Jaime Landman: Welcome to another episode of Kidney Cancer Today. It's Jaime Landman from the University of California Irvine, and I'm here as always with my good friend and oncologic mentor, Dr. Monty Pal.

Monty Pal: Thank you, Jaime. How are you? Really excited to kick this show off. I have one of my really good friends and colleagues, Brad McGregor, here on the line. Brad and I did the ASCO Leadership Development Program together, which is a year long curriculum. We really got to know each other very well, and he has just had a remarkably, astronomical rise in the renal cell carcinoma space. In fact, we're catching him now, not at the Dana-Farber Cancer Institute in Boston, which is his home, but rather in Brazil. Brad, how are you?

Brad McGregor: I'm doing well. Glad to be here.

Jaime Landman: Well, why don't I kick this off, Brad. You have really been in the midst of a number of big trials in advanced renal cell carcinoma. What are some of the practice-changing studies that you've seen come out over this past year?

Brad McGregor: I think really you go back about three years ago. At that point, sunitinib and bisphosphonates was the standard of care. And then since that point, we've had this evolution of therapy. First, with CABOSUN data showing improvement in progression-free survival with cabozantinib, the enemy of poor risk disease, and then nivolumab and ipilimumab showing an improvement in overall survival in those intermediate porous disease, and then CheckMate 214. And then, the past year we've had two different approvals in the United States with both avelumab and axitinib at as well as pembrolizumab and axitinib both showing an improvement in progression-free survival across all risk groups with the combination of pembrolizumab and axitinib showing improvement not only progression-free survival but also overall survival across all risk groups. So really there's been a remarkable change in the therapies available for our patients in the frontline setting.

I guess sort of delving down to the details of these different trials. I think when we look at the three major trials and combinations starting with nivolumab and ipilimumab, while that was presented back in 2017 where we have seen in the last year is sort of some updated data on the durability response. So with prolonged follow up, we've seen that those patients should do respond, have a very durable response. So specifically looking at those with intermediate and poor-risk disease for the duration response over 18 months is 52% versus 28%, and those who had a CR, nearly 90% of those maintain that CR at that over 18 month followup. So it really shows that in those patients who do respond, this is a very durable, durable response.

Jaime Landman: So Brad, just a great summary, but what is your kind of first-line approach to good risk disease?

Brad McGregor: So I think for good risk disease, it really comes down to a discussion with the patient. And when we look at nivolumab and ipilimumab, it is only approved in those patients with immuno-porous disease. Because when we looked at the initial data, even the updated data, there tends, seems to be a trend towards improvement in progression-free survival and overall survival, would those patients receive sunitinib therapy versus immunotherapy? That being said, even those patients with good risk disease responded nivolumab and ipilimumab and there was a chance for a complete response.

So it comes down to a discussion with the patient about nivolumab, ipilimumab versus TKI, but now with the advent of TKI/I-O and with pembrolizumab and axitinib and axitinib avelumab, both showing an improvement and progression-free survival and pembro actually showing an improvement overall survival. There's another option as well. So when I meet with my patients, I really talked about three options that would be TKI alone, nivolumab/ipilimumab, or the combination of pembrolizumab and axitinib with a combination pembrolizumab and axitinib showing improvement in overall survival. Even though it's a good risk disease, I'm much less inclined to offer TKI alone at their adjuvant immunotherapy, and I really have a discussion between pembrolizumab, axitinib, and nivolumab, ipilimumab.

Monty Pal: And Brad. I've got to just point out that you didn't mention axitinib with nivolumab. What are your thoughts on that in terms of...

Brad McGregor: I think axitinib is approved, and I think it did start an improvement and progression-free survival, but at this point, there's no improvement in overall survival. And so we're going to have two different regimens. One that has improvement to overall survival and one that doesn't, I'll talk about the patient with that. I think with longer followup that may change as we get continued followup of the JAVELIN trial, we may see an improvement in overall survival.

And then that would certainly be something I would strongly consider my patients. Because when you do look at that data, it does seem to be a relatively well-tolerated regimen, and we don't have all the data for toxicity, how many patients needed steroids, and those patients who received the combination of pembrolizumab and axitinib. But we do know in those who received the combination axitinib and nivolumab only 11% of patients required high dose steroids, which is comparable to that with what we saw with atezolizumab and bevacizumab. It seems to be a well-tolerated regimen and so with longer follow up there is an improvement in overall survival. I think that would be something that's very compelling.

Jaime Landman: Brad, really. Thanks for that summary. That's awesome. A quick question and maybe it's not so quick, are there any biomarkers that you're using or you think we can use to optimize these treatments?

Brad McGregor: Not yet. I mean I think there's been a lot of very elegant work that's been looking at trying to establish biomarkers for response in different gene signatures. We have publication from Dave McDermott and looking at the combination of atezolizumab and bevacizumab, looking at those different markers, the myeloid-rich and framed environment and really seeing who benefits and the combination versus immunotherapy alone. Tony Choueiri presented some data on biomarker axitinib/nivolumab at ASCO this year. And while I think all that is very interesting and hypothesis-generating, I don't think at this point in time we can use any biomarkers that are clinically available to help us decide which therapy we should choose. You are really left with, you know, still using INDC misclassifications to help us sort of assess, first off are they immuno-poor risk where we're moving more towards I-O therapy and less away from TKI and monotherapy as well as just their ability to tolerate therapies and what side effects they should expect.

