Renal Cell Carcinoma Podcast

Frontline Treatment of Renal Cell Carcinoma

Sumanta Pal, MD; Brian Rini, MD


September 01, 2022

This transcript has been edited for clarity.

Sumanta Pal, MD: Hi. I'm Dr Monty Pal, and I am a medical oncologist at the City of Hope Comprehensive Cancer Center in Los Angeles, California. Welcome to Medscape InDiscussion. We'll start our series with Dr Brian Rini, who is going to be discussing frontline management of metastatic kidney cancer. Brian is a true legend in the field. Brian, welcome to the show.

Brian Rini, MD: Thanks, Monty. I appreciate it.

Pal: Now, you're a professor at Vanderbilt, but you've had an illustrious career and trained at some great places. Where have you been, and who have been your principal mentors in the field leading up to today?

Rini: I did my residency and fellowship at the University of Chicago back in the mid- to late 1990s and early 2000s. Nick Vogelzang and Walt Stadler were there at the time. Walt's still there. They were my primary mentors and the reason I got into to genitourinary (GU) cancer and kidney cancer specifically.

My first faculty job was at UCSF, and I trained with Eric Small out there. Eric's a prostate guy, as you know, and he really helped me sort of figure out which way was up when it comes to getting into projects and making connections, and he introduced me to a lot of people. If you remember, this was the early 2000s, right when the tyrosine kinase inhibitors (TKIs) were in their infancy in phase 1 studies — early signals of activity. So the timing was very good to get involved with those studies.

I stayed there for 4 years, and then in 2005, I moved to Cleveland, which is my hometown and where much of my family still lives, and I stayed there for almost 15 years at Cleveland Clinic. I worked with Ron Bukowski, who is a real legend in the field, for many years before he retired, and then I took over the program there until about 2 years ago, when I moved to Vanderbilt.

Pal: That's awesome. That's also a really great pathway, with great mentors along the way.

The first time that I saw you was at ASCO 2009, and that was when you presented the data for bevacizumab-interferon from a CALGB study. Clearly, things have come a long way since then. But the discussion always comes back to frontline management of kidney cancer. You've done a lot to really inform the field, both in terms of clinical trials and in terms of medical education. You put something on Twitter that I find incredibly helpful: a concise table of outcomes across frontline studies. What was your motivation to do that?

Rini: I think I must have first created it for a talk. And I remember that as all these data were coming out, it was a lot of data for the field. And of course, we're comparing across trials and doing all the things we say we shouldn't do. I don't remember when I first did it, but I think I made the table for a talk, and it's really evolved over the years, not only as data have matured but also what to put as endpoints. What are the important data? I've tried to make it comprehensive, but not so data-dense that it's uninterpretable. So it's taken on some forms.

Pal: I personally think it's brilliant. I think it's a terrific resource. You are really entrenched in these data. It's something that we're seeing day in and day out in clinical practice. I think the beauty of Twitter and social media is that you have hundreds, if not thousands, of medical oncologists who are looking at your slide and trying to take that information and interpret it in terms of clinical practice. Tell us how we can look at your table and then distill a treatment choice based on that.

Rini: I always encourage understanding a regimen, understanding the nuances of toxicity and dosing and such. We spend a lot of time comparing across regimens and talking about hazard ratios and subsets. And some academic things, some of which are worthwhile and perhaps some of which aren't. But for the practicing oncologists, I would back up and look at the major endpoints. There's four PD-1–based regimens (nivolumab, ipilimumab, avelumab, and pembrolizumab) that have extended survival. So that's a good thing we have for doublets that extend survival. And all of their hazard ratios are about the same for the intention-to-treat population; they're all about 0.7.

Then there are some differences. The TKI regimens give you higher response rates and longer progression-free survival (PFS), so more of the early tumor shrinkage endpoints. Ipilimumab-nivolumab (ipi-nivo) has the longest follow-up, at more than 5 years, and it may very well have the best long-term outcomes. There's 30% PFS for, again, the intention-to-treat population, and as for duration of response, the durable responses that you have come to perhaps now expect with immune therapy are certainly established for ipi-nivo. The TKIs don't quite have the follow-up to say whether they're going to meet them or not, but I suspect that that ipi-nivo may win on the durability piece.

