Clinical Trials in Non-clear Cell Kidney Cancer - Darren Feldman

January 15, 2020

Darren Feldman, MD, and Alicia Morgans, MD, MPH, discuss the nuances of treating non-clear cell kidney cancer, a disease that has historically been underrepresented in phase 3 clinical trials of kidney cancer and is also histologically heterogeneous. This heterogeneity makes variations of the disease rare, and thus single-agent VEGF Tyrosine Kinase Inhibitors (TKIs) aren't always effective. Dr. Feldman and his colleagues at Memorial Sloan Kettering Cancer Center have focused on developing novel therapeutic regimens for non-clear cell kidney cancer. Dr. Feldman also gives advice to patients facing a non-clear cell diagnosis, advising them to seek out opinion at a center of excellence in kidney cancer and to understand the specific histology they present with.


Darren R. Feldman, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi, my name is Alicia Morgans and I am so excited to have here with me today Dr. Darren Feldman who is the Section Head of Germ Cell Cancer at Memorial Sloan Kettering, where he's also an Associate Attending. Thank you so much for being here.

Darren Feldman: Thank you for having me. It's a pleasure.

Alicia Morgans: Of course. I wanted to talk with you a little bit about kidney cancer, because I know that's one of the things that you do so well at Memorial, and specifically focus in on a population that is sometimes underrepresented in some of the therapeutic trials that we have, the non-clear cell patient population. This is an area where I know we need more therapeutics and I know that your group is doing what it can to try to address that problem. Can you tell us about some of the trials that you're doing to address non-clear cell kidney cancer?

Darren Feldman: Yeah, that's right. You know, all the major Phase III trials that have led to the development of a barrage of therapeutics over the last 10 to 15 years in kidney cancer have been based on patients with clear cell kidney cancer. And so, patients with non-clear cell kidney cancer haven't really been in those trials as much and we don't have as much information. What information we do have suggests that when you apply single agents, at least VEGF TKIs for example, against these non-clear cell kidney cancers, the patients don't do as well. The other thing that's notable is non-clear cell kidney cancer, while used as one term, is really made up of a heterogeneous group of histologies. You have papillary kidney cancer and even within papillary kidney cancer, there are multiple subtypes. And then you have chromophobe RCC, you have unclassified RCC collecting duct RCC.

And so it gets even rarer when you break down by individual histologies. Even the small trials that have been done, randomized Phase II studies, for example, have had a limited number of patients with any individual histology, probably papillary being the most commonly represented. So our group realized pretty early on that we were not seeing the same levels of efficacy with single-agent VEGF TKIs as we were seeing in clear cell RCC. And so, we sought to develop novel regimens.

The first study that we did, which we published in the JCO, was a combination of everolimus plus bevacizumab, and we started out testing that in patients with all types of non-clear cell kidney cancer and we realized that we were seeing a really strong signal of efficacy in patients with the papillary type of RCC or unclassified RCC with papillary features. And with the combination of bevacizumab, a monoclonal antibody against VEGF and the everolimus, an mTOR inhibitor, we saw efficacy that was pretty similar to what you would get with a single-agent VEGF TKI like sunitinib in patients with clear cell RCC. We saw that as a significant advance.

Building on that, we have a currently ongoing trial of cabozantinib plus nivolumab in patients with non-clear cell RCC. We have, it's a Phase II study, it's being conducted at Memorial Sloan Kettering and my colleague, Joe Lee, is the Principal Investigator and I'm a Co-Principal Investigator. The trial is a Phase II design. It has two separate cohorts, one cohort of patients with unclassified or papillary RCC. And then, we have another cohort of patients with chromophobe RCC. We're currently enrolling in both cohorts and have seen a signal of efficacy particularly in the unclassified and papillary RCC cohort.

Alicia Morgans: That's really exciting. Is this a randomized trial or is everyone in the trial getting treatment for the primary outcome of, is it radiographic progression-free survival?

Darren Feldman: Yeah. The primary outcome for this study is response rate and that's what we're testing, but we also have a secondary endpoint of progression-free survival. It's a Phase II study, single-arm, everybody gets cabozantinib plus nivolumab and patients with non-clear cell RCC who are interested can look up the study on and contact our group, we'd be very happy to see them expeditiously.

Alicia Morgans: That's great. Just to really reiterate that for everybody, for patients who have non-clear cell cancers, they can contact the group if they're interested in a clinical trial. And in this trial with these two different cohorts, which really encompasses pretty much all of the heterogeneity of non-clear cell, but just has two different treatment cohorts. All patients are actually undergoing active therapy. There is no placebo arm and they're all followed for response rate and radiographic progression-free survival or progression-free survival. That's nice that everybody who does make the effort to come to Memorial to undergo treatment will have access to the active drug, which is really important if they're going to travel especially, I think.

Darren Feldman: Yes, exactly. As long as they're eligible for this study, they will get active treatment.

Alicia Morgans: Wonderful. We will make sure that we put all the information for the trial up with the number and the access information so that they can contact your team if they're interested. And in general, I think as a field we're all just very, very excited to see the outcomes from this trial. Hopefully in the next year or so as you guys finish things up and hopefully we'll see that we're able to move the needle on to a Phase III, or even eventual approval for these patients who really have been somewhat left behind with all of the excitement that's going on for these combination studies that seem to be making such a difference for clear cell kidney cancer.

As you're giving a final message to the audience, do you have any messages, just sort of overarching themes for patients with non-clear cell renal cancer? What can they think about and hope for in the future?

Darren Feldman: I think that if you're diagnosed with non-clear cell RCC, the first thing you need to do is make sure you understand what histology you have, because they are different and they may be treated differently, especially differentiating collecting duct and medullary RCC, from papillary or unclassified RCC and even chromophobe. They're not the same, and I think that that is one really important message.

The other is, even though kidney cancer itself is not a rare tumor, non-clear cell RCC is somewhat of a rare tumor. I think that is a disease state where it would be very reasonable, and maybe even encouraged for you to get an opinion at a center of excellence that sees a lot of kidney cancer. Maybe at least a pathologic second opinion to confirm the diagnosis, because it's not that easy of a diagnosis to make.

Alicia Morgans: Absolutely.

Darren Feldman: And then lastly, you may not be eligible for clinical trials at the center that you're being seen at, but that doesn't mean that there aren't clinical trials available like the one we've been discussing today. And so, if you're interested in clinical trial participation, we really encourage you to look up the trials going on at our center and other major centers for kidney cancer around the country and around the world, so that you can also be involved and benefit from the novel combinations of drugs that are so effective in other forms of this cancer.

Alicia Morgans: Wonderful. Thank you so much for sharing your expertise and that message of hope for how patients can really get involved, get engaged, get access to therapies that they wouldn't necessarily have access to because they are enrolling in clinical trials. Thank you so much for your time.

Darren Feldman: Thank you.