Histologic Features, Risk Help Reduce Uncertainties Around Frontline Treatment Selection in RCC

Adam E. Singer, MD, PhD

Determining the optimal immuno-oncology (IO) only or TKI plus IO combination for patients with advanced renal cell carcinoma (RCC) rests on several considerations, chief among them is risk status, according to Adam E. Singer, MD, PhD, who noted that each of the 4 National Comprehensive Cancer Network (NCCN) first-line preferred regimens have bested sunitinib (Sutent) in intention-to-treat (ITT) populations.

Singer added that ipilimumab (Yervoy) plus nivolumab (Opdivo) stands as the only entirely immune-based combination therapy among the 3 NCCN first-line preferred TKI/IO combinations of axitinib (Inlyta) plus pembrolizumab (Keytruda), cabozantinib (Cabometyx) plus nivolumab, and lenvatinib (Lenvima) plus pembrolizumab.¹

“The ipilimumab/nivolumab study was similar to the other upfront TKI/IO combination studies,” Singer said in an interview with OncLive®. “In the ITT population, the combination improved progression-free survival [PFS] and overall survival [OS], and in the intermediate- and poor-risk groups that was true, but in the favorable-risk group, PFS was significantly better with sunitinib than with ipilimumab/nivolumab.”

He added “That’s why in the NCCN guidelines ipilimumab/nivolumab is a category 1 recommendation for patients with intermediate- and poor-risk disease, but for patients with favorable-risk [disease] it is not a category 1 recommendation, it’s considered a recommended option; that’s a recent change in NCCN guidelines.”

In the interview, Singer detailed additional considerations of optimal regimen selection beyond the frontline setting and how sarcomatoid features affect decision-making. He also highlighted ongoing research in clear cell RCC as well as work needed in the non–clear cell paradigm.

Singer is a health sciences clinical instructor of medicine and division lead for kidney cancer in the Division of Hematology/Oncology at University of California Los Angeles Health in Torrance.

OncLive: How do you select between the available IO/IO and TKI/IO combinations for patients with RCC?

Singer: The ipilimumab/nivolumab [combination] is in a bit [of a] different class because it doesn’t involve a TKI in the upfront setting and the response rates tend to be lower. In the ITT population PFS is lower [with nivolumab/ipilimumab], but the regimen does have a higher chance of leading to a long-term response. It’s not super high, but it’s higher than the other options. It mimics what we see when immunotherapy is used for other diseases. For example, with ipilimumab/nivolumab for melanoma, you see this long tail on the curve, and we see this in other diseases where immunotherapy is used [as well].

The TKI/IO combinations do have the tails, but the tail doesn’t land quite as high in terms of ongoing PFS [as] it does with ipilimumab/nivolumab. That said, [treatment with] ipilimumab/nivolumab also [results in] a higher rate of primary progression than [seen with] the TKI/IO combinations. The way I often discuss this with my patients [presents the choice as] a bit of a gamble. If you’re willing to accept a higher risk and it doesn’t work, you may on the back end get a higher chance that it works for a very long time. There’s no way we can predict whether an individual patient is going to benefit from this or experience that tail so to speak.

The other thing about ipilimumab/nivolumab is [the association between immunotherapy and sarcomatoid RCC]; sarcomatoid RCC is sometimes classified specifically as sarcomatoid if that’s what’s found on pathology [and] sometimes [patients have] clear cell RCC with a high percentage of sarcomatoid features. Sarcomatoid elements tend to predict response to immunotherapy, so we are more likely to recommend the dual IO combination over the TKI/IO combinations for those patients [with sarcomatoid features].

What ongoing research will help to further elucidate which combination is optimal?

People are trying to see if gene expression patterns can predict responsiveness to these various regimens, specifically [IO/IO vs IO/TKI regimens]. There’s a lot of basic science work that has gone into this, and people have come up with clusters of disease. There’s a handful of these, and some are thought to lend more responsiveness to immunotherapy, whereas [others] are thought to lend more responsiveness to TKIs.

There’s a trial that’s trying to evaluate this in an upfront fashion and we eagerly anticipate the results of that in the future because it is a challenge right now. You have TKI/IO combinations and an IO/IO combination, [and] most patients could qualify for either of them. It’d be great to get additional guidance on which option might have a better response for an individual patient.

Importantly, we have data saying that using immunotherapy after progression on immunotherapy does not improve PFS or OS. This was suggested back with the phase 3 CONTACT-03 trial [NCT04338269] a few years ago, which randomly assigned patients to atezolizumab [Tecentriq] plus cabozantinib vs cabozantinib alone in the second- or third-line [setting] and there was absolutely no difference in PFS or OS [with the addition of atezolizumab].

The study was essentially replicated with the phase 3 TiNivo-2 trial [NCT04987203] which randomly assigned patients to receive tivozanib [Fotivda]/nivolumab or tivozanib alone. A press release showed this was a negative trial, but the final data are being presented at the upcoming 2024 ESMO Congress, so we don’t know exactly what it shows yet, but presumably it shows something very similar to CONTACT-03. We now have 2 high quality phase 3 randomized trials saying that immunotherapy after immunotherapy is not an effective strategy for treating these patients, and it leads to increased toxicity.

Which combinations are ideal for patients with advanced non–clear cell RCC?

Non–clear cell RCC has always lagged a bit with clear cell RCC because it is much less common. Approximately 75% of RCC is clear cell, 20% is papillary, 5% is chromophobe, and those numbers add up to approximately 100% and then there’s a small percent of all these other [disease presentations]. People have lumped [these rarer histologic subtypes] together and applied our clear cell therapies to the non–clear cell bucket [to] see what happens.

We need more studies in non–clear cell RCC, and we need more rationally designed therapies and approaches in this population. In the past few years, we’ve seen important updates. Data showed that the combination of a TKI and immunotherapy is effective. For a long time sunitinib was the standard of care, then it was cabozantinib monotherapy, and for a long time, the NCCN guidelines for non–clear cell metastatic RCC reflected cabozantinib or a clinical trial in the recommended first-line setting.

But we have data showing there are good responses with cabozantinib plus nivolumab and more recently, lenvatinib plus pembrolizumab. These were not phase 3 trials [and] were not randomized, but the response rates [seen in the trials] are good, and we will often use these [combinations] in the frontline [setting]—I believe the field is shifting more to that. It’s my personal practice to use a TKI/IO combination in the frontline setting and the NCCN guidelines now reflect those 2 combinations in the frontline setting [in the non–clear cell population].

Reference

NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 2.2025. Accessed September 11, 2024. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf