Renal Cell Carcinoma Podcast

Non–Clear Cell Renal Cell Carcinoma: A Conversation About Subtypes, Clinical Trials, Treatment Options, and Outcomes

Sumanta Pal, MD; Mehmet Asim Bilen, MD


October 04, 2022

This transcript has been edited for clarity.

Sumanta Pal, MD: Hi. My name is Dr Monty Pal. I'm a medical oncologist at the City of Hope Comprehensive Cancer Center. I'm here today for Medscape's InDiscussion series on renal cell carcinoma. We've done several of these, and today we're going to be tackling a topic that is very near and dear to my heart, and that's non–clear cell kidney cancer. I'm really delighted today to have one of my dear friends, Dr Mehmet Asim Bilen — I know him as Asim — who's here today to discuss with us this particular topic. Now, Dr Bilen is an associate professor in the Department of Hematology and Medical Oncology at Emory. He's a board-certified medical oncologist. I know him well from his role in multiple clinical research projects in genitourinary cancers, and he's certainly done a lot in the way of kidney cancer as well. He's the director of the GU Medical Oncology Program at Winship Cancer Institute over at Emory. Asim, welcome to InDiscussion.

Mehmet Asim Bilen, MD: Thank you so much, Dr Monty Pal. Thank you so much for having me.

Pal: It's my pleasure. I wanted to start out by getting a flavor for how you got into renal cell carcinoma. It's a fairly narrow specialty, and we're all close in the field. But what drew you in?

Bilen: Monty, as you know, I'm from Turkey originally and went to medical school at Hacettepe. During medical school, I came to the United States a couple of times for some research programs, and I really had great mentors within the GU field. After that, I said "I have to come to the US for my future career." I did my residency at Baylor and my fellowship at MD Anderson. And particularly at MD Anderson, I really fell in love with kidney cancer. I think we all have special people in our life, and for me, Dr Nizar Tannir really helped me a lot with research and career and clinical development. I really saw his passion for patient care and research and clinical trials, and my interest in renal cell carcinoma grew. And then after that, I joined Emory as a faculty member, and I am still doing what I love to do, which is research clinical trials in GU and particularly kidney cancer.

Pal: It's funny how that happens, isn't it? I started out in the field and I didn't really have a mentor when I started on faculty at City of Hope, but I leaned on a lot of folks outside. Nizar was certainly one of them. I learned a lot from Nick Vogelzang, and Toni Choueiri, as you know, has been a very close friend and mentor for over a decade now. And you really do need those individuals to guide you along, don't you?

Bilen: I think this is really important because we follow a direction just because of our mentors. Either we love something or we hate something. And for me, I'm lucky to have many mentors. It helped me a lot. I wrote my first IIT [investigator-initiated trial] during my fellowship and went to the Vail workshop. I just gave this example … it's like in the Matrix movies, the blue pill and the red pill. I think those are my red pills that really push me in the field. I really love to be part of this big GU family.

Pal: Absolutely. It really is a family and I think there's a lot of cohesiveness, which really helps the research along. So, with that in mind, I think that's a good segue for us to start talking about some research. Non–clear cell kidney cancer is a complicated topic. I don't know if everyone in the audience will be familiar with some of the breakdowns there, but tell us in broad terms what is non–clear cell disease?

Bilen: This is a very important area and I think it is a huge unmet need for our patients that we see in clinic. But this is the breakdown I give my patients all the time. If we have 100 patients with kidney cancer, 75% of them have clear cell and then the leftover 25% is non–clear cell. But the problem is that within the 25%, we have all these small subgroups, including papillary renal cell carcinoma, which is maybe around 10%-15%, and chromophobe renal cell carcinoma is around 5%. But we also have many other small subtypes such as collecting duct renal cell carcinoma, unclassified [types] like translocation renal cell carcinoma, renomedullary carcinoma, and so on. This is a very diverse, heterogeneous population, but it is very aggressive in terms of clinical course. The problem is that doing clinical trial and drug development is particularly quite challenging just because of the diverse nature. But overall, we see a lot of patients and those tend to be younger and hopefully we're going to move the field forward to have good therapy options for our patients on a day-to-day basis.

