NCCN Guideline Updates Expand IO/TKI Options and Precision Medicine Approaches in RCC

Moshe Ornstein, MD, MA

Recent updates to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for kidney cancer management reflect expanding evidence in support of tailored approaches based on histologic subtype and mark a shift toward broader accessibility of immunotherapy regimens in renal cell carcinoma (RCC), according to Moshe Ornstein, MD, MA.

On September 6, 2024, the NCCN released version 2.2025 of the guidelines, which further adjusts the recommendations made in version 1.2025, previously released in July 2024. In version 1.2025 pembrolizumab (Keytruda) was upgraded to a category 1 recommendation for adjuvant treatment in patients with clear cell histology in the stage II and III pathways. Additionally, ipilimumab (Yervoy) plus nivolumab (Opdivo) was highlighted as a preferred first-line regimen for favorable-risk patients with relapsed or stage IV disease.¹

Among the changes made for non–clear cell histology, lenvatinib (Lenvima) combined with pembrolizumab was introduced as a preferred regimen with a category 2A recommendation, and cabozantinib (Cabometyx) plus nivolumab was moved to the preferred regimens section.

“IO [immuno-oncology]/TKI combinations are a standard of care [SOC] in the [non–clear cell] setting, and these are both good options for patients,” said Ornstein, who is a medical oncologist in the Department of Hematology and Medical Oncology at Cleveland Clinic in Ohio. “The choice of treatment comes down to personal preference and interpretation of the data, but I’m glad to see these options available for patients and included in the NCCN guidelines, which makes them more accessible to patients.”

In an interview with OncLive®, Ornstein highlighted ongoing research aimed at better understanding non–clear cell RCC subtypes to enable tailored treatment approaches, recent trials that led to the inclusion of select IO/TKI doublets in the NCCN guidelines, and the need for clinical trial prioritization for patients with these histologies.

OncLive: What has research shown about the makeup of makeup of RCC subtypes, and how could this allow for more tailor treatment approaches?

Ornstein: Historically, RCC has been broken down into clear cell vs non–clear cell [histologies]. One of the primary challenges with that [categorization] is that non–clear cell [RCC] is not 1 type of disease. There are different [types of] non–clear cell RCCs. There’s papillary, there’s chromophobe, there’s unclassified, there’s translocation, etc. Therefore, the primary unmet need in this space has been the identification of treatment options that are not just for all non–clear cell RCC [variants]. [We are] trying to better understand the biology of the individual non–clear cell subtypes and specific treatment recommendations that would be appropriate for each one.

It has been difficult, and lot of work has been done [to address this]. [For one], papillary RCC has been reclassified as this larger group that is potentially a MET-driven tumor. In chromophobe RCC, there are some TSC mutations that may be more responsive to, for example, mTOR inhibition. There’s a lot of genomic work ongoing right now. The treatment paradigm seems to be a one-size-fits-all [approach] across the non–clear cell variants. Hopefully, as we develop more trials and a better understanding of the underlying biology of each variant, those treatments will be more tailored for specific subtypes.

What was the rationale for designating clinical trials and cabozantinib monotherapy as preferred options for non–clear cell RCC prior to recent developments?

Up until recently, the preferred regimens for non–clear cell histology in the NCCN guidelines were either a clinical trial or cabozantinib as monotherapy. The rationale for clinical trial enrollment was that this area has not been studied extensively in terms of large, randomized trials, and these patients tend to do poorly relative to patients with clear cell RCC. Therefore, enrolling onto a clinical trial with a novel therapy, novel mechanisms, or even approved agents [in RCC] that are being studied prospectively in the non–clear cell setting makes sense. The rationale for cabozantinib monotherapy really came from the phase 2 PAPMET study [NCT02761057],which investigated cabozantinib vs 3 other TKIs and demonstrated that cabozantinib was the TKI of choice as a monotherapy in papillary RCC. That became a standard and preferred regimen for non–clear cell histology.

What findings led to the inclusion of lenvatinib plus pembrolizumab and cabozantinib plus nivolumab in the NCCN guidelines for first-line non–clear cell RCC?

Fortunately, over the past couple of years, there have been prospective investigations in the non–clear cell setting of IO/TKI combinations that we’re familiar with from the clear cell setting. The largest of these studies was the phase 2 KEYNOTE-B61 trial [NCT04704219] that evaluated lenvatinib plus pembrolizumab, which is a regimen that we’re comfortable with in the clear cell setting, in all-comers in the non–clear cell space. The study included [patients with] papillary, chromophobe, unclassified, and translocation [histologies]. This was a large international study that enrolled 158 patients at the standard dosing of lenvatinib plus pembrolizumab.

