Treating Advanced RCC After First-Line Therapy (Full Video)

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

Key Points

• Tyrosine kinase inhibitors (TKIs) or belzutifan are standard treatment options for renal cell carcinoma (RCC) that progresses after first-line treatment with TKI or immunotherapy regimens.

• In the advanced RCC setting, treatments should be selected and adjusted to balance disease control with manageable toxicity.

• Patients must be educated on expected side effects before starting second-line treatments so that toxicities are reported and managed swiftly.

• Tivozanib is highly tolerated compared with other TKIs, but more toxic agents may offer increased efficacy.

Second-Line Treatment of RCC

Medical oncologists, Bradley McGregor, MD, of Dana-Farber Cancer Institute, David Braun, MD, PhD, of Yale School of Medicine, and Ulka Vaishampayan, MBBS, of University of Michigan, joined the Oncology Brothers podcast to share their insights on treating patients with RCC who progress after first-line treatment with TKI plus immunotherapy or dual immunotherapy regimens.

Standard second-line and later therapies for advanced RCC include cabozantinib, lenvatinib (with everolimus), axitinib, tivozanib, and belzutifan. While the first four agents are anti-vascular endothelial growth factor (VEGF) TKIs, belzutifan is a hypoxia-inducible factor-2α (HIF-2α) inhibitor.

Key Considerations for Treating Advanced RCC

Given the palliative intent of second-line and later therapy for patients with advanced RCC, the goal should be to give patients the least-toxic treatment that will still control their disease. Data have shown that response to TKIs in RCC is dose-dependent, so maintaining the highest possible dose is preferable.

Patients should be educated on all potential side effects so they can report them if they occur, and so oncologists can intervene early with supportive care or dose holds to avoid dose reductions. That said, the majority of patients on TKIs other than tivozanib will require a reduction, and oncologists should aim to find a dose that patients can tolerate long-term without constant interruptions, said Dr. McGregor.

Tivozanib

Tivozanib was the latest TKI approved for relapsed or refractory advanced RCC based on the TIVO-3 trial. In the study, tivozanib improved progression-free survival (PFS) and response rates compared with sorafenib in patients with at least two prior systemic treatments, including at least one previous VEGF receptor inhibitor. Tivozanib had a response rate of about 18%, but an additional 55% of patients treated with tivozanib had stable disease, suggesting the majority of patients derived some clinical benefit, said Dr. Vaishampayan.

Tivozanib showed lower rates of most toxicities associated with TKIs, and only 20% of patients on tivozanib required a dose reduction during the trial, a much lower rate than with other TKIs. Though tivozanib was associated with hypertension, it can usually be managed with antihypertensive medications and a dose hold for up to 5 days.

Belzutifan

Most recently, the FDA approved belzutifan for advanced RCC based on the LITESPARK-005 trial, in which it improved PFS and response rate compared with everolimus in patients with advanced RCC who had previously received immunotherapy. Compared with the approved TKIs, belzutifan has a unique toxicity profile that includes anemia and hypoxia. The majority of patients treated with belzutifan experience anemia, but it can be effectively managed with erythropoietin support, dose holds, or transfusions, said Dr. McGregor. 

Hypoxia is more concerning. In LITESPARK-005, it occurred in only 15% of patients, but 10% of those had grade 3 or higher events. When using belzutifan, oncologists should have patients regularly monitor themselves at home with a pulse oximeter and pause the treatment if hypoxia starts to develop. Oncologists should also check for comorbidities that could perpetuate or exacerbate hypoxia, such as sleep apnea or chronic obstructive pulmonary disease. 

Advanced RCC Treatment Selection

Selecting second-line treatments depends on the patient’s disease progression, the first-line treatment they received, and how they tolerated it. Even if a patient received TKI-based first-line therapy, TKIs should still be a priority in later lines because of the potential for more rapid responses, particularly for highly symptomatic patients, said Dr. Vaishampayan. 

Among the approved TKIs, tivozanib’s tolerability profile is highly appealing, though other TKIs may be appropriate if the increased toxicity is offset by improved disease control and symptom reduction. Dr. McGregor cited a randomized phase 2 trial that showed lenvatinib plus everolimus improved PFS and response rates, but had more discontinuations due to toxicity than cabozantinib.

Switching to a non-TKI therapy like belzutifan may be more appropriate if a patient experiences significant side effects from first-line TKIs. However, the possibility of greater efficacy with TKIs could still outweigh the potential toxicities.

Notable RCC Trials 

To end the discussion, the panel highlighted ongoing trials and future research avenues in RCC. Dr. McGregor was a lead investigator of the STRIKE trial on tivozanib with or without pembrolizumab for adjuvant therapy. In the advanced setting, Dr. Vaishampayan led the PROBE trial, which explored adding cytoreductive nephrectomy to standard immunotherapy-based therapy. 

Dr. Braun referenced the variety of studies on novel immunotherapies, TKIs, and combinations, including the ARCITECT trial in treatment-naive advanced RCC, and suggested that further research is needed to determine the role of other HIF-2 agents.