Risk, Histology, and Metastatic Site Guide First-Line RCC Treatment Choices

With multiple immunotherapy-based combinations available for metastatic renal cell carcinoma (RCC), treatment selection often comes down to the clinical features of the individual patient. In a virtual Case-Based Roundtable event, Daniel Geynisman, MD, medical oncologist at Fox Chase Cancer Center of Temple University Health System, and oncologists in the Southeast region discussed treatment selection in metastatic RCC,the influence of disease characteristics and metastatic sites, and treatment sequencing after progression.

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This is part 2 of a 2-part series. Read part 1.

DISCUSSION QUESTION

• What are your perspectives on the long-term follow-up from the CheckMate 214 (NCT03075423) data?

Daniel Geynisman, MD: What do you think about these CheckMate 214 data? Do they support your practice? Or is anybody looking at this and saying, “You know what, I'm going to use more or less ipilimumab [Yervoy]-nivolumab [Opdivo]”?

Vikas Singh, MD: I think since the longer follow-up in favorable-risk patients came along, I have used ipilimumab-nivolumab in a couple of my favorable-risk patients because I really hate to put these slow-progressing patients on a long-term tyrosine kinase inhibitor [TKI]. With ipilimumab-nivolumab, I can do 4 rounds of ipilimumab and just keep them on maintenance nivolumab, so it's much safer and more tolerable for those patients.

Geynisman: How has it been? Have you had the favorable-risk patients respond?

Singh: Yes, they haven’t progressed yet.

Aneel Chowdhary, MD: I’ve had one patient for about 6 years, and he's currently on nivolumab [every 4 weeks].

Xuan Huang, MD: I love this regimen. I have many lucky winners. They’re not totally free of disease, but they are left with [some] lung nodules, so stay there for many years. Just a stable disease with a minimal disease burden. False lab is so much better, so they are living a regular, good life, but I also had cases that, like injured, a pro-risk disease, I use ipilimumab-nivolumab, and patient died quickly, just couldn't hold it.

Chowdhary: Dr Geynisman, I was going to add, histology probably also impacts our decision in certain cases as well. I think more and more we're seeing if you have those some of the rare histologies—especially if it's papillary—TKI [and] nivolumab, [such as] cabozantinib [Cabometyx]-nivolumab, seems better. But I must say, though, that for sarcomatoid or rhabdoid histologies, again, ipilimumab-nivolumab is probably a better option.

In fact, I have a patient right now; she's only 52 and had a nephrectomy 2 years ago in 2024, but she had clear cell with rhabdoid features. She now has lung-only metastases. Now, again, because rhabdoid histology is a dedifferentiated sarcomatoid-like histology, I am thinking about ipilimumab-nivolumab for her. Again, based on that, that rhabdoid comes under the same subsetting for sarcomatoid. I just wanted to see what your thoughts were.

Geynisman: I agree with you. I think ipilimumab-nivolumab would certainly be a very good option for this patient. If you're talking about pure sarcomatoid, ipilimumab-nivolumab does have the most data. I will say, I think other immunotherapy [IO] regimens can also do really well. The important part is giving IO, no question about it. Just sarcomatoid, rhabdoid, grade 4. But I think you're always going to be correct if you choose ipilimumab-nivolumab for somebody like that. I think she could do really well and have a nice response.

POLLING QUESTION

What first-line therapy are you likely to recommend if your patient was asymptomatic with metastatic disease limited to the liver?

1. Axitinib (Inlyta) + pembrolizumab (Keytruda)
2. Cabozantinib
3. Cabozantinib + nivolumab
4. Nivolumab + ipilimumab
5. Lenvatinib (Lenvima) + pembrolizumab
6. Other

DISCUSSION QUESTIONS

• What if the patient was asymptomatic or mildly symptomatic with disease limited to bone?
• Does site(s) of metastasis influence how you use nivolumab + ipilimumab?

Geynisman: I’m seeing a lot of ipilimumab-nivolumab… is the asymptomatic part the one that is really driving folks’ decision for ipilimumab-nivolumab here?

Tarek Chidiac, MD: Why is that important? Did I miss something?

Geynisman: Well, in terms of whether you need a quick response, or the differentiator of response rates. So, if somebody is symptomatic and you're hoping for a response, and you're worried that if they don't have a response, you may not be able to get to the next line of therapy vs they're asymptomatic. I'm just asking: Is that what people are thinking, or just because of everything else we've been talking about, you like ipilimumab-nivolumab?