[The study] showed remarkable response rates of approximately 50% across [histologies], [although] the chromophobe subpopulation had a lower response rate closer to 35%. Even more impressive than that was the median progression-free survival [(PFS) data]. We’re used to seeing [a median PFS of] 10 or 11 months in this setting, but with lenvatinib and pembrolizumab, we saw a median PFS of 17.9 months. Overall survival [OS] had not yet been reached. This [combination of lenvatinib plus pembrolizumab] is a wonderful choice for patients with non–clear cell RCC regardless of [subtype]. KEYNOTE-B61 ultimately led to its inclusion as a preferred regimen in the NCCN guidelines.

Cabozantinib plus nivolumab is also included in the NCCN guidelines as a preferred regimen for non–clear cell RCC, which is based on data from a single-arm phase 2 study [NCT03635892]. [There are] a couple of differences between the cabozantinib/nivolumab study and [KEYNOTE-B61]. [In the phase 2 study of cabozantinib plus nivolumab], there was a chromophobe cohort that was closed early, so we don’t have a deep analysis of patients in [this subpopulation.] The study enrolled [47] patients, which is much smaller than the [KEYNOTE-B61 trial], and it evaluated the standard dosing of cabozantinib plus nivolumab in papillary, unclassified, [chromophobe], and translocation RCC. Here, the easiest number to keep in mind is also the [approximately] 50% [response rate achieved] by patients who received cabozantinib plus nivolumab in the first line. When we narrow it down to the papillary cohort, because that was the most common [histology] of the non–clear cell patients [n = 32], the response rate was 47%. The median PFS for the cohort at large was 12.5 months, and the median OS was 28 months. This is another terrific option for non–clear cell RCC.

Given these recommendations, how do you decide between these potential options and clinical trial enrollment for patients with non–clear cell histologies?

We always view clinical trials as a priority. Even though we have better options now for non– clear cell RCC than we used to have, we still know that a lot of patients will not respond to treatment. These trials don’t tell us much about the specific biology behind these tumors. We might be talking about response rates of approximately 50% with approved agents, but we see response rates of 70% in the clear cell setting. We’re certainly hoping that clinical trials can improve on that.

The rationale to continue to pursue clinical trials in non–clear cell RCC, even with these options available, is to have randomized phase 3 data available to us, to conduct studies that are more biologically-driven towards specific subtypes, and to improve outcomes [with current SOC agents]. We’re very excited about these outcomes because they’re so much better than what we had historically, but there’s still a long way to go to get that response rate higher, the PFS longer, and ultimately, to improve upon the gold standard of survival.

What are the potential clinical implications of the NCCN recommendation for ipilimumab plus nivolumab as a preferred treatment option in favorable-risk clear cell RCC?

There was a very important update to the NCCN guidelines [regarding] the preferred regimen in favorable-risk clear cell RCC. Up until a couple of months ago, the way the NCCN guidelines were broken down was that the IO/TKI regimens of axitinib [Inlyta] plus pembrolizumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab were approved and preferred regimens across International Metastatic RCC Database Consortium [IMDC] risk groups. However, ipilimumab and nivolumab was only a preferred regimen in intermediate- and poor-risk RCC by IMDC criteria. This was because the primary end point in the phase 3 CheckMate 214 trial [NCT02231749], which ultimately led to the FDA approval of ipilimumab and nivolumab in clear cell RCC, was [evaluated] in intermediate- and poor-risk patients. That was one of the preferred options in the NCCN guidelines. With this recent update, ipilimumab plus nivolumab is an approved and preferred regimen for the IMDC favorable-risk population as well.

A lot of this [decision] has to do with prolonged follow-up from the CheckMate 214 study. When we look at the favorable-risk population in CheckMate-214, the outcomes for those patients with favorable risk who were treated with sunitinib [Sutent] were superior to those patients treated with ipilimumab plus nivolumab up until approximately 48 months. However, with approximately 100 months of median follow up, there was a crossing of the curves, and the survival curve now favors ipilimumab plus nivolumab in the favorable-risk population with a HR of 0.82.

Looking at landmark OS after 72 months of median follow-up, 52% of patients treated with ipilimumab plus nivolumab are still alive vs 46% with sunitinib. When we look at these data after 90 months, that number is approximately 43% with ipilimumab plus nivolumab in the favorable-risk population compared with only 34% with sunitinib. As we see these additional follow-up data for favorable-risk patients treated with ipilimumab plus nivolumab, we’re seeing a shift within the guidelines to include it as a preferred regimen. It’s not the right treatment for all patients, obviously; patients who need [to achieve] a response and who might be symptomatic [could likely achieve] a better response rate with an IO/TKI regimen. [However], having this discussion and considering [the use of] IO/TKI and IO/IO regimens even in the favorable-risk group is important, and I’m certainly glad to see it included as a preferred regimen for favorable-risk clear cell RCC.

Reference

NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 2.2025. Accessed September 16, 2024. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf