Non–Clear Cell RCC Trials Support Regimens Approved for Clear Cell RCC

Non-clear cell renal cell carcinoma (nccRCC) is a less common disease state than clear cell RCC (ccRCC), with far less trial data on using tyrosine kinase inhibitor (TKIs) and immunotherapy (IO) combinations that are now commonly used in ccRCC. However, there are now several trials have supported the use of the same IO/TKI and IO/IO regimens in nccRCC. In a virtual Case-Based Roundtable event for oncologists in Illinois, Indiana, and Missouri, Randy F. Sweis, MD, presented data from these trials. Sweis, assistant professor of medicine at University of Chicago Medicine, moderated a discussion on how to select treatment with consideration of the role of the different histological subtypes of nccRCC.

DISCUSSION QUESTIONS

• Thinking about the data for nccRCC trials:​

What data impress you related to efficacy and safety? Which are most impactful when choosing a treatment regimen?​

• Do the data change your perspective on prescribing monotherapy vs a combination? IO/TKI vs IO/IO?

Randy F. Sweis, MD: What in particular impressed you related to safety and efficacy, and which was most impactful in terms of your thought process for nccRCC?

Neel Shah, MD: Progression-free survival [PFS] and overall survival [OS] would always be the No. 1 thing that I’d look at.

Sweis: Do you want one more than the other in this context?

Shah: Like with breast cancer, we now have so many therapies, so I think PFS is certainly something that [we look at] if appropriate. For those patients [whose disease does not respond] to immunotherapy, you can go to cabozantinib [Cabometyx], but what are you using in the third line?

Sweis: For nccRCC, a clinical trial is always preferred, but let’s put that aside. We have the similar options that you can cycle through with ccRCC in terms of different TKIs. We have data now for several TKIs, including sunitinib [Sutent], cabozantinib, and lenvatinib [Lenvima]. Whichever one they haven’t had, you have that option. There is also consideration of the subtype. For the FH [fumarate hydratase] deficient, they have the erlotinib [Tarceva] plus bevacizumab [Avastin] combination. For the chromophobe [histology], you might lean more towards lenvatinib plus everolimus [Afinitor]. It depends on the histology.

Unfortunately, a lot of the armamentarium is just drawn from ccRCC. In the long run, we need to get smarter about treating these as independent diseases, but they’re so rare that we don’t have that much data with drugs that are not used for ccRCC, so we end up cycling through similar drugs that we use for ccRCC.

These single-arm data are important because at least they give you confidence that there is a response rate, and you’re not just trying it because it’s used for ccRCC. There are real data now to support these drugs, including ipilimumab [Yervoy] plus nivolumab [Opdivo], which previously, I don’t think many people thought of [using].¹

Raymond Lobins, DO: The SUNNIFORECAST trial [NCT03075423] mirrors the CheckMate 214 trial [NCT02231749] in ccRCC, where you can compare it with TKIs and IOs, and you’re going to get a higher response rate with the TKI and IO, but you can argue that OS is about the same. It’s just how many are cured. I think SUNNIFORECAST, instead of separating them out, has lumped it all together, and I could treat nccRCC the same as I treat ccRCC.

Sweis: That’s a really insightful comment, and it’s interesting. We do all these studies, and then we end up going in a circle and end up back where we started with ccRCC. We wouldn’t necessarily have known that was going to be the outcome as these trials were launched, but at the end of the day, I agree. It does look like it’s emerging as a paradigm that can probably be more similar than different.

Bilal Siddiqui, MD: How much impact did the sarcomatoid histology of ccRCC or nccRCC have on ipilimumab/nivolumab? I would expect they would have a better response rate. Did that skew the data more towards ipilimumab/nivolumab?

Sweis: That’s a great point; you might expect that. I think that the data were not broken out in the forest plot. But I think you could still look at the data in isolation for the papillary alone, because that was not the sarcomatoid group, which was separate.¹ I think that is accounted for in the subgroups.

But that’s a good point. Ipilimumab/nivolumab is thought to have higher efficacy when tumors have sarcomatoid features in ccRCC and potentially in nccRCC, although those data are more in ccRCC.² It’s not necessarily true that it carries in nccRCC, but one might expect that it should.

Lisa Baddi, DO: It might be helpful because on the NCCN guidelines, it lumps all of the nccRCC [histologies] together.³ If you looked at it, you would think you can use any of these. But with chromophobe, they didn’t get any [response] with cabozantinib.⁴ If you’re somebody who doesn’t [treat] this a lot, you go to these guidelines, and it’s listed as an option. Maybe they need to have a [footnote] on it that says chromophobe [should not be treated] with this [regimen].

Sweis: I agree, we need some updating with the NCCN. I think it was limited by data before, because you can only separate as much as data you have, but now we have more data. There needs to be more updates to it. The only one they did call out was the hereditary leiomyomatosis and RCC syndrome for bevacizumab/erlotinib as a specific subtype. But lenvatinib/everolimus could be called out for chromophobe histology, or [it could say] cabozantinib/nivolumab is maybe not the best [for that]. There could be more nuance added. There’s always some carefulness about excluding options because we know that insurance and things are so dependent on it, so you don’t want to give a reason for something to be denied unless you’re sure.

Baddi: But you also don’t want to give somebody something when there’s a 0% response rate.

_{DISCLOSURES:Sweis previously reported consulting fees from Eisai; institutional research support from ALX Oncology, Ascendis, Astellas, AstraZeneca, Bayer, Bristol‐Myers Squibb, CytomX, Eisai, Genentech/Roche, Gilead, Immunocore, Jounce, Lilly, Loxo, Merck, Mirati, Moderna, Novartis, Pfizer, Pionyr, Pyxis, QED Therapeutics, and Scholar Rock; and a patent: neoantigens in cancer, PCT/US2020/031357.}

_REFERENCES:

_{1. Bergmann L, Albiges L, Ahrens M, et al. Prospective randomized phase-II trial of ipilimumab/nivolumab versus standard of care in non-clear cell renal cell cancer - results of the SUNNIFORECAST trial. Ann Oncol. 2025;36(7):796-806. doi:10.1016/j.annonc.2025.03.016}

_{2. Tannir NM, Signoretti S, Choueiri TK, et al. Efficacy and safety of nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma. Clin Cancer Res. 2021;27(1):78-86. doi:10.1158/1078-0432.CCR-20-2063}

_{3. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 1.2026. Accessed October 27, 2025. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf}

_{4. Lee CH, Voss MH, Carlo MI, et al. Phase II trial of cabozantinib plus nivolumab in patients with non-clear-cell renal cell carcinoma and genomic correlates. J Clin Oncol. 2022;40(21):2333-2341. doi:10.1200/JCO.21.01944}