a bright medical setting. Rohit Gosain, MD

Key Points

  • Selecting second-line and later treatments for advanced renal cell carcinoma (RCC) depends on prior therapies, tolerability, and disease progression.
  • The goal of therapy should be to strike a balance between manageable toxicity and disease control that patients can tolerate long-term.
  • It may be appropriate to use more toxic therapies to increase short-term disease control.

Balancing Toxicity and Efficacy in Advanced RCC

As part of a roundtable discussion, three medical oncologists joined the Oncology Brothers podcast cohosts, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, to discuss balancing tolerability and the need for disease control when selecting treatments for patients with advanced RCC after first-line therapy. 

Standard-of-care therapies for RCC in second-line and later settings include four anti-VEGF tyrosine kinase inhibitors (TKIs), cabozantinib, lenvatinib (with everolimus), axitinib, tivozanib, and the hypoxia-inducible factor-2α inhibitor, belzutifan. 

While tivozanib has the most favorable tolerability profile among the approved TKIs, “if someone’s disease is causing a significant burden of symptoms, you may need to go with something that has more toxicities to get better disease control,” said Bradley McGregor, MD, of Dana-Farber Cancer Institute. Oncologists should always plan for subsequent lines of therapy with different agents, especially when making this tradeoff, said Dr. McGregor.

Prior upfront therapies can also impact second-line treatment selection. If a patient experienced significant toxicity with first-line TKI-based regimens and may not be able to sustain a second-line TKI at a reasonable dose, alternating to belzutifan may be appropriate. However, TKIs should still be prioritized in later lines given the possibility for more rapid responses, particularly for more symptomatic patients, said Ulka Vaishampayan, MBBS, of University of Michigan.

Though selecting more toxic treatments to improve disease control is occasionally necessary, the ultimate goal is to identify the treatment and dose level that allows patients to remain on therapy for as long as possible. Both tivozanib and belzutifan offer promising toxicity profiles for this goal. Still, tivozanib is more indicated than belzutifan when a dual immunotherapy regimen is used upfront, said David Braun, MD, PhD, of Yale School of Medicine.