Pedro Barata: Hello. I'm Pedro Barata. I'm a GU oncologist out of University Hospital Seidman Cancer Center in Cleveland, Ohio. Today I'm super excited to be here, joined by my friend and colleague Dr. Tian Zhang from UT Southwestern, who's Associate Director of Clinical Research at Simmons Cancer Center at UT Southwestern in Dallas. Tian, thank you so much for joining us.

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

Pedro Barata: We're here around ASCO 2025. Huge meeting, super important meeting, we're always excited to come in. And I'm actually even more excited and thrilled to be talking to you about the PDIGREE phase III trial. What an endeavor.

So congratulations, first of all, for presenting that data here. Fantastic presentation that you did. Maybe just a reminder for the audience, can you walk us through a little bit of the design? And I know it was a lot of work from over 10 years.

Tian Zhang: That's right. So thank you so much. PDIGREE is this flagship phase III adaptive trial that we've been running in the co-operative group's near, on, eight, nine years now, if you count all the concept, design, and ramp up. It officially opened in May of 2019, and we enrolled more than 1,000 patients over the last five years. So we finished accrual in May of 2024.

And so this meeting, I'm really excited to have presented the data on step one enrollment and step two. So the design is very much an adaptive design based on patients' responses. So all patients with metastatic, IMDC, intermediate/poor-risk disease who have not had any other treatments, systemic treatments, were allowed to come on. And in step one, they were given ipilimumab and nivolumab, similar to the CheckMate 214 regimen. We saw the overall survival improvement there.

And then after that three-month radiographic response, we either gave them nivolumab only for complete responses, cabozantinib only for progressive disease. Or for people who achieved stable disease or partial response, those patients were randomized to either nivolumab alone, per CheckMate 214, or cabozantinib with nivolumab. And our primary endpoint is three-year overall survival of that randomized cohort. So that's the premise of maybe we don't have to wait until progressive disease to escalate therapy a bit.

Pedro Barata: So beautiful concept. Super smart. We were sharing earlier today about a lot of people already have that thought process. It's like, why waiting for progression in scans?

Some patients we feel like we need to treat to intensify. But we got to prove it. Is that the right approach?

So from that perspective, it's a super elegant, well-thought-out design that really answers the question that a lot of us have in the field. And I would assume, obviously-- I can ask you a lot of stuff. I'll start by the effort that put together, over 1,000 patients, as you mentioned, really across the country.

It's a huge effort. Community, academia all came together in a role, and it speaks to how seamless the design is. And actually people want to be part of it because they wanted to be part of answering a question that everybody has.

So can you tell us a little bit about what have you learned actually from working for everybody, really, around the country? Almost all states were involved into enrolling patients to this study. So can you tell us a bit about that? What did you learn from that?

Tian Zhang: Sure. Huge effort. So supported by NCI Cooperative Group setting through the CTEP program. Alliance led the efforts. And so we were about 50% of our enrollments came from National Cooperative Oncology community oncology sites, so NCORP sites, we call them, and the other 50% from academic centers and regional centers.

So that's important, that we had a huge participation from community oncology centers. One of our partners out in Kaiser Permanente, Southern California, Dr. Helen Moon, she wrote it into their pathways. And so it was part of their pathways for treatment of metastatic kidney cancer.

And those patients who were coming in with intermediate/poor-risk disease went on trial, and so gigantic effort from everybody involved. And we couldn't enroll more than 1,100 patients without all of those people and investigators, more than 500 sites overall and open PDIGREE. And more than 450 investigators treated at least one patient, and about 20 people treated more than 10 patients in their clinics.

So that's the breadth of all the people that were involved in the huge effort that everybody put in across the nation. I was looking at a map of all the sites of where PDIGREE is open, and it was open at 46 states, including Hawaii as well as DC. And I was chuckling to myself because there's not red states and blue states. There's just green PDIGREE states. That's the concept of having something that's so good that we didn't know it at the time, but that helped to answer some questions that are pertinent for patients and for doctors.

I would be remiss if I didn't credit some of the patient advocacy groups in kidney cancer, the Kidney Cancer Association and KCCure, UroToday did a lot of publicity about this trial as it was launching in 2019. And I do think those efforts really helped spur that initial momentum and then continued.

Pedro Barata: Yeah. I mean, you were exemplifying really what it means for the entire community coming together. So between step one and step two, you basically have about three months, and you had not everybody make it to step two. And of course, one of the questions is, if you expect around 20% progressions based on the CheckMate 214 data-- so that's the first question. Is that what you saw?