So again, it's not right or wrong, or good or bad. It's that different patients may have different needs, and different endpoints may be important to different docs, too. They may put different weight behind endpoints. I think we all probably interpret studies a little differently and what's important, whether it's complete response (CR) rate or a primary progression rate.

What I tried to highlight in those tables are the major endpoints. They're all perhaps equally valuable on the surface and then allow people to interpret them as they will.

Pal: I think it's brilliant, as I've mentioned, To get back to that favorable risk question, I'd say that's probably one of the most contentious issues when we have academic debates around what to use in the frontline setting. How do you sit in terms of that debate? Are you a proponent of IO-IO (dual immuno-oncology agent therapy)? Are you a proponent of vascular endothelial growth factor (VEGF) TKI in that context? What are your thoughts there? Because I've heard great arguments on both sides.

Rini: Probably the major point is that we're referring to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification, which is an entirely clinical classification for lab values and clinical features. It's been great. I think it's served us well. But if you look at the biology within each risk group, it's very heterogeneous. So if you look at the IMmotion151 gene expression (and I think there are certainly other datasets), within a clinically defined risk group such as "favorable," the biology is very heterogeneous, right? And that's why that's my favorite figure from that IMmotion151 gene expression; it shows you that we're really missing the mark when we're classifying patients solely by clinical features.

There is clearly an immune responsive subset, right? The ipi-nivo CR rate in favorable risk patients, I believe, is about 12%, something like that. Most probably 60% of those patients, however, are angiogenic-responsive. That's why you see high response rates and long PFS — really impressive data for the IO-TKI regimens in favorable-risk patients.

I am a strong proponent that all patients, including favorable-risk, should get immune-based therapy. There is a segment of thought out there that TKI monotherapy is acceptable. The reason I don't think so is that, even though these patients do very well on TKI monotherapy (again, they're largely angiogenic-responsive), they have more indolent disease and TKI monotherapy is not curative. And second-line immune therapy — largely, single-agent nivolumab is the most proven — is not really curative either. There's no tail to the curve to that second-line CheckMate 025 study. So the sequential argument to me really robs patients of the chance to be cured.

And the added toxicity of, say, an IO-TKI vs a TKI is fairly minimal. There's definitely some, but I think for the benefit of potential cure, it's fairly minimal. That was a long-winded way to say that I think IO-TKIs are the standard there; I think they have the best data. People often point to the hazard ratios for survival that are on either side of 1, but I don't know that it's about showing a survival benefit in that cohort. If I'm remembering the data correctly, the CR rate for lenvatinib-pembrolizumab (len-pembro) in favorable-risk patients was remarkably high — really robust results. So I think ipi-nivo can be given to those patients. I don't know how to select them as an immune-responsive subset, but we're a ways from selecting those patients, I think.

Pal: That's totally fair. I struggle with that too in the clinics. And obviously, you want to give those favorable-risk patients the benefit of the doubt and get them on the tail end of that nivo-ipi curve. But how do you do it, acknowledging that maybe more than a handful of those folks have an angiogenic signature, as you referred to it? It's just not one of those things that we could easily predict in the current climate.

Rini: We can talk about triplets if you want and move from there, but I think we're going to be debating "favorable risk" for a really long time. I just debated Dave McDermott on this on the Uromigos podcast. It's fun to debate Dave, as you know, but we didn't really come to a conclusion and people seem sort of settled in their camps: their TKI monotherapy, their IO-IO. That just shows you that there's no right answer. There's different ways to look at it.

Pal: I'm Uromigos' biggest fan. I think I often text you after I listen to an episode, and you guys do some really great stuff there.

You've also had some conversations on that podcast around probably the bigger chunk of what we see in the kidney cancer clinic, which is intermediate- and poor-risk disease. Again, I can refer to your tables there. This is probably a place where, if I'm a community-based oncologist, if I'm putting that hat on for a moment and I look at your table, I walk away with a lot of equipoise. As opposed to being able to tease apart the differences between studies, I probably see more similarities. What do you think? How do you look at that table for intermediate or—?