Chidiac: Response is response, regardless of whether you're symptomatic or not. And you showed that the deeper the response, the better. I chose lenvatinib and pembrolizumab.

Geynisman: How about someone who chose ipilimumab-nivolumab?

Singh: I picked ipilimumab-nivolumab because I think the asymptomatic part of the question swayed me with ipilimumab-nivolumab. Again, I understand the arguments for IO-TKIs, but I would still lean towards ipilimumab-nivolumab and keep TKIs as a later option.

Geynisman: Sure. I don't think there are necessarily right or wrong answers here; it's preference and judgment calls. Do you guys think of or worry aboutthe liver any differently than you would bone or lung or lymph nodes? Do you separate those out, or is that where you simply say, I'm going to go by the IMDC [International Metastatic RCC Database Consortium] criteria: favorable, intermediate ,and poor, and that's that?

Some people worry about the liver, and they say, "Brain, bone, liver are bad players, and I worry about that.” Other people say, "We will go by the IMDC criteria, and if somebody is asymptomatic and feeling pretty good, I feel comfortable treating them based on that, and ipilimumab-nivolumab would be perfectly fine.” Other folks would want to make sure to give their best report in terms of response. So, again, I don't think there's necessarily a right answer here.

Chowdhary: I was going to add, I generally go for ipilimumab-nivolumab 60% to 70% of the time unless there's a very high burden of disease or there's an acute need for a higher response rate.

I did have a question about early progression on ipilimumab-nivolumab, and I've rethought about this. I thankfully haven't had such a patient, but if you have someone you start on ipilimumab-nivolumab and they're having primary progressive disease in the first couple of months, would it be reasonable to switch them to cabozantinib-nivolumab instead of scuttling immune therapy entirely and not losing out on that combination of TKI and nivolumab, or even lenvatinib-pembrolizumab? Is there any rationale to do that? I know there’s kind of really no answer.

Geynisman: If somebody is truly progressing on ipilimumab-nivolumab, I tend to go to single-agent TKI. I tend to think that it’s very unlikely that they're going to have some benefit from further immunotherapy at that point. I think that's different than if somebody's had immunotherapy in the beginning and had something in the middle. For ipilimumab-nivolumab in the beginning, for example, I've had patients that then progressed, had single-agent TKI, and sometimes I have gone back to lenvatinib-pembrolizumab later on and they've had a very nice response. I can't prove [why], obviously.... But I don't think it's absolutely wrong to retry immunotherapy at some point. I don't think I would do it directly after ipilimumab-nivolumab progression or while somebody's progressing on ipilimumab-nivolumab. As you correctly said, I think that's hard to prove, one way or another.

What we do know from 2 second-line trials…is patients that have had immunotherapy and progressed were randomized to TKI alone vs IO-TKI right afterwards, and there was no benefit. There was a tivozanib [Fotivda]-nivolumab trial [NCT04987203], and there was a cabozantinib-atezolizumab [Tecentriq] trial [NCT04338269]. Both trials showed no benefit to continuing to treat with an IO drug, even if it's a different one right afterward.^2,3 That's why I tend not to do it.

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DISCLOSURES: Geynisman previously disclosed a consulting or advisory role with Exelixis, UpToDate, Pfizer, AstraZeneca, Seattle Genetics/Astellas, Eisai, Merck, Myovant Sciences, 2nd.MD, and NCCN, as well as institutional receipt of research funding from Merck, Astellas Pharma, Harpoon Therapeutics, Arvinas, CG Oncology, Novartis, and Regeneron.

REFERENCES

1. CheckMate-214 Final Results Confirm Survival Advantage, Long Durable Responses for Nivo/Ipi Versus Sunitinib in mRCC. News release. ASCO Daily News. June 1, 2025. Accessed September 24, 2026. https://tinyurl.com/ycypyyp4

2. Choueiri TK, Albiges L, Barthélémy P, et al. Tivozanib plus nivolumab versus tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 Study. Lancet (London, England). doi:10.1016/S0140-6736(24)01758-6

3. Pal SK, Albiges L, Tomczak P, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet (London, England). doi:10.1016/S0140-6736(23)00922-4