Pal: Absolutely. We could probably spend all day dissecting non–clear cell disease, but since we're a little bit limited in time, I thought one thing we could do is narrow the discussion to some of the more common subtypes that you highlighted. As you pointed out, collecting duct renal cell carcinoma or renomedullary … these constitute less than 1 percentage point of our RCC cases, thankfully. They're very aggressive diseases. But why don't we start by talking about papillary renal cell carcinoma, which is kind of near and dear to my heart. Maybe you could tell us about how you approach your patients with papillary kidney cancer these days?

Bilen: If you look at the NCCN guidelines, which really help all oncologists in the field, a clinical trial is always listed. I think this always a very high priority. But because of your data and others in the field, we have more and more options for our patients with papillary kidney cancer. We can split it into two groups, papillary 1 and papillary 2. I think clinically, their course might be different but overall how we treat them is similar, based on the PAPMET trial, which is a Phase 2 trial for patients with papillary RCC. It is a four-arm trial, but at the end, we have cabozantinib vs sunitinib compared. Overall, the data is very strong for cabozantinib with a PFS [progression-free survival] of 9 months and a response rate of 23%. I think this is one drug I really want to use for my patients with papillary RCC.

Pal: Absolutely. And I think that these days, we're so tempted to consider immunotherapy in these patients. Can you give us a sense of what your experience has been like using immunotherapy here and maybe some of the data that might lend itself to using immunotherapy in this setting? I definitely agree with you, and this is not at all meant to be self-serving, but since we have such limited data in papillary, cabozantinib probably does represent a relative standard, but talk to us about immunotherapy and how you use it in this population.

Bilen: Again, we are all in the era of immunotherapy or immuno-oncology and now we are the era of combinations. We start with single agent and then switch to doublet, and I think in the near future we're going to start using triplet. Some of the data that is very important to me, which was published recently by the Memorial Sloan Kettering group, was a phase 2 trial of combination of nivolumab plus cabozantinib in non–clear cell renal cell carcinoma. This is a relatively small trial of forty-seven patients, but I think this is still important. They split the group into two cohorts. Cohort 1 is the important one, which is papillary, unclassified, translocation-associated renal cell carcinoma. But when we look at the data, the median PFS is very encouraging at 12.5 months and the response rate is close to 50%, which is quite remarkable. The median overall survival is around 28 months; overall, the data look great. Cohort 2 is chromophobe renal cell carcinoma. There is no response in that group. But overall, this is really encouraging data that suggests there might be some synergistic role with immunotherapy and VEGF TKI [vascular endothelial growth factor tyrosine kinase inhibitor] combination, particularly with cabozantinib. And there are other trials. For example, Dr Apolo, she's a pioneer with the combination nivo-cabo, and she has another trial currently enrolling, ICONIC, that has a cohort of patients with nivo/ipi/cabo. And there is a multicenter IIT that is led by the Dana-Farber group with nivo/ipi/cabo. Down the road, we're going to have more and more data in this unmet population.

Pal: I couldn't agree with you more. It's really exciting to see what's coming out. You know, what really struck me is that in the data from Memorial Sloan Kettering that was published in JCO [Journal of Clinical Oncology] not long ago, the response rate in papillary renal cell carcinoma with cabo/nivo was 47%. And it certainly bests what we saw, albeit in the single-arm study, in PAPMET. I thought it was just curious that when we published our data for cabo/atezo in JCO in that non–clear cell cohort, (we had) a smaller number of patients, I think we had a total of fifteen. But having said that, the response rate, again, was 47% … so, really encouraging. And on that basis, we're going to be launching this study through the cooperative groups’ Ben Maughan, who you know well from the University of Utah. He is going to be the PI on it through SWOG and it's going to compare cabo with or without atezo for papillary renal cell carcinoma. I think that'll be really promising. You know, we talked about the cabo/nivo, cabo-based combinations, and so forth. What about other targeted therapy regimens? You know, one that comes to mind that I use a lot in the salvage setting is lenvatinib/everolimus. Is that something that you consider for your non–clear cell patients?

Bilen: Definitely. This is something I also use, especially if I start an IO [immuno-oncology] TKI combination such as nivo/cabo, which is one of the combinations I really like to use in the first line, especially after the data we discussed a minute ago. In the second line in the salvage setting, lenvatinib plus everolimus is going to be very important. And we have another multicenter single-arm phase 2 trial presented by Dr. Hutson and also published. This is again a small cohort of thirty-one patients, mainly papillary (twenty patients). And when you look at the overall response rate it is still very encouraging … it is around 26%. More papillary driven — I think eight responses were from papillary. But we also have three responders in chromophobe because sometimes we have the mindset that maybe the papillary is the only group to respond to this approach. But we still need more and more data to understand those rare subgroups. But overall, 26% response rate, close to 10 months of PFS, because of this reason, that is also another option that we can use in our patients. And also this year at ESMO, which is going to happen very soon, we are going to learn more about the combination of pembro/lenvatinib in this patient population. I'm really looking forward to seeing the data and hopefully we carry over the momentum after ESMO.

