Charles B. Nguyen, MD, is an assistant clinical professor in the Department of Medical Oncology & Therapeutics Research at City of Hope in Irvine, California. 

Charles B. Nguyen, MD, details treatment selection in clinical practice for patients with non–clear cell renal cell carcinoma.

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.

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Charles B. Nguyen, MD, discusses the updated 2024 NCCN Guidelines and their effect on treatment decisions for non–clear cell RCC. 

Dr Nguyen on Updated NCCN Guidelines for Non–Clear Cell RCC

“We don't have randomized data to just recommend and support new clinical trials for patients with non–clear cell kidney cancers. We have several randomized phase 3 studies that are ongoing that should hopefully be a meaningful contribution [to] data in this space, and hopefully we really improve the guidelines for this group of patients.”

Charles B. Nguyen, MD, assistant clinical professor, Department of Medical Oncology & Therapeutics Research, City of Hope, discusses the updated 2024 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for non–clear cell renal cell carcinoma (RCC) and their effect on treatment decision-making.

Randomized data are still lacking to drive treatment decisions for the non–clear cell RCC popilation, Nguyen begins. Therefore, there isn’t a category 1 preferred regimen to treat non-clear cell RCC. Otherwise, 3 preferred regimens include cabozantinib (Cabometyx) monotherapy, cabozantinib plus nivolumab (Opdivo), and lenvatinib (Lenvima) plus pembrolizumab (Keytruda), he explains; clinical trial enrollment is another preferred approach. Based on these preferred regimens, he says the combinations of cabozantinib plus nivolumab and lenvatinib plus pembrolizumab have raised the bar regarding response rates among patients with non–clear cell RCC. Although there are many single-arm phase 2 studies, he emphasizes the need for more randomized trials to further support the use of these regimens.

Data from a phase 2 study (NCT03635892) published in 

cabozantinib/nivolumab demonstrated efficacy

 and sustained responses in patients with non–clear cell RCC. Specifically, at a median follow-up of 34 months (range, 20-51), combination led to an overall response rate of 48% (95% CI, 32%-64%) in this patient population (n = 40).

Based on the NCCN’s updated guidelines, Nguyen emphasizes that recommending and supporting new clinical trials for this patient population is crucial because there aren’t randomized data in the space. Nevertheless, he concludes that there are several phase 3 randomized studies ongoing that will hopefully contribute meaningful data to improve treatment guidelines for patients with non–clear cell RCC.

Charles B. Nguyen, MD

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

Dr Nguyen on Updated NCCN Guidelines for Non–Clear Cell RCC