Rini: I think that's right. When I look at that table again, when I've talked to the community oncology segment, a lot of them say, give IO-TKI for favorable-risk patients; give ipi-nivo for intermediate- and poor-risk patients. But if you look at the data on intermediate and poor risk, the IO-TKI regimens have as good or better data. Now again, I will grant that the long-term durability is not established for IO-TKI. We don't know whether they're going to meet that 30%, which it was for ipi-nivo — 30%, 31% — at 5 years. It's not. That's not the only important endpoint, but it certainly is an important endpoint and I think it will probably favor the dual immune therapy.

But the other endpoints — response rate, CR, PFS — I think all are as good or better with IO-TKI and the survival hazard ratio is the same, right? It's in the 0.6's — the mid-0.6s.

There are a lot of similarities. I think it comes down to what I mentioned before of finding a regimen you're comfortable with, just like in all of oncology, right? When you're giving a regimen for the first time, there's a learning curve. When do I hold? Do I dose-reduce? Do I not? Am I giving steroids here? And so on. That's just part of medicine, right? So I think really understanding a regimen well and, frankly, having your staff understand it well [is critical]. We all work with pharmacists and nurse practitioners who are doing most of the heavy lifting when it comes toxicity management, at least for me. So if I'm jumping around regimen to regimen, that's probably going to get fairly confusing for them and maybe we won't deliver optimal supportive care to those patients.

To your point of more similarities, they all extend survival. I think you could reasonably defend [either choice], and I'm not sure that A vs B vs C is that important.

Pal: As time goes on, I lean on something you said in the past: "Pick a TKI and use it well." That premise resonates with what you just said there.

So clinicians tend to have preferences frontline. I've gotten to know particular TKIs better than others. One thing that oftentimes comes up, though, when I'm talking to folks in the community — and this is taking off my clinical investigator hats — is that they've come to acknowledge some challenges with specific TKIs. Over time, people have gotten used to using axitinib frontline. Over time, people have probably gained some familiarity with cabozantinib at the higher dose. So using that lower dose of 40 mg, which is used in the frontline trials, has been a bit easier for them. But lenvatinib: In all the conversations that I've had (and this might be true in just my geographic catchment), this has been maybe a little bit more of an issue. We're dosing it at 20 mg in the upfront setting. I've used 18 mg, you've used 18 mg in the refractory disease setting. I find it to be a little tough.

Does that at all resonate with conversations that you've had with community-based oncologists? Are folks comfortable with the dosing in general and on the east side of town, there?

Rini: Not at all. The consistent feedback I get is that 20 mg is a difficult dose, and many start off-label with 14 mg or 10 mg. They take an axitinib-based approach of, let's start in the middle and go up if needed.

You know, it's interesting that all three of the TKI-based regimens that have extended survival took a very different approach to dosing. Axitinib-pembrolizumab, start in the middle, titrate up; cabozantinib-nivolumab, pick a lower dose than the monotherapy, as you mentioned; and lenvatinib-pembrolizumab, start high and come down. I think it was 75%, 78% of patients who had to dose-reduce lenvatinib in that study, if I remember the numbers — it was about three quarters. And those are trial patients, right? Those are very fit trial patients who can make it to the centers. I think in community practice, and in my own practice, I tend to start at 20 mg. I tend to follow the data, if you will. But I have a very, very low threshold to go down. We're in touch with those patients very frequently because it doesn't take long if they're going to get into trouble at 20 mg; boy, it doesn't take long to see it. Then I'll go see the next patient, who remarkably, has been on 20 mg for 3 months, who's cruising along with no side effects. So it's very different.

Pal: I want to bring this up specifically because one of the things that's come up in conversation is exactly what you had suggested — which is that there some folks out there who are starting at 10 mg, starting at 14 mg. And I'm not so sure that you can infer the same clinical benefit you're seeing in the phase 3 CLEAR trial if you're going to start with those lower doses. I have a little bit of skepticism around that. I'm wondering how you feel about starting low, and with what regimens?

