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Monty Pal: Hi, I'm Monty pal. I'm a medical oncologist at the City of Hope Comprehensive Cancer Center and I'm here on behalf of UroToday to interview someone who I think is a superstar in the world of GU medical oncology. I follow her on the daily, on Twitter and it's just wonderful to be sitting across the table from her, doctor Tian Zhang from Duke. Welcome.

Tian Zhang: Thank you so much for having me, Monty.

Monty Pal: So Tian, tell us a little bit about your perspectives on renal cell carcinoma and specifically this really evolving frontline landscape.

Tian Zhang: Yeah. I think it's super exciting, first of all, that we have so many options for our patients these days in first line treatment and now we have four different options that are really great. You have three that are immunotherapy- based ipilimumab, nivolumab, we have pembrolizumab, axitinib, as well as avelumab/axitinib combinations. Then we have cabozantinib too for these patients in the frontline setting. What really separates these treatments, I think is the disease setting, right? Right now we're basing that on IMDC criteria for risk stratification. Thinking about who might benefit from what treatment. We saw that the nivo/ipi combination really slam dunk, right? Of the 30-month follow-up, we saw a great overall survival improvement in that intermediate poor-risk patients. Then, the complete response rate was 10.8% in that population. So, we kind of contrast that with the KEYNOTE data and the JAVELIN data that had been presented and now approved for frontline use.

In thinking about that favorable risk population where nivo/ipi really didn't show as good a benefit as to sunitinib itself, these combination strategies, the favorable risk patients seem to be a bit more angiogenic driven, right? Dependent on their androgenesis pathway, some of the canonical sort of the VHL loss of clear cell kidney cancer that really helped us understand the biology right, and how to target these patients. Adding axitinib with, with pembrolizumab in that setting or with avelumab in that setting seems to really increase the responses of favorable risk patients.

Brian Rini is going to present some great data from KEYNOTE 426 about this subset analysis and in particular about intermediate poor risk patients and also in the sarcomatoid population from that trial. I think, kind of thinking through those complete responders, we'd love for these metastatic patients to get to a complete response.

So, can we optimize these complete responses? So, if we look at the intermediate poor-risk group of KEYNOTE 426, the complete response rate there is about 4.8% so certainly not as high as ipi/nivo for that intermediate and poor-risk patients, but if you think about the reverse side of that, we know that in all comers the CR rate was 5.8%. I think the CR rate for KEYNOTE was actually driven by favorable risk patients. I think this is an interesting perspective to think about. You know, should we tailor that favorable risk patient to a combination approach, who can benefit from that and get to a complete response? So, I'm really excited to see that data, how it pans out, and how we can apply it to our practice for the patients that we see in the clinic on Monday morning.

Monty Pal: Well I think that was a really thoughtful overview of the current landscape. You know, just for our UroToday viewership, if you're seeing that newly diagnosed patient with intermediate or poor-risk disease, is the consideration universally then for nivo/ipi in that particular context, in your opinion?

Tian Zhang: In my opinion, to optimize complete responses. I use a lot of the ipi/nivo in that setting. You know, we have cabozantinib also approved in that setting. So, there are some patients who I think may really benefit from a very directed approach or bone met patients for example or patients who have metastatic disease in a very critical spot. So vertebral met for example with epidural extension, or something in the retroperitoneum that might block the biliary tree, or cause hydronephrosis. Those are the patients who I'm worried about. Maybe there's some inflammation in the tumor microenvironment and can cause obstructive symptoms or can cause cord compression. In those cases, those are the patients I favor using a monotherapy like cabozantinib, but the majority of my patients, absolutely the standard of care I think is still ipilimumab/nivolumab to optimize this complete response rates.

Monty Pal: I tend to side with you there. I can't think of much of a different perspective from my end, but take me through that patient, you know intermediate, poor-risk disease, you started them on nivo and ipi, what do you do in terms of response assessments? What would you offer that patient if he or she has stability or progresses?

Tian Zhang: Yeah, I think this is where I'm really excited about our front-line trial that we've designed in the Alliance Cooperative Group and that's now activated throughout the National Clinical Trials Network supported by the NCI. So, we start out with this induction of ipilimumab and nivolumab and then it's an adaptive design at the three month imaging assessment. So, the complete response patients go on to receive nivolumab alone. The progressive disease patients go on to receive cabozantinib alone and everybody in between. So the non-complete response, non-progressive disease patients, they get randomized to either nivolumab or nivolumab with cabozantinib. We're still optimizing that frontline ipi use and the potential for that CR rate, but also integrating and adding in cabozantinib early during that maintenance phase. What I love about the trial, it is powered on overall survival, but there's a key secondary endpoint of one year complete response rates and really optimizing these complete responders.

We would love more prospective data on who we can discontinue treatment on. Right now my practice has been to think about it after a year or so of treatment, but it's really hard to get prospective data. So as part of this trial, we've designed it to discontinue treatment for all patients with complete response at one year, including the patients who are on the nivo/cabo arm of the trial. So, I'm hopeful that we will increase our complete responses that we see, as well as now potentially to improve treatment-free intervals. Wouldn't it be great if we can get a patient to a complete response taking them off treatment and really improve quality of life with treatment-free survival intervals?

