Risk Status Provides Less Clear Picture in IO/TKI Era of RCC Treatment

Long-term trial data on combination therapy for advanced clear cell renal cell carcinoma (ccRCC) have been shared in the past 2 years, shedding light on subsets of patients who may benefit more from immunotherapy (IO) plus tyrosine kinase inhibitor (TKI) or dual IO therapy. In a virtual Case-Based Roundtable event, Kathryn E. Beckermann, MD, PhD, presented the data and discussed key takeaways with participants. Beckermann, director of genitourinary cancer research at Tennessee Oncology and Instructor in Medicine at Rathmell Lab for the Vanderbilt University School of Medicine in Nashville, offered insight into the value of IO in patients with favorable International Metastatic RCC Database Consortium (IMDC) risk. The participants agreed that the need for a quick response to aggressive disease is the key factor favoring use of combination IO/TKI.

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DISCUSSION QUESTION

• After reviewing the CheckMate-9ER (NCT03141177), KEYNOTE-426 (NCT02853331), and CLEAR (NCT02811861) trials, what is your preferred regimen for metastatic RCC?​

Kathyrn E. Beckermann, MD, PhD: After seeing the longest follow-up for these 3 different IO/TKI regimens, do the updated data change your preferred regimen? What was it about these data that would have been impactful…?

Husam Tarawneh, MD: If there is predominantly bone disease, I would maybe go to cabozantinib [Cabometyx] combined with nivolumab [Opdivo]. What I’m seeing here that in the favorable-risk patients, which, we hardly see…at the end the survival is the same.^1.2 Single-agent TKI may be appropriate if you don’t need a quick response for a patient.

Beckermann: I agree. This is hypothesis generating but underpowered, and those favorable-risk patients are so hard to find. I still think that there’s probably a minority of those patients who are IO responsive…. Even though I recognize that it increases toxicity in a [favorable]-risk patient…my first [step] will be a conversation with the patient [about doing] surveillance in that [highly favorable]-risk patient. But once I’ve made the decision to start systemic therapy, I still tend to use some IO agent in that first-line setting.

Raymond Lobins, DO: …If I see favorable risk, when I look at these data, what I’m inclined to do is give them a single agent, and if they [experience progression], give them IO. It looks like with IO/IO, you’re just trying to see how many of them will be cured by the IO/IO. The data was…suggesting for favorable risk, just giving them a TKI, and then if they fail, [give IO]. But a lot of people do exactly the opposite.

Christopher Wee, MD: I’m not sure how much we can put on the risk stratification these days given that this is such an old model. You can just do the eyeball test of whether a patient looks sick and needs a response now or not. Some of these indolent [tumors], you don’t even have to treat.

Kevin M. Gallagher, MD: I was supervising fellows, and I asked about risk stratification. They said, “What is that?” When I was training, that was the first thing you were supposed to calculate, but then I realized, does it really matter, especially when it doesn’t necessarily impact your treatment choice anymore?

Beckermann: I agree both with Dr Wee’s comment and Dr Gallagher’s comment. A lot of work is trying to go into defining new prognostic criteria that would be more IO-specific. The IMDC [risk] can tell us about the underlying biology and aggressiveness of a disease, but I think it does come down to that gut feeling of if this patient needs a rapid response immediately vs having time to rescue them, perhaps with a second agent. That’s still a hard thought, and I’ve missed that mark before. I’m hopeful that we’ll have better biomarkers or better prognostic criteria in future years.

DISCUSSION QUESTIONS

• What other factors drive your selection of first-line therapy for metastatic ccRCC? For example: ​​
• Based on your own experience, how does the efficacy and safety profile of IO/TKI regimens compare with those of IO/IO regimens? ​

Beckermann: What other things are important to you when choosing what you’re going to start a patient on?

Gallagher: How quick the response is.

Maryada S. Reddy, MD: If they have a lot of tumor burden, IO/IO combination may not be a good idea because of concern about progression. Also, performance status. Those are the 2 things. If a patient has minimal disease burden, is otherwise young and minimally symptomatic, and I have time to work, then I’d go to the IO combination, hoping that some of these patients could be long-term responders.

Beckermann: In your practice, how many people walk in the door [who] have that less symptomatic timeframe where you could do a [dual] IO, vs how many of your patients are…symptomatic and [have] to start an IO/TKI?

Reddy: The majority of the patients are going to be symptomatic by the time they manifest. The rare patients where they may have 1 or 2 small lung nodules…those who are asymptomatic with minimal disease, I may not even treat them. I may just watch them, along with the urologist and the surgeon. If they have a small, solitary nodule in the lung or 1 nodule in the rib, we might just do some radiation to that local area. But the majority of the patients are very symptomatic… [and] end up getting an IO/TKI combination.

Tarawneh: We have an open study [PROBE (NCT04510597)]. You get treatment, and if you have stable disease or partial response, you either go for surgery or continuation…of systemic treatment. This study is still open, so we are trying to recruit those patients, unless you have very minimal [disease] that you can just watch it. Also, usually for any sarcomatoid histology, we gravitate to IO/IO.

Beckermann: That’s a great point…we recognize that sarcomatoid does enrich for a response to a pure IO agent. That’s a great trial too. I’m excited to see what that shows. We knew back [when we used] interferon, if you did a nephrectomy, that tended to enrich for survival in patients on an IO-based regimen. After the CARMENA trial [NCT00930033], in the TKI era, we got away from doing cytoreductive nephrectomy. It’s exciting that you’re participating in that study, and hopefully we’ll have a good answer for what to do in the contemporary setting with IO agents.

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_{DISCLOSURES: Beckermann previously reported a consultant/advisor/speaker position for Aravive, Arcus, Alpine Bioscience, Aveo, Bristol Myers Squibb, Eisai, Exelixis, Merck, Nimbus, and Xencor.}

_REFERENCES

_{1. Motzer RJ, Porta C, Eto M, et al. Lenvatinib plus pembrolizumab versus sunitinib in first-line treatment of advanced renal cell carcinoma: final prespecified overall survival analysis of CLEAR, a phase III study. J Clin Oncol. 2024;42(11):1222-1228. doi:10.1200/JCO.23.01569}

_{2. Motzer RJ, Escudier B, Burotto M, et al. Nivolumab plus cabozantinib (N+C) vs sunitinib (S) for previously untreated advanced renal cell carcinoma (aRCC): Final follow-up results from the CheckMate 9ER trial. J Clin Oncol. 2025;43(suppl 5):439. doi:10.1200/JCO.2025.43.5_suppl.439}