Focus on Nonclear Cell RCC: Frontline Treatment Options, Research Limitations, and More

By Brian Rini, MD, FASCO, Tian Zhang, MD, David F. McDermott, MD, Hans Hammers, MD, PhD - Last Updated: November 14, 2023

A roundtable discussion, moderated by Brian Rini, MD, addressed considerations for clear versus nonclear cell kidney cancer, as well as recent data from ESMO 2023. Dr. Rini was joined by Tian Zhang, MD; David McDermott, MD; and Hans Hammers, MD.

In the next segment of the roundtable series, the panel talks about nonclear cell kidney cancer, including treatment options and clinical trial data in this subgroup.

Watch the next segment in this series.

Dr. Rini: Let’s move to nonclear cell, which is the poor stepbrother of clear cell, and we lump it all together, which it’s not. I guess maybe just same question as I asked for clear cell. We’ll go in reverse order; Hans, I’ll let you go first. A typical nonclear cell patient, and I know you may want to differentiate by histology, but this frontline metastatic, papillary, or whatever, how do you approach that patient?

Dr. Hammers: Papillary is easier among the nonclear cell. I think it’s very clear that we do actually have activity of immunotherapy in papillary renal cell carcinomas, depending what you look at. Maybe around 20%-plus a little bit. TKIs [tyrosine kinase inhibitors] can work, and then there are these combinations now, obviously the doublets, cabozantinib/nivolumab, lenvatinib/pembrolizumab, shows very nice respectable response rates, 50%. I think 1 of those would be actually my go-to frontline work. Now, may I be tempted in some select patients maybe to use single-agent immunotherapy? Maybe in some with really small disease burden, but otherwise the disease control is not good enough for me. I’m really tempted to combine it with IO [immunotherapy].

Dr. Rini: So an IO/TKI. Do you use ipilimumab/nivolumab in any nonclear cell patients?

Dr. Hammers: The data has not been strong. There is some data sets, actually another data set coming out that is being presented at SITC, for example, is actually uniquely strong with response at like 40%. But I would say other data sets are more in the high 20%. It didn’t seem to add as much as what we’ve seen with clear cell, so I was less tempted to do it. Maybe if it’s a young person who wants to go for immunotherapy, but it’s also not in the guidelines; it’s not necessarily approved for it. It’s a little bit of an uphill fight to get it approved. I tend to stick with IO-/TKI for now.

Dr. Rini: David, what’s your approach?

Dr. McDermott: I think it’s similar. There’s some trials out there in papillary that are interesting. The SAMETA trial could help us as far as a randomized trial

Dr. Rini: Tell us what that is, SAMETA trial.

Dr. McDermott: I believe it’s durvalumab versus sunitinib versus the combination of durvalumab and the MET inhibitor…

Dr. Zhang: Savolitinib?

Dr. McDermott: Savolitinib.

Dr. Rini: Savolitinib. Yes. It’s a 3-arm study.

Dr. McDermott: That’s an interesting design and looking at not quite component parts but sort of, and give us a sense of whether a MET inhibitor that seems active in papillary, can you add IO and enhance the benefit? I think 1 of the things that’s exciting to me about the field in the last 5 years is our colleagues have shown you can actually accrue these trials. Back in my day, you couldn’t enroll these trials, and now we’ve done a series of them, which I think helps in 2 ways. It gives us more clinical data to look at, and it also gives us more tissue to analyze. There are data sets that we need to get out there and analyze. One trial that I’m in theory responsible for, the KEYNOTE-427, big group of nonclear cell patients with…

Dr. Rini: Biggest trial ever done, right?

Dr. McDermott: Yeah. I guess.

Dr. Rini: It’s up there.

Dr. McDermott: As far as single-agent checkpoint. But the point of the story is the story is only partial. We have early clinical outcomes. We don’t have late. We’ve had some translational data; we don’t have all of it. It would be great to try to connect outcome with these modern techniques of interrogating the tumor, which people have done. But we need more of that. We need companies to support that analysis so we can actually connect outcomes with tissue data.

Dr. Rini: But in clinic you’re giving IO/TKI to the majority of patients?

Dr. McDermott: Yeah, I think so. For papillary type 1.

Dr. Rini: For papillary.

Dr. McDermott: Yeah. I think for chromophobe we still believe in Tom Hudson[, MD]’s awesome lenvatinib/everolimus data.

Dr. Rini: Nine patients.

Dr. McDermott: Yeah, small, but…

Dr. Rini: The most highly-cited 9-patient cohort ever.

Dr. McDermott: I know. I’m a desperate man. We do that there, but I don’t know that it’s great.

Dr. Rini: If you look at, I think it was lenvatinib/pembrolizumab, the chromophobe subset, which was, I don’t remember the numbers, but it was pretty robust. It was a decent number. It was more than 9; it was pretty robust.

Dr. McDermott: There’s a KEYNOTE trial that they did in multiple countries that showed a close to 50% response rate in nonclear cell patients with lenvatinib/pembrolizumab. I think you have things to build on, but we need much better connections between the tissue and the clinical outcomes that we have now.

Dr. Rini: Agreed. Tian, anything to add to that approach?

Dr. Zhang: Yeah, I agree with my colleagues. If we focus on chromophobe for a minute from the early trials, SPM and ASPEN, that chromophobe population tended to actually favor everolimus and mTOR signaling. Lisa Henske, MD, has done some really careful biology around chromophobe renal cells, and there’s some hint of ferroptosis driving some of the susceptibilities. I’d be really interested to see if there’s ways where we can target those cystine receptors and think about how do we undermine the biology of each of the subtypes because we know chromophobe is different than papillary and is different than translocation type. We want to be able to figure out the best options for those subsets of patients.

Dr. Rini: It sounds like we’re all, and I agree, IO/TKI, based on single arm, but reasonably impressive data. I think lenvatinib/everolimus is a good regimen, albeit toxic and not curative. I think immune-based regimens can be curative in nonclear cell. I’m not sure what those numbers are, but that’s what I tend to do as well. But I think, and David, I think you said this, the best news is that we’re actually enrolling these patients. We’re realizing that it’s not 1 biology and then the next step I think is translational and new targets.

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