Clinical Trials, Randomized Data Are Key to Further Refine Treatment Selection in Advanced Non–Clear Cell RCC

Although the National Comprehensive Cancer Network (NCCN) updated its Clinical Practice Guidelines in Oncology in 2024 with additional preferred regimens for patients with advanced non–clear cell renal cell carcinoma (RCC), clinical trial enrollment and the emergence of more randomized data will be key to improve treatment options and recommendations in this space, according to Charles B. Nguyen, MD.

“Non–clear cell RCC [comprises] a rare group of kidney cancers—about 25% of all kidney cancers—and they encompass a pretty broad group of different histologies and biologies,” said Nguyen, an assistant clinical professor in the Department of Medical Oncology & Therapeutics Research at City of Hope in Irvine, California.

The updated 2024 guidelines and current 2025 specifications include cabozantinib (Cabometyx) monotherapy, cabozantinib plus nivolumab (Opdivo), and lenvatinib (Lenvima) plus pembrolizumab (Keytruda) as preferred regimens with category 2A recommendations for patients with advanced non–clear cell RCC. Clinical trials are also listed as a preferred regimen.

In an interview with OncLive® following the State of the Science Summit in genitourinary cancers, Nguyen discussed the current treatment challenges in non–clear cell RCC, the 2024 updates to the NCCN Clinical Practice Guidelines, and the importance of developing more clinical trials for this patient population.

OncLive: What are some treatment challenges in non–clear cell RCC compared with clear cell RCC?

Nguyen: Unfortunately, kidney cancer trials in the past have mainly focused on the more common clear cell subtype, where these trials have excluded patients with variant histology. Therefore, we don't have a lot of large [datasets] to guide our treatment decisions in non–clear cell kidney cancers.

What are the current NCCN Clinical Practice Guidelines for non–clear cell RCC following an update in 2024?

We mainly have single-arm, phase 2 data [to support recommendations], so we don't have a lot of robust, randomized data. As of now, we don't have a category 1 preferred regimen in the NCCN guidelines. There are 3 preferred regimens [with category 2A recommendations], which are listed as cabozantinib monotherapy; cabozantinib plus nivolumab; and lenvatinib plus pembrolizumab. The combinations of cabozantinib/nivolumab and lenvatinib/pembrolizumab are quite compelling in that they raised the bar in terms of response rates of closer to 50%, but I think it's also important to note that [these data were derived from] single-arm, phase 2 studies. We need more randomized data to support this approach.

How have these guideline updates affected treatment decision-making in clinical practice?

[This is important to] highlight because we don't have [much] randomized data for patients with non–clear cell kidney cancers. We have several randomized phase 3 studies that are ongoing, which should hopefully be a meaningful contribution to data in the space and hopefully will [help] improve the guidelines for this group of patients.

We do have the [phase 2] PAPMET2 study [NCT05411081] looking at cabozantinib plus atezolizumab [vs cabozantinib alone] in patients with [advanced] papillary RCC that is running through SWOG. We also have the [phase 3] STELLAR-304 study [NCT05678673] looking at a novel TKI called zanzalintinib [XL092] plus nivolumab [vs sunitinib (Sutent) in previously untreated patients with advanced clear cell RCC]. Based on the current guidelines, we should be focusing our efforts on better strategies for patients through clinical trials.

What factors do you consider when selecting a therapy for a patient with advanced non–clear cell RCC?

We really lean on the immuno-oncology/TKI combinations for non–clear cell kidney cancer. In my practice, I pick the one that I'm most comfortable with. [Within our reach,] we have lenvatinib plus pembrolizumab, and then cabozantinib plus nivolumab. I commonly use cabozantinib with nivolumab for [patients with advanced] clear cell RCC. It has a pretty predictable toxicity profile that I'm used to. It has some flexibility in terms of dose reductions and modifications for [adverse] effects. Because of that, it tends to be my preferred [regimen] for patients with non–clear cell kidney cancers; however, the other ones are acceptable, as well. [The treatment decision] certainly depends on each oncologist’s preference in terms of their preferred regimen.

Clinical trials are also a preferred option for patients with non–clear cell RCC in the NCCN Guidelines. How do you weigh selecting a preferred treatment vs evaluating potential clinical trial opportunities for this patient population?

Some centers do not have clinical trials for [patients with] non–clear cell kidney cancer. In that case, we might have to think about whether the patient can be referred or has time to be sent to a tertiary academic center that might have these trials. I'm fortunate to work at a place that has a lot of non–clear cell kidney cancer trials.

The challenge is looking at the histologies, because each trial [with non–clear cell RCC] has historically [grouped] different histologies together, and some have mainly focused on some refined histology groups. The histology of the patient—after a pathology interpretation and review—dictates which trials they would be eligible for. Therefore, looking at the availability and the practicality of [enrolling a patient in] a clinical trial are the factors I lean on in terms of identifying clinical trials.

Reference

NCCN. Clinical Practice Guidelines in Oncology. Kidney Cancer, version 3.2025. Accessed February 25, 2025. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf