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Alicia Morgans: Hi, my name is Alicia Morgans, and I am a medical oncologist at Northwestern University. I am thrilled to have here with me today, Dr. Tian Zhang, who is an Assistant Professor of Medicine and a member of the Duke Cancer Institute, where she is the GU Medical Oncologist. Thank you so much for taking the time to speak with me today, Tian.

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

Alicia Morgans: Well, I am excited to have you always, but today, really excited to talk about the PDIGREE Study, which has been a real labor of love on your part, and I know Toni Choueiri at the Dana Farber, and many others really collaborating to make this trial for kidney cancer come together. Before we get into the details of the PDIGREE trial, I'd just like to hear your thoughts on the current landscape, which is really complicated in kidney cancer at present, and why a study was really even necessary, because there's a lot going on, and I think there's a real need for further investigation, so what do things look like and why is this trial necessary?

Tian Zhang: Absolutely. As you and most of our audience know, in the past year and a half we've had three new approvals for first line treatment of metastatic renal cell carcinoma. This is really an exciting time in kidney cancer, where we have cabozantinib with targeted agents, we have ipilimumab, nivolumab, a combination immunotherapy, and also, the combination of pembrolizumab with axitinib now approved in April of 2019. And so, with all of this, these agents it's really an exciting time for patients but also we want to know, can we improve outcomes? In February we heard the 30-month survival follow up for the CHECKMATE 214 study of ipilimumab and nivolumab where the survival benefit for nivo and ipi combination really was significant in patients with intermediate core risk renal cell carcinoma.

And we knew that from that 30-month follow-up, the complete response rates and what I think people are excited about for ipilimumab/nivolumab combination, the complete response rate was 10.8%. However, of these patients, there's still about 20% of patients who progress on immunotherapy combinations and we can always do better for those patients who have stable disease who ultimately then develop progression later on. We know from the CABOSUN Trial, which always led through the Alliance Cooperative Group that cabozantinib also has a progression free survival improvement compared to sunitinib in the upfront setting.

Finally, in the pembrolizumab/axitinib data was presented at GU ASCO this year showing both overall survival and progression free survival improvements. And in that trial, it hasn't been broken out by risk groups but the complete response rate for all-comers was about 5.8%. And so, we're really trying to improve upon outcomes and this PDIGREE trial is really the first trial that does not have a sunitinib control arm where we're really adapting based on our contemporary practices of immunotherapy combinations being adapted by the response to randomized patients to a combination beget with the immunotherapy versus immunotherapy alone.

Alicia Morgans: Yeah, exactly. What I love about this trial and we're going ask you who those patients are that might be included and what the schema looks like and what happens to patients when they're in the trial in just a moment. But what I love about the trial is that it's not only trying to certainly improve survival in metastatic kidney cancer, clear cell kidney cancer but it's also trying to enhance the complete response rate and then also trying to say, "Hey, if patients are responding, can we back off, can we stop treatment, is there a way to really optimize the utilization of these medications to improve efficacy but also reduce the side effect burden."

So, it's a really... and of course as we've said we've gotten rid of the sunitinib control, so it's a really smart trial and a trial that I think is incredibly timely. So, who are the patients who might be eligible for the PDIGREE trial?

Tian Zhang: Yeah, we're specifically focusing on metastatic clear cell kidney cancer without prior systemic therapies. And we're specifically focusing on the intermediate and poor risk renal cell carcinoma patients that fall in the IMDC criteria and those patients in particular benefit from the combination immunotherapy approach upfront. So, those are the main patients that we're including in PDIGREE.

Alicia Morgans: Great. And so what's the treatment that these patients will receive when they enroll?

Tian Zhang: Yes, everyone starts with the combination of ipilimumab at one milligram per kilogram every three weeks as well as nivolumab, three milligrams per kilogram ever three weeks. And so these are given for up to four cycles, given a real-world approach, we know that not everyone needs all four cycles of combination immunotherapy. Some of these patients may develop toxicities and so we built into this study also the possibility of patients who actually develop toxicities and need to come off the combination, they can and as long as toxicities improve to grade one or less we allow them to continue on with the study.

Alicia Morgans: Great, so what's the adaptive part of design after the ipi/nivo?

Tian Zhang: Yeah, so this induction phase after patients are complete with that, we really adapt based on responses at around three months or the twelve week scans. Patients who have complete responses already after the immunotherapy, those patients should not be subjected to more toxicity of the combination therapies. So, those patients just continue on to receive nivolumab monotherapy. Patients with progressive disease after three months, those patients really shouldn't be randomized to immunotherapies. So, they go on to receive cabozantinib at 60 milligrams daily. And that will actually provide us some information about sequencing approaches of nivo/ipi upfront followed by cabozantinib.

The remainder of these patients, patients with non-complete responses and non-progressive disease, those patients will be randomized to receive either nivolumab maintenance, so 480 milligrams every four weeks or the combination of nivolumab, 480 milligrams every four weeks with cabozantinib 40 milligrams daily. And so this is really adaptive design based on clinical responses and radiographic responses at