Pal: Absolutely. I think it's going to be really interesting to see what evolves there. And now we touched on this broader approach for papillary disease where we use targeted therapies or immunotherapy but in an unselected fashion. A couple of years ago, Toni Choueiri put out some data that I was really curious about. He's done this whole slew of really fascinating studies with more MET-selected therapies. But he also focused on a drug called savolitinib. I wonder if you can share with our audience some of the experiences around that.

Bilen: I think this is another important drug. We are in the era of precision medicine and really dissecting our patients and choosing what we do based on biology and molecular background. By doing that, maybe we can improve the clinical outcome but also maybe minimize the toxicity. Dr. Choueiri had a fantastic phase 2 trial, which is very encouraging. And then after that they launched a phase 3 trial, comparing savolitinib vs sunitinib. But unfortunately, the study closed early, and it may need time for sequencing and evolving data. But I think that story is not over yet. Now we are in the era of immunology, MET inhibitors plus immune checkpoint inhibitors might be a very appealing combination that we're going to explore in the near future.

Pal: Absolutely. It's so curious that you mentioned that because I saw the data for savolitinib with durvalumab and I thought it was pretty compelling and now of course, Toni Choueiri and Tom Powles have launched a study. We're not participating in this one, but I think it's a very ambitious study, but a good one, looking at MET-selected patients and specifically assessing whether or not they benefit from either savo/durva vs sunitinib. That study is enrolling now and it will be an alternative for the cabo plus/minus atezo study that I just mentioned … a really interesting landscape. I think we've covered clinical management of papillary renal cell carcinoma in a good amount of detail. One other element of non–clear cell disease I thought we might cover that I think our audience is going to run into with some frequency is sarcomatoid disease. And this one is tough. This goes way back, but when I was in fellowship, the only data we had was from this trial called ECOG 8802 that Naomi Haas led, and it was looking at Adriamycin (doxorubicin)/gemcitabine with, unfortunately, a really abysmal response rate in that setting with cytotoxic chemotherapy. Now tell us how sarcomatoid disease has morphed over the years.

Bilen: I think this is a wonderful experience, when we see an aggressive subgroup become a very appealing subgroup after we understand the immune checkpoint inhibitors and the role of immune checkpoint inhibitors in this population. Because right now when we see a patient with sarcomatoid, we are more encouraged that this will be someone who will have a great response to an immunotherapy-based approach and then hopefully that response is going to be durable. But as you said in the past, it was a very tough population that we didn't have too many options for. I think after the CheckMate trial with new subgroup analysis, we see that subgroup has high PD-L1 [programmed death-ligand 1] and more CR [complete responses] and PR [partial responses] and has a durable benefit from an immunotherapy-based option. And I think later with the nivo/cabo trial CheckMate 9ER, we see that sarcomatoid subgroup had a good benefit. We also look for other large clinical trials including avelumab, axitinib, and pembro/axitinib. All of these immunotherapy-based approaches have really changed the landscape of sarcomatoid. I think overall this is not a patient population that we worry about. And to be honest, I'm very encouraged by immunotherapy and the success of immunotherapy in this group.

Pal: Yeah, it's fascinating how it has just transformed from the time that I started in the field. And it's so great for patients that we finally have some relevant options in that setting. I was worried for a long time that this would be one of those diseases left behind. You see sarcomatoid features and, back in the day, you had this feeling of helplessness in some respects, but that's just completely evolved over the years and it's really thrilling. Why don't we shift gears and actually try to tackle some of these really rare histologies? Maybe the one that I'll pick out — only because you and I, at tertiary centers, come across this every now and then — is collecting duct vs renal medullary cancer. Maybe you can just give us a blurb on that and how you manage those two disease states.

