KEYNOTE-B61: Putting a Focus on Non-Clear Cell RCC Treatment

By Brian Rini, MD, FASCO, Elizabeth Plimack, MD, MS - Last Updated: August 23, 2023

In a one-on-one conversation between Brian Rini, MD, and Elizabeth Plimack, MD, MS, they discuss outcomes of the KEYNOTE-B61 study, which assessed lenvatinib plus pembrolizumab in patients with non-clear cell RCC and showed “impressive” results.

Watch the final segment of this conversation.

Dr. Plimack: In the next segment we’re going to talk about non-clear cell kidney cancer. The vast majority of kidney cancers are what we call clear cell kidney cancers, and most of the frontline trials were geared toward that population. We were fortunate to see at ASCO [2023] the results from the KEYNOTE-B61 study, looking at lenvatinib with pembrolizumab in patients with non-clear renal cell carcinoma. We’ll talk a little bit about those data. This study impressively enrolled 158 non-clear cell patients. One of the common themes in studies of non-clear cell is that it’s really an array of different diseases and different histologies. They’re lumped together because each on its own is rare, but I commend this study for taking a look at the regimen used in the CLEAR trial in clear cell kidney cancer in this non-clear cell population.

Brian, what were your thoughts looking at the KEYNOTE-B61 results?

Dr. Rini: I thought it was pretty impressive. First of all, we’re doing a better job doing studies in non-clear cell; companies seem to be more interested even though there’s not really a clear registration path. But once developed in clear cell, they’re being applied to non-clear cell.

Lenvatinib/pembrolizumab, in clear cell, certainly is characterized by the highest response rates, longest progression-free survival (PFS). It has the most robust tumor shrinkage numbers, let’s call it. I think that extended to non-clear cell. I know there are single-agent TKI data in non-clear cell, largely with cabozantinib from Monty [Pal’s] SWOG trial. For me, I think an immunotherapy (IO)/tyrosine kinase inhibitor (TKI) doublet is the standard of care in non-clear cell. Ipilimumab/nivolumab doesn’t appear to be active, so we can sort of take that out of the discussion, I think. Then it’s really pick your favorite, and if it’s lenvatinib/pembrolizumab fine, and there’s some tolerability issues with lenvatinib, we can talk about dosing if we want or not. But to me, even though it’s single-arm data, I think an IO/TKI doublet is the standard of care.

Dr. Plimack: Yeah, that’s great. I agree. I think when I first saw these data presented at ESMO, my practice changed, and this became my first line go-to for non-clear cell kidney cancer. I think one of the challenges in this, of course, is getting enough numbers to have some confidence around the results, papillary being the most common version of non-clear cell that we see, there were 93 patients; that’s a lot that were enrolled to this. It did enroll really quickly and close really quickly. We’re looking at long-term, all of the things we talked about for clear cell, I think will be important for this as well.

I think where it gets confusing is when we’re talking about chromophobe, that’s a totally different disease. There was efficacy there as well, but I think that question is less definitively answered by this study. Then the buckets of unclassified and translocation, which may have some overlap with clear cell or other histologies, are a little harder to parse. But I think for papillary, this sets the new standard of care, in my opinion.

Dr. Rini: Yeah, chromophobe’s interesting. Other studies like KEYNOTE-427 of pembrolizumab monotherapy and others haven’t really shown immune responsiveness, but in this study, response rate was almost 30% in chromophobe, which is pretty decent, right? It’s kind of like single-agent TKI in the old days. Even in chromophobe, and I’d be interested in your practice, I still tend to start with IO/TKI. I know lenvatinib/everolimus has some tiny, tiny data of activity, and we all have our anecdotes, but I still think there’s not going to be long-term durable outcome without an immune component, in my opinion. I default to that.

Dr. Plimack: Yeah. I guess I would say I don’t know how much the pembrolizumab is doing, supporting the lenvatinib in this combination. I have tended to use cabozantinib. I wouldn’t object to using IO doublet, but it’s a conversation. It’s nice to have options for chromophobe. We didn’t really before.

Dr. Rini: Yeah, exactly. But I think it’s exciting data. I think, again, we’re doing a better job of including non-clear cell patients. They’ve sort of always been left out, and we just borrow from clear cell, but without any data. When you’re talking to a patient, you like to say… And patients ask, as you all know, hey, what’s my chance of responding? How long am I likely to be on therapy? These are very common questions. To have some relatively robust data, it’s probably the largest non-clear cell trial ever done. Am I right? Something in there. It’s nice to have some relatively firm data to advise patients.