Tell us a little bit because it sounds like a little bit over 20%, about 30% or so, if I recall the data correctly, end up not making it to step two. What have you learned from that? And why was that?

Tian Zhang: That's right. So initially when we designed the trial, we had statistical assumptions of about 10% complete responses, 20% progressive disease, like what we saw in CheckMate 214.

But along the way, we noticed a lot more attrition for adverse events. And about 40% of folks came off during step one due to adverse events. And it was all the expected immunotherapy-mediated side effects of colitis, endocrinopathies, liver dysfunction.

So those are things that you can't prevent. And so we tried to amend the protocol so that we would capture the most number of people. So we allowed people to have even one cycle of ipi/nivo, and if they had recovered within that 12 weeks, they could still go on to step two. But unfortunately, even those types of protocol modifications, some of the patients weren't quite ready to go to step two.

Pedro Barata: So just to clarify for the audience, basically for you to make it to step two, you would have to be eligible again to go on the maintenance nivolumab with or without cabozantinib. Is that correct?

Tian Zhang: Absolutely. So if people had a severe enough side effect, that they weren't recovered or eligible to receive more PD-1 therapy with nivolumab, then we wouldn't want them to be subject to the potential toxicity. And so they had to make it on within a window. And I think it speaks a lot on just the noise around adaptive phase III real-world trials.

The other portion that we learned was there were a portion of patients who-- I would say about a quarter of the patients who came off during step one came off because of progressive disease. Some of them died, unfortunately, within step one. So this was a sicker population than we would have enrolled to CheckMate 214, for example.

Pedro Barata: So this data will be even more valuable because it appears to be the best representation of the patients that we treat commonly in clinical practice, and not all of them are going to make it to the other trials that might be available.

Tian Zhang: That's right. Yeah.

Pedro Barata: So tell us just a little bit about the future. Everybody obviously will be interested in understanding exactly what the impact of being cabo not upfront. That question has been answered with COSMIC 313 and now the phase III, very important trial. In here, you're doing a three-month mark for patients who don't achieve a CR and, of course, have not progressed. So tell us a little bit. When do you expect us to see that data?

Tian Zhang: Yeah, so primary endpoint is still not ready yet. The events have not matured. So the longer we wait, the better for our patients. But I'm hopeful we'll see that data come out in the next one to two years, maybe 2026, 2027, just by modeling when these patients were enrolled and when we expect those events.

Pedro Barata: Gotcha.

Tian Zhang: I would say, on the representation front, that we were able-- because we were so spread out in terms of the sites that were open, that there are a good representation of racial and ethnic diversity within the country. So about 10% of our patients were Hispanic or Latinx, and another 8% were Black, Asian. Or we even had a few Alaska Natives and American Indians. We were open to Hawaii. We had some Native Hawaiians.

And so I think that also helps that representation of across the melting pot of the United States. Just when we were able to open at so many places, we get some representation across the board.

Pedro Barata: Right. Beautiful. And I'm sure that a lot of people are-- as they think about their academic careers and what kind of contributions they can make and what kind of groups they can be part of, I'm pretty sure a lot of folks are thinking about how the NCI groups, cooperative groups, Alliance, SWOG, and NRG, ECOG-ACRIN, how they can play a pivotal role and an active role in answering questions that we have in clinical practice.

So I'm pretty sure that it is actually your trial may trigger a lot of those thoughts. And I'm sure a lot of the younger and the future generations are joining the cooperative groups, and we need the help from everybody.

Tian Zhang: I hope so. You're leading a phase III in SWOG BioFront. And I do hope that as we ask these important questions that patients will want to contribute. But I do think that as we're asking those questions, we need to engage those patient advocates. We need to engage our community oncology partners and figure out which trials are truly feasible to enroll and really gathered those stakeholders early because, if people don't have equipoise or if our patients-- I mean, they're our decision makers.

So if they're not willing to go on trial, then it will be harder to enroll those trials. So I'm really looking forward to your BIOFRONT trial for probiotics in the first-line setting to augment our immunotherapies and these trials that industry potentially won't do right to answer these questions.

So I'm excited for you. And hopefully that also inspires more early career investigators to follow our path.

Pedro Barata: Yeah. Thank you for the shout out. I think it will be, again, another community taking it and leading the effort. That's the great thing about doing this as a group, as a team.

So congratulations. Really well done. There's a lot of lessons learned, and we are really, really excited for the next steps for PDIGREE. And so, really, thank you so much for taking the time and teaching us about it, PDIGREE, today.

Tian Zhang: Thanks so much, Pedro. Great to be here.