Bilen: Yeah, Monty, as you said, this is a very rare subtype, maybe less than 1%, but it's very aggressive, a very tough prognosis. Being in cancer centers, we see those patients and we feel that we need to have more options for this patient population. And when I discuss with my fellows, those are the two subtypes that we use chemotherapy for, because most of the time in kidney cancer we don't use chemotherapy. But those two subtypes are when we use our chemotherapy options. Particularly in chromophobe, we use platinum-based chemotherapy for first line, either gem/cis, gem/carbo [carboplatin], or carbo/Taxol. After that, I typically like cabo-based options. I think a couple of years ago we had the European data with cabozantinib in this patient population and to me it was encouraging. We also have some data with immune checkpoint inhibitors in this patient population. But again, if you have a clinical trial, I think it makes sense to enroll those people. Otherwise, chemotherapy and cabo-based targeted therapy and immunotherapy is something I want to try for this patient population.

Pal: Beautifully said. That's a really nice, concise summary and makes a lot of sense. I would also encourage folks to feel free to reach out when you get these patients. I have to tell you, I always call Pavlos Msaouel, who you know well from MD Anderson; he is really running a terrific renal medullary program out there. It is so critical. And with that in mind, with this theme of lending a helping hand, maybe we could wrap up by you telling us a little bit about your advice for junior faculty and fellows. I view you as somebody who's a rising star in the field and somebody who's quite established already and a well-respected kidney cancer doc. What advice do you have for folks, faculty, fellows, etc., who are in their early years and are getting into this game?

Bilen: Monty, I think mentors are really, really important. My recommendation is to find multiple mentors who will guide you, be your best supporter and also your advocate. Because being successful in academic medicine requires a lot of guidance, direction, and support. Because of this reason, I think mentors play a huge role. The other thing I tell my junior faculty is really look at your institution and understand the strengths of your institution and maybe shape your research idea based on the people around you. I think kidney cancer, and cancer in general, is a team sport. We collaborate with multiple people, different clinicians, different basic scientists, and your collaborators are also going to help you to move things forward. I think sharing is caring. You always collaborate, share, and include everyone because at the end we are better with people around us. I think this is very important. Academic medicine is like a marathon. We have to keep running, sometimes slow, sometimes fast, but always keep running. And last, I remember advice from one of my previous mentors: one thing that is always going to be with you is your family. We have to invest in them. Burnout is real in academic life. We need to find a way to relax and recharge. And I think that family is going to play a huge role, and we have to invest in our family and hopefully they will make us successful in this field.

Pal: That is such terrific advice. I love all of that … I love the idea of finding great mentors, and I love the idea of harnessing the strengths of your institution. And that's a great note to close on, Asim. Just really making sure you take care of the ones you love back at home. You're absolutely right that kids, spouses, etc., deserve the utmost attention. And I think that's a great reminder for folks who are gung-ho about making it in the field. Asim, thank you so much for joining us today.

Bilen: Thank you.

Pal: And this is Dr Pal for InDiscussion.


Renal Cell Carcinoma

Kidney Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology

PAPMET Trial: Testing Cabozantinib, Crizotinib, Savolitinib and Sunitinib in Kidney Cancer Which Has Progressed

Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non–Clear-Cell Renal Cell Carcinoma and Genomic Correlates

Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors

Cabozantinib Plus Nivolumab Phase I Expansion Study in Patients With Metastatic Urothelial Carcinoma Refractory to Immune Checkpoint Inhibitor Therapy

Cabozantinib in Combination With Atezolizumab for Advanced Renal Cell Carcinoma: Results From the COSMIC-021 Study

A Single-Arm, Multicenter, Phase 2 Study of Lenvatinib Plus Everolimus in Patients With Advanced Non–Clear Cell Renal Cell Carcinoma

ESMO 2022

Efficacy of Savolitinib vs Sunitinib in Patients With MET-Driven Papillary Renal Cell Carcinoma. The SAVOIR Phase 3 Randomized Clinical Trial

SAMETA: An Open-Label, Three-Arm, Multicenter, Phase III Study of Savolitinib + Durvalumab Versus Sunitinib and Durvalumab Monotherapy in Patients With MET-Driven, Unresectable, Locally Advanced/Metastatic Papillary Renal Cell Carcinoma (PRCC).

A Phase II Trial of Doxorubicin and Gemcitabine in Renal Cell Carcinoma With Sarcomatoid Features: ECOG 8802

A Study of Nivolumab Combined With Cabozantinib Compared to Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 9ER)

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