Monty Pal: That's such a brilliant design, and of course, what I love about the NCTN mechanism is that almost all individuals across the country are going to have access to this. You know, if you're at a community center, there's likely going to be some of the in corpse that is available, etc. So hopefully this is a study that we can all contribute to and get done very quickly.

Tian Zhang: Absolutely. I'm really excited. We just activated in the NCTN, in early May and we're about to see the first sights, about to start opening pending regulatory processes. So, as you say, community sites, academic centers, everyone will have access to this trial.

Monty Pal: Do patients need to have nephrectomy up front in order to participate? Can they go in with a kidney intact?

Tian Zhang: Yeah, absolutely. So we don't specify, if they've had a cytoreductive nephrectomy, great, if they haven't, we still allow those patients on study. There's updated information about CARMENA as well, that will be presented on Monday. I think these patients who... Where we've gotten cytoreductive nephrectomy data from was really in the days of interferon and now that we've had more and more systemic therapies that are very active, cytoreductive nephrectomy may not need to happen when we can stabilize the systemic disease and then potentially offer them consolidative nephrectomy. So the CARMENA abstract actually says that the patients who go on to do sunitinib first and then go on to have a consolidative nephrectomy, those are the patients who have the best outcomes. So, if we can layer our systemic treatments first and stabilize disease elsewhere and then get them a consolidated nephrectomy, I think this is one of the ways we can optimize our approaches.

Monty Pal: Yeah. Cause the CARMENA data to me really signifies this sort of process of natural selection if you will. You know, you have those great responders who go on to have surgery and then do well beyond that. Makes a lot of sense. What about brain mets? Are you allowing brain mets on your study?

Tian Zhang: Yeah, we do allow well-controlled brain mets who have finished their radiation for example, or have had a surgical resection and then not on treatment for the last two or four weeks. So, we give them a recovery time, but we do allow those patients as well.

Monty Pal: Very good. I think that's important. The last eligibility question I have for you is pertaining to histology. Can they have a smidgen of papillary too or sarcomatoid features?

Tian Zhang: We ask for clear-cell component, but if they have a small fraction of papillary, that's fine. If they have some sarcomatoid features, the CheckMate 214 data really suggests that sarcomatoid patients do well with ipi/nivo up front. They have 18% complete response rates. So we welcome those patients as well.

Monty Pal: You know, I've had an increasing number of patients, actually watch sources like UroToday, etc., and they've approached me about studies after the fact. If there's a patient watching this and they're interested in the trial that you're proposing, what's the best way to get more details about its availability in their area? Any tips on that?

Tian Zhang: There is a page on clinicaltrials.gov and we are being featured in the KCA as well as KCCure, these advocacy groups. So there's multiple ways to have access, you know, our network of sites and understand who's open at what time. So I assume with the regulatory processes being the way they are that some of our community sites will actually open sooner than the academic centers, but we are activated and certainly, anyone who wants to download the protocol from the NCTN website can do so and start that process.

Monty Pal: That's excellent, and congrats on the study. My last question for you actually is only loosely related to kidney cancer.

Tian Zhang: Okay.

Monty Pal: But I was sitting down at a table here at ASCO with a bunch of junior faculty and trainees in the training room, and I was fielding their questions around their career development, etc.

Tian Zhang: You being the great mentor that you are, I'm sure you had some great advice for them.

Monty Pal: I hope so, but I sort of stumbled in terms of my response to one question and that is how should they perceive their interactions with the cooperative groups? I mean you've been very successful in developing PDIGREE very early on in your career and now taking it to trial opening. What's your advice for folks who have an interest in a career as a clinical trialist and want to utilize the cooperative groups?

Tian Zhang: Right. I think I was at the new investigator meeting this time at the Alliance and Monica Bertagnolli, of course, sits as our chair for all of the Alliance. So, she had had a really nice introduction for new investigators. Her advice and I would think the same, is really be persistent, and come to the meetings, and really cooperate and talk, right?

Talk to them, the group chairs that they're interested in, and if you come often enough and be there for enough sessions, and really help with other ongoing proposals, as well as your own ideas, these young trainees and junior faculty can really start to rise up through the ranks and lead their own trials. That's really what cooperative groups are meant to do, is really to foster the junior faculty in leading their trials.

I know I've really benefited from that with Dan George being my mentor, and really designing this trial so that it would fit into a landscape, even as these VEGF IO therapies are coming on board. I think this trial still has a relevant place and you want that from a mentor perspective, right? So, if these young people have identified great mentors in the field, they come to the cooperative group meetings and then little by little start to lead their own trials. I think it's a really great mechanism to foster young careers.

Monty Pal: I think that's brilliant advice and I'm going to use that in my next discussion. Do you want to be good in the cooperative groups? Cooperate. That's very intuitive. It makes a lot of sense. Yeah, that was perfect. The only bit of advice that I gave them in common with you is to show up and I totally agree with you. You gotta be there.

Tian Zhang: You gotta be there to actually see it and the development, right? PDIGREE took four or five years. You know, we started talking about this when I was a fellow and it's now really gratifying to see it activated.

Monty Pal: Well, congratulations. I'm so insanely proud of you. Thrilled with this huge accomplishment and I wish you all the success in this study. Congrats to you.

Tian Zhang: Thank you so much.