Recent Data Updates in the Treatment of Non-Clear Cell RCC


Drs Robert Motzer and Moshe Ornstein discuss the results of the KEYNOTE-B61 study in patients with non-clear cell renal cell carcinoma.

Robert Motzer, MD: I think we'll touch base on some of the non-clear cell data that was presented at ASCO is also of interest in the poster discussion section. So, the non-clear cell RCC is a much less defined space. These are really a heterogeneous group of tumors that have been collected and are the other side of renal cell cancer and been much more difficult to identify effective therapy and identified specific targets based on their rarity and also the fact that it's really a heterogeneous group. So, while there's studies, the two big studies that were reported at ASCO, the three big studies are starting to distinguish different cell types. They really do mostly focus on this entity of non-clear cell RCC. In NCCN recommendations, there has been a recommendation primarily for clinical trial for these tumors. cabozantinib and sunitinib have been recommended based on low levels of activity as single agents. So, the one trial that was presented by Dr Lee from MSK was the results of the KEYNOTE-B61 study, which was a single arm trial of Lenvatinib plus pembrolizumab across non-clear cell RCC. And this was a large multicentric global trial. The eligibility was fairly wide to non-clear cell RCC, without prior systemic therapy. It was a first line study, and there was a large cohort of over 160 patients that were treated with pembrolizumab, 400 milligrams every six weeks, and Lenvatinib 20 milligrams daily as an oral dose. Primary endpoint for this phase two was objective response rate. The preliminary results of a subset from this trial were reported at ESMO and received quite a bit of attention. And at the ASCO presentation was the entirety of the trial showing a long median progression-free survival of almost 18 months in this population. Now, in most of the other studies including the sunitinib studies, for a group like this, you would expect a median progression-free survival of 12 months or less. In addition, although this was a single arm study, the survival was not reached in this study, and appeared to be quite long with 82% 12-month survival. Next. The other study that is notable was an update of the phase two trial of nivolumab plus cabozantinib in the similar group of patients with non-clear cell RCC that was also reported by Dr Chung-Han Lee from MSKCC. Next. So, this is a combination of nivolumab plus cabozantinib that was taken from the experience in clear cell RCC with a similar dosing strategy. This was a single center trial in which there was really two cohorts. One cohort consisted of patients with chromophobe tumors, and the other were patients that had a wider spectrum of papillary, unclassified, or other cell types. They were broken down into two cohorts because the chromophobe cohort has been historically considered to be pretty resistant to IO therapy. And so, they were considered separately. The initial results of this were published in Journal of Clinical Oncology, and this was an extended follow up period for that 40-patient cohort. The progression-free survival, the median was about 19 months. And again, the survival data, although it was single arm, was encouraging for this particular program in the cohort of patients with papillary or unclassified tumors. In contrast, the group with chromophobe tumors was closed early because of a lack of response in the first 14 or so patients. The lenvatinib/pembrolizumab data was of high interest since it was really the first time this trial was presented in its entirety. And in 158 patients in the entire trial, the response rate was nearly 50%. One of the things that was notable with lenvatinib/pembrolizumab was that in addition to activity across the board for papillary unclassified tumors, there was actually a response rate that was observed in patients with chromophobe tumors too, which was unanticipated based on the lack of efficacy that's seen with IO therapies in other cohorts. We'll come back to that, but some people attribute that to the Lenvatinib component.

So, coming back to this, I would like your kind of input, Dr Ornstein in terms of what was your kind of take on this data. And do you feel that this is compelling enough to use one or two of these combination programs as a standard-of-care program for your non-clear cell tumor patients?

Moshe Ornstein, MD: Both the lenvatinib/pembrolizumab data and the cabozantinib/nivolumab data were really exciting in the non-clear cell space at ASCO 2023. [I have] two introductory comments; number one is kudos to the companies for presenting data and putting an effort to have prospective data in what's really an orphan disease group. And the second comment is that, just based on the word group, we've been grouping all these non-clear cell patients into one category as non-clear cell, when in reality, each of these subtypes is driven by different biologies. So, the papillaries are different than the chromophobes, which are different than translocation, which are certainly different than, let's say, renal medullary or even unclassified. I think what these data tell us is that combination-based therapy is a real option for these patients. And really in some ways, let's start with papillary and really focus on papillary from my perspective, because that's the highest cohort. The historical data that's used for papillary is the data from pap/met with cabozantinib versus sunitinib and other TKIs, which really set a benchmark of a PFS for monotherapy TKI of about nine months with cabozantinib and response rates of somewhere between 20 and 25%. And here you're seeing in two large data sets, even when you break it down into the papillary subsets, you're seeing response rates of approximately 50%, and you're seeing PFS numbers of more than a year. And for me, this should really be considered as a strong option for patients. I know it's not randomized data, but for patients with papillary RCC, I'm not convinced that there's a major difference between the two regimens. The response rates are fairly similar. PFS may be a little bit longer with lenvatinib/pembrolizumab, but again; small Phase 2 studies, they're not randomized, and we're doing the cross-trial comparisons. I think either of them are appropriate options for patients. For patients with chromophobe RCC, I tend to treat them a little bit differently. I will treat them with Lenvatinib and everolimus based on some older data, but I have seen some good efficacy with Lenvatinib and everolimus. And I do think there's different types of, even in the chromophobe subset, some patients who will respond very nicely to Lenvatinib and everolimus. And some patients who just have a rip-roaring advanced kidney cancer that is not likely to respond to anything. But for the two major subsets, again, for papillary, I lean more towards IO based IO-TKI combinations, lenvatinib/pembrolizumab or cabozantinib/nivolumab. And then for chromophobe, I'll usually start them with lenvatinib and everolimus. But these are really important data for the field.

Robert Motzer, MD: Well, those are great comments.

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