Combination Therapies in Metastatic Kidney Cancer - Chung-Han (Joe) Lee

July 7, 2020

The development of novel combination therapies in kidney cancer is on the rise due to the approval of combination immunotherapies. Joining Alicia Morgans is Chung-Han (Joe) Lee, who highlights his recent advancements in TKI-IO combination therapies. Dr. Lee also concentrates on the responses of biomarkers with aims to aid in personalized treatment for kidney cancer patients, especially those for non-clear cell kidney cancer.


Chung-Han (Joe) Lee, MD, Ph.D. 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, I'm thrilled to have here with me today, Dr. Joe Lee, who is a medical oncologist at Memorial Sloan Kettering. Thank you so much for talking with us today.

Joe Lee: Thank you for having me.

Alicia Morgans: Wonderful. So you have done a lot of innovative work in kidney cancer, really pushing the boundary in the metastatic setting. And I'd love to hear about the recent advances that you've worked on to help the audience understand where kidney cancer care is going.

Joe Lee: Right now it's a very exciting time in the field of kidney cancer with the approval of several regimens with combination immunotherapies. A lot of the work that I've been developing is not only these novel combinations, looking at biomarkers for combination immunotherapies like ipi/nivo, but also various TKI-IO combinations. Among the regimens that I've worked on have included the use of the combination of that plus pembrolizumab for patients who are P1-naïve and also for people who were previously progressed on checkpoint inhibitors.

Alicia Morgans: Great. I know you've done some biomarker work in those studies to help identify which patients might be the most likely to respond. Can you tell us a little bit about that?

Joe Lee: Yeah. Right now the response rates that we see for these regimens are incredibly high. But there's still an incredible diversity of potential outcomes. So we're starting the process of trying to better delineate where these responses may end up falling out. We've done whole-exome sequencing on these tumors and looked at things like tumor mutation burden. And we've also started to characterize things like HLA zygosity and whether or not by better characterizing the entire antigen presentation on the system, whether or not that can be a better predictor for responses. Certainly, these are very preliminary, but you can hypothesize that the idea of tumor mutation burden gives you a baseline level of the total potential number of antigens that you can have. And then things like HLA diversity might become important for seeing what percentage of those antigens can be presented.

Alicia Morgans: Absolutely. One of the things I think about in metastatic kidney cancer is one of the most basic questions I think, thinking about the use of ipi/nivo as a combination or pembro/axi.

Joe Lee: Yeah.

Alicia Morgans: Could approaches like the work you're doing currently in biomarker development, help us to understand which patients might respond better to a given a combination so that we could have some direction on which one is necessarily the one we should pursue for our patients?

Joe Lee: Yeah. Especially now that we have multiple regimens that have shown efficacy and superiority against single-agent TKIs with both ipi/nivo, for axi/pembro, for axi/avelumab and then two additional clinical trials likely to readout. Hopefully sometime next year with cabo/nivo and lenva/pembro, we really are in a quandary in trying to decide what is going to be the optimal treatment regimen. A lot of that comes down to clinical metrics and the cross-trial comparisons that we are always told that we're not supposed to do. 

Alicia Morgans: Not supposed to do, yeah.

Joe Lee: Really right now until we can get a head-to-head trial comparing these sorts of regimens, we're going to have to rely on some of the biomarker analysis to give us a better sense of how to better stratify patients to each of these regimens.

Alicia Morgans: Do you think that any of the biomarkers that you're developing might be able to help us because immunologic biomarkers might be able to help us understand which patients might develop complications from some of these therapeutic combinations?

Joe Lee: That's one of those things in which certainly is an area of very active interest with us to try to figure out whether or not there are more pharmacodynamic biomarkers to see whether or not we can, in some ways, stress test the immune system in some sort of way to see whether or not there is going to be some way to predict those people who have severe side effects from immunotherapies. Right now the potential side effects related to immunotherapies remain very, very unpredictable. As we learn more I think that we can hopefully gain a little bit more insight into not only optimizing people in terms of clinical outcomes, in terms of efficacy but also minimizing the potential risks related to severe side effects.

Alicia Morgans: Absolutely. What other projects are you and your group working on that you see potentially impacting clinical care in the next couple of years?

Joe Lee: The other thing that is of great interest to us is the development of therapies for non-clear cell kidney cancer. Right now non-clear cell has become this orphan entity of sorts, with most of the clinical trials requiring people to have either clear cell histology or having at least a clear cell component. We certainly have tried using the clear cell regimens. The approvals often are done in all disease histologies without restricting to clear cell. One of the big trials that we're doing right now is a Phase II clinical trial of cabozantinib plus nivolumab to see whether or not this type of TKI-IO combination could be effective for the non-clear cell histologies.

Alicia Morgans: I think that's absolutely an area that we're continuing to watch because like you said that group of non-clear cell patients seems to have become not exactly ignored, certainly, but orphaned is a good word. We definitely need advances for that particular patient population.

Joe Lee: It's really one of those things in which I think it's always been very challenging for the non-clear cell space because it is actually a much more diverse group of diseases.

Alicia Morgans: Yes.

Joe Lee: Certainly sometimes when we do our studies, we've grouped all non-clear cell together-

Alicia Morgans: Which isn't fair.

Joe Lee: Which is not necessarily fair. I think that what we certainly worry when we do those types of things is are we missing potentially active agents just because from a numbers perspective it was only a small fraction of that non-clear cell cohort?

Alicia Morgans: Absolutely. So designing smarter trials to really understand and target the heterogeneity that exists in the non-clear cell population will be a priority, I'm sure, in future work.

Joe Lee: Yeah.

Alicia Morgans: As you think about the landscape of metastatic kidney cancer, clear cell or non-clear cell, what is your overarching message to viewers about that disease space?

Joe Lee: I think that this is a very exciting time that we're in for kidney cancer. I think that there's been the rapid approval of multiple agents. Very broadly speaking we are talking about three classes of medications that can be effective for kidney cancer that seem to combine well with each other with VEGF targeted therapy combined with IO, with IO combinations with VEGF targeted therapy plus mTOR targeted agents that can be combined together. A lot of biomarker development is going to be really necessary to really stratify patients in terms of what are optimal treatment approaches. As we better understand biology, we can certainly make additional advances in terms of not only treatment selection, but also the development of novel new agents that can help.

Alicia Morgans: Absolutely. That's a wonderful message of hope and a great direction for us to move as a field in the future. I really thank you for your time and for going through all of this with us today.

Joe Lee: Okay. Thank you so much for having me.