Rini: I don't know. I've probably thought about TKI dosing almost every day for the past 10-15 years, and I still don't know what to do. I still don't think as a field we really know how to nail the optimal dose-exposure for patients. We've thought a lot about this. I agree that the data are the data, and it started at 20 mg and went down. Maybe you're giving up a little bit of response rate, some of that tumor shrinkage, and are you going to compromise their survival benefit by starting at 14 mg? Probably not. It's hard for me to believe that. We don't know. We'll never know, right? Those studies will never be done.

So I guess the counterargument is that I've had patients where I've started at 20 mg, and they get bad toxicity even if I stop it relatively early. Then their motivation to take any dose is zero. And they're like, "Hey, Doc, I don't want to go back on that drug ever again." So suddenly, maybe now they're just getting IO monotherapy — which although there are some good data out, there isn't a proven standard of care in this setting. So the counterargument is that at the end of the day, you want a patient to at least take some dose, some dose that they can tolerate. Ultimately, you hope it's enough to affect their tumor shrinkage, but you don't really know. So it's tricky. I do start at 20 mg, but I totally understand a different approach of starting lower.

Pal: That makes perfect sense. I can certainly see both sides of the equation there.

You alluded previously to triplet therapies. And of course, we see diseases like myeloma, where they're already at quadruplets and so forth. I always wonder whether or not renal cell carcinoma is getting there. Can you give us a sense of what's on the horizon, as far as you know, in terms of this additive approach?

Rini: We should have the results of the COSMIC-313 study, which is ipi-nivo-cabo vs ipo-nivo within the next year, I believe. That'll be the first to report. Merck also has a big frontline triplet study going on, which is len-pembro as a control, adding either CTLA4 inhibition or HIF inhibition. And then there may be others planned as well. I think those are the only randomized studies that I'm aware of. We'll have some results very soon.

I think we know that ipi-nivo-cabo will beat ipi-nivo based on response rate and PFS, right? Because cabo-nivo would beat it. So the real question will be about survival and will it extend survival? It'll be interesting. I don't doubt that [the triplet will beat the doublet]. My doubts are more centered around toxicity. You've given ipi-nivo, and you've given cabo — they both can be tough. I think putting the triplet together will be tough in a community setting. So I think the benefits are going to have to be substantial, which means a solid survival signal — the PFS and response rate, or let's say a CR rate of 20% or something really substantial. I think for the community to adopt the triplet given the toxicity, it can't be marginally positive. So it's interesting. I'm not sure when we're going to see the data, but it could be by the end of the calendar year.

Pal: I've been stewing over what the potential outcomes might be. You actually put out a poll on Twitter about this, right? You know, around COSMIC-313 and its potential results. Can you give us a sense of what that showed?

Rini: I asked three questions: 1, 2, 3. One was on the magnitude of survival benefit, and most respondents were in the hazard ratio of 0.6 to 0.7, maybe not surprisingly. I asked, if OS is negative, would you give it on a PFS benefit? And it was pretty much a resounding no, even out to 9-12 months of PFS benefit. I think 75%, 80% said that there has to be an OS benefit, to my earlier point.

And then the last one was, what's the most important endpoint: OS? A large PFS signal, a doubling of the CR rate, or something else? And again, it was an OS signal that won. I thought maybe doubling of the CR rate would get more votes. I could maybe convince myself with a marginal or no OS benefit, but a 25% CR rate. You know that you could see room for adoption in selected patients, but at least in this Twitter poll, as scientific as that is, that didn't get much weight.

So I think it's going to be really interesting to see those data. I have a feeling we'll be doing a lot of these debates and discussions once we see them.

Pal: I think it's a good hint toward what that conversation is going to look like a couple of months from now. So it's nice to have a little primer for that.

I wanted to close on something that you're doing that I think is quite pioneering. A lot of people have talked about prospective studies looking at gene signatures and kidney cancer. I think — correct me if I'm wrong — you're going to be the first to really explore this prospectively in your OPTIC trial. Can you tell the audience a little bit about that?