Because while nivolumab and ipilimumab certainly has the highest rate of mean high dose steroids over 35% required high dose steroids, 60% required some form of steroids. You know, it tends to be a situation where you do the four cycles and then you're on maintenance nivolumab as opposed to when you look at something like the TKI/I-O combos, once you start those, that TKI/I-O, the way the trial design, you started continued them both indefinitely and the decided profile is different in terms of what the patient undergoes and how they feel.

Monty Pal: So, let me ask you another controversial question, that was a great discussion of biomarkers. But one thing I hear a lot of oncologists and practice saying is that look, I've got nivo/ipi I can put that on the back burner and use it as second-line treatment. Is that something that you're doing in clinical practice? What do you think of that approach?

Brad McGregor: So I mean I think we really, the idea of we need more data. Can we rescue patients who fail I-O alone, our IoT guy with nivo/ipi, I think we don't really, we don't really know that answer. So I think that is something that really ... I think ongoing trials may be addressing that, there's an ongoing trial right now looking at patients start with nivolumab and then on progression we're getting nivo/ipi back to patients. I think that'll be interesting to see is there a chance for [inaudible], but I think right now we don't know that. I do think that with the data we have at our disposal showing that both TKI/I-O combination proved PFS and that I-O/I-O combinations improve PFS and OS that if a patient's eligible for immunotherapy it really should be a part of their first-line armamentarium.

Jaime Landman: So I'm going to ask a question for both you Brad, as well as for Monty. I think never has it been more important that we take a collaborative approach, basically, a multidisciplinary approach and you guys are shooting out a lot of data. I think there's a lot of non-oncologists who also are interested in this topic and are participating in the care of these patients. How do we keep up with all this information? Obviously I cheat, I call Monty all the time, and get the leg up on what I should be doing. But in terms of my being able to keep up with these patients when I'm seeing them watching out for their complications, knowing the side effects of all of these different strategies, you guys have a resource or a place you think that is good to keep up?

Brad McGregor: So I think podcasts such as this, I mean I think opportunities just to hear people chatting about these regimens and their experiences with regimens are going to be a really helpful resource because you can read through the studies and note what the complications are, what their rates are, but you know, hearing someone talking about how they deal with the complications and what they look for I think is going to be incredibly helpful and just working with their colleagues as well.

I mean I think for instance the combination of TKI and I-O, while it's certainly very appealing, it has a very different toxicity profile than I-O alone. There is the nuance of when you have a side effect, which is it? Is it the I-O side effect, is it a TKI of side effect? That's only something that comes with, sort of, experiencing the regimen and sort of an understanding of, okay, well extended has a very short half-life, so I can stop that if symptoms go away within 24 hours, the half-life, which by then it should be cleared on the system, then it's likely TKI, not the I-O as opposed to the diarrhea gets worse with cessation of axitinib that could be the immunotherapy. So I think it really comes down to sort of discussion with your colleagues. Things such as the podcast and available guidelines to help guide your treatment decisions.

Jaime Landman: Yeah, I think you're right, this is one of the reasons we do this podcast, but I wish that we had more venues because there's some subtleties as you alluded to that make it sometimes challenging to do the right thing. I'm going to go in a little different direction with my next question. As you know, and I think urologists sometimes forget kidney cancer is not a disease but rather a series of different diseases. What's your first-line approach to nonconventional or clear cell carcinomas?

Brad McGregor: I think for non-clear cell carcinoma we know that unfortunately stage for stage they do worse than their clear cell counterparts and for a while we were relying on data showing that it enabled the standard of care because it'd be [inaudible]. I think in the past year we've had some major developments in non-clear cell RCC books and at GU ASCO. So one was the Phase II data of pembrolizumab showing that single-agent pembrolizumab has activity in those patients with advanced non-clear cell carcinoma. Then there was also what we presented a Phase II study looking at a combination of atezolizumab and bevacizumab, while this is not approved by regulatory agencies, the combination did show efficacy in non-clear cell renal cell carcinoma across subgroups including things such as collecting duct and medullary that are often underrepresented with a meaningful response rate in progression-free survival.

So it supports the idea that what the advances we're seeing in clear cell renal cell carcinoma using I-O therapy using I-O VEGF approach, there are applicable in the non-clear cell space as well. With the current data on outside of a clinical trial, which there's several ongoing such as Monty's trial looking at PAPMET. There's also the ongoing trials with cabozantinib/atezolizumab that are ongoing. I will often think about using an immunotherapy-based approach, either nivo/ipi or with given our data by the atezolizumab/bevacizumab using any I-O VEGF combination.

Monty Pal: Oh perfect, Brad. I think you've really taken us through a whole host of issues that are relevant in advanced renal cell carcinoma, front line therapy, non-clear cell disease. You really walked us through considerations around biomarkers, great perspective here, and I hope you'll join us on the program with that again. Jaime, I'll turn it over to you to sign off.

Jaime Landman: Right. Again, I just want to echo what Monty said. I want to thank you for a great summary and really catching us up. I do have to say I'm incredibly impressed cause I have trouble saying the names of the medication quickly as you do. I think that's probably one of the most challenging aspects of this field. And with that, we'll end. Thanks again, Brad McGregor. Outstanding job. Thanks so much.

Brad McGregor: Thank you.