Targeted Therapies for Non-Clear Cell Renal Cell Carcinoma

The first-line treatment options for advanced and metastatic non-clear cell renal cell carcinoma (RCC) are growing, and various long-term updates on phase II trials were presented at the American Society of Clinical Oncology (ASCO) annual meeting.

MedPage Today brought together three expert leaders in the field: Moderator Elizabeth Plimack, MD, from the Fox Chase Cancer Center in Philadelphia, is joined by Amishi Y. Shah, MD, from the University of Texas MD Anderson Cancer Center in Houston, and Tian Zhang, MD, MHS, from the University of Texas Southwestern Medical Center in Dallas, for a virtual roundtable discussion. This third of four exclusive episodes focuses on treatment options for non-clear cell RCC.

Following is a transcript of their remarks:

Plimack: So one of the topics that comes up for those of us who treat renal cell carcinoma all the time is how do we think about non-clear cell? How much can we extrapolate from the very large clear cell trials to non-clear cell? And where are we with the sort of smaller phase IIs that have explored certain combinations in this space?

So we can talk about non-clear cell as a group or — as we more commonly do — subset them out. But there was some data evolving in both chromophobe and papillary and I wanted to get both your thoughts on that. So Dr. Shah, let’s start with you. How do you think about non-clear cell in your clinic?

Shah: Yeah, absolutely. So I think it’s important, even though our trials lump them, I think it’s important to think about it separately because the biology of these diseases are just so different. So I’ll talk about papillary first because it’s the most prevalent of the non-clear cells. And actually we’ve kind of gone from not having many options at all to having an abundance of multiple promising data sets.

So in my clinic, anybody who has non-clear cell we’ll fire off molecular testing just to kind of have that at the ready and open up clinical trial options down the line if we can. For most patients I have three pretty solid lines that we can rely on. So for papillary patients, particularly if they have HLRCC [hereditary leiomyomatosis and renal cell cancer], but even the sporadic, there’s data for bevacizumab [Avastin plus] erlotinib [Tarceva] out of the NIH with [Ramaprasad] Srinivasan. And this is an incredible regimen for patients with HLRCC, 66% of HLRCC patients have a response. And I’ve had multiple patients do well for years on this therapy. Pretty reasonably well tolerated. Obviously we don’t use a lot of erlotinib in the GU [genitourinary] world, so you gotta reach back to that head and neck knowledge and kind of manage some of that. But it’s fairly well tolerated and it’s an active regimen.

There is data for cabozantinib [Cabometyx] and nivolumab [Opdivo] in the non-clear cell population, and then highlighted at this meeting was also some lenvatinib [Lenvima]/pembrolizumab [Keytruda] data — that looked really, really good as well. And so we have these lines to rely on.

I’ll just quickly add on chromophobe. This is one where I never want to not give everolimus [Afinitor] a try because everolimus is active in these chromophobe patients. Now chromophobe is a lot more indolent in its sort of biology than the typical [papillary] patient. Obviously if you throw [in] sarcomatoid it’s a different story. But for a true chromophobe — a lot of times if it’s something where it’s locally recurrent or just one or two sites of disease — I’ll talk to my surgeon and see if we can actually … resect it, because it is more amenable to that type of treatment. But if you need something systemic, I actually like lenvatinib/pembrolizumab for the chromophobe patients.

Plimack: Great. Dr. Zhang, what’s your approach?

Zhang: Well, great approach. I agree with Dr. Shah here. What I found interesting at ASCO this year was the subsets of the non-clear cell data sets that read out. So there were two trials that I found very interesting. One was the lenvatinib with pembrolizumab trial from Memorial Sloan Kettering, Dr. [Chung-Han] Lee presenting that one, and then also the triplet approach — cabozantinib, ipilimumab [Yervoy], and nivolumab — presented by Dr. [Bradley] McGregor out of Dana-Farber.

So, the lenvatinib and pembrolizumab study actually had a good number of chromophobe patients with chromophobe histology, about 29 patients. And almost 30% had partial responses. So I thought that was as promising as any that I’ve seen in chromophobe disease. And so that was good.

And then in papillary kidney cancer, of the 93 patients who were enrolled there were a few complete responders. And then a good amount, 45% or so, of partial responders. And so for me that’s a great combination to use in those two histologies.

And then when we’re looking at the cabozantinib, ipilimumab, and nivolumab study, certainly there were responses seen in the papillary cohort. Unfortunately a lot of toxicity, particularly with elevated liver function, elevated enzymes. And so it’s a little bit harder to get patients through it. And of note, there was only one patient with chromophobe histology that responded. So it is not my go-to for chromophobe histology. And in fact the study was tailored to really focus on non-chromophobe histologies.

That said, you know, there is a big SWOG trial that is still out there for papillary renal cell carcinoma, randomization between cabozantinib versus cabozantinib with atezolizumab [Tecentriq]. The PAPMET 2 trial led by Dr. [Benjamin] Maughan and his colleagues in SWOG.

So that’s how I approach it in my clinic. I would love to get these patients onto trials when available.

Plimack: Absolutely.

Shah: And I’ll just add one more, I’m sorry. I’ll add one more thing, which is for these patients, especially if they’re younger, send them to your genetics counselor because sometimes we uncover some interesting backstory there.

Plimack: Right, right. No, absolutely. Well thank you for that great overview. I’ll just summarize, it sounds like [lenvatinib/pembrolizumab] was really poised in both chromophobe, but especially papillary to maybe be where we start, especially since we love IO [immunotherapy] when it works. It sounds like cabozantinib still has role in papillary for sure, and then everolimus in chromophobe is one to try, either in combination or separate. And of course [bevacizumab]-erlotinib can be magical in patients who respond, especially those with HLRCC and maybe others.

So nice to actually have some data in this space and some data showing efficacy with different sort of targets and agents. We’ve come a long way. And again, continue trials. Thank you Dr. Zhang for PAPMET 2, which is open through SWOG. I still think that’s the priority, we need to learn more. Thank you.

Click here to watch the other videos from this ASCO roundtable series on RCC.