Rini: We're going to do a trial based on the IMmotion151 data that were published in Cancer Cell in summer 2020. Without going into too many details, patients were basically segregated patients into biologic clusters: two of them more angiogenic, three of them more inflammatory, and then two of them probably some other biology. We're going to determine a patient's cluster, determine presumably their underlying driving biology, and then assign them treatment based on that biology. So the angiogenic clusters will get IO-TKI; the immune inflammatory clusters will get ipi-nivo; and the other clusters, not part of that, won't be part of the study. It's to say, can we enrich the response generally speaking — objective response, PFS, et cetera — by applying what we think could be the appropriate therapy to the appropriate patients?

It's been challenging. We've spent well over a year just getting the informatics right and the mechanics, and we haven't started yet, but hopefully by the summer. So this study, I think, will be proof of principle number one. Can we do it? Can we do RNA sequencing and determine these biologic clusters in real time? Can we assign patients, and do we see a signal? If we do, then it sets the stage to do some more exciting, bigger studies involving novel drugs and regimens.

Then hopefully, it'll help transition us to an era where we're not giving empirical therapy, because everything we've talked about in the past 20 minutes has been all empirical. I like this regimen for this or that regimen for that, and I have my bias and you have yours and that's fine. That's a lot of medicine, but it's not terribly personalized. So we're hoping this study will help get us there.

Pal: One of the things I really like about your approach in this trial is you're integrating a lot of your junior faculty. Give the fellows in the audience a sense of what they should be doing at this point in time in their careers to put themselves on that same path. Maybe fellows and the folks out there that are a year or two in the faculty, what can they do?

Rini: The most important thing is finding a good mentor or mentors. It doesn't have to be in your institution. That was key for me. It's just somebody to provide you opportunities, introduce you to people, tell you where to allocate your time and effort. There's a lot of things you could be doing in a lot of areas that may not be as fruitful. That's, I think, what a good mentor does. There's nothing more satisfying than seeing your mentees succeed, and you've had a lot of that as well. I think you realize it's a way to impact the field far beyond what you can do personally. There's a limit to what you're going be able to do as one person. But when you have trained others and then they start succeeding, it sort of multiplies your success. So it's been very rewarding.

Pal: I couldn't agree more, and Brian, I want to extend a hearty thank you for a great conversation today on frontline therapy, and we want to thank our audience for listening to InDiscussion.


Bevacizumab Plus Interferon-alpha Versus Interferon-alpha Monotherapy in Patients With Metastatic Renal Cell Carcinoma: Results of Overall Survival for CALGB 90206

An updated table of the front-line IO combination RCC studies that have shown an OS advantage

Targeting PD-1 or PD-L1 in Metastatic Kidney Cancer: Combination Therapy in the First-Line Setting

Conditional Survival and Long-term Efficacy With Nivolumab Plus Ipilimumab Versus Sunitinib in Patients With Advanced Renal Cell Carcinoma

International Metastatic Renal Cell Carcinoma Database Consortium Criteria

Molecular Correlates Differentiate Response to Atezolizumab (atezo) + Bevacizumab (bev) vs Sunitinib (sun): Results From a Phase III Study (IMmotion151) in Untreated Metastatic Renal Cell Carcinoma (mRCC)

Nivolumab Versus Everolimus in Patients With Advanced Renal Cell Carcinoma: Updated Results With Long-term Follow-up of the Randomized, Open-Label, Phase 3 CheckMate 025 Trial

Lenvatinib Plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma

The Uromigos Debate: Treatment of Favorable Risk Renal Cancer

Health-Related Quality-of-Life Outcomes in Patients With Advanced Renal Cell Carcinoma Treated With Lenvatinib Plus Pembrolizumab or Everolimus Versus Sunitinib (CLEAR): A Randomised, Phase 3 Study

Study of Cabozantinib in Combination With Nivolumab and Ipilimumab in Patients With Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (COSMIC-313)

A Study of Pembrolizumab (MK-3475) in Combination With Belzutifan (MK-6482) and Lenvatinib (MK-7902), or Pembrolizumab/Quavonlimab (MK-1308A) in Combination With Lenvatinib, Versus Pembrolizumab and Lenvatinib, for Treatment of Advanced Clear Cell Renal Cell Carcinoma (MK-6482-012)

Twitter poll questions:

Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade

OPtimal Treatment by Invoking biologic Clusters in Renal Cell Carcinoma (OPTIC RCC)

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