Dr Nguyen on Treatment Selection Considerations for Non–Clear Cell RCC

“We really lean on the IO/TKI combinations for non–clear cell kidney cancer; in my practice, I [generally] pick the one that I'm most comfortable with, [which is cabozantinib with nivolumab].”

Charles B. Nguyen, MD, an assistant clinical professor in the Department of Medical Oncology & Therapeutics Research at City of Hope, detailed treatment selection for patients with non–clear cell renal carcinoma (RCC).

The 2024 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for RCC, which included updated treatment guidelines for stage IV non–clear cell RCC, described 3 preferred regimens, which remain in the 2025 guidelines. These included cabozantinib (Cabometyx) monotherapy, cabozantinib plus nivolumab (Opdivo), and lenvatinib (Lenvima) plus pembrolizumab (Keytruda), which all carry category 2A recommendations. Notably, clinical trials are also listed as a preferred regimen.

In the non–clear cell RCC space, immuno-oncology/TKI combinations are utilized the most, Nguyen began. He noted that in his practice, he commonly uses cabozantinib with nivolumab for clear cell RCC because of its predictable toxicity profile, along with some flexibility regarding dose reductions and modifications for adverse effects. Therefore, he tends to use this combination when treating patients with non–clear cell RCC, he explained. Lenvatinib plus pembrolizumab is also acceptable, but treatment choices in clinical practice may depend on personal preference and preferred regimens, Nguyen said.

Of note, several clinical trials are evaluating different regimens for RCC subsets, which may help further improve guidelines. For instance, the phase 2 PAPMET 2 study (NCT05411081) is evaluating cabozantinib plus atezolizumab (Tecentriq) compared with atezolizumab monotherapy for the treatment of patients with advanced papillary RCC. Patients on the trial are being randomly assigned 1:1 to either receive cabozantinib at 60 mg per day vs the same dose of cabozantinib plus atezolizumab at 1200 mg every 3 weeks. Furthermore, the ongoing phase 3 STELLAR-304 study (NCT05678673) is assessing zanzalintinib (XL092)—a novel TKI—with nivolumab vs sunitinib (Sutent) in previously untreated patients with advanced non–clear cell RCC. In the study, patients are randomly assigned 2:1 to oral zanzalintinib once daily with intravenous nivolumab every 4 weeks; or oral sunitinib once daily for 4 weeks on and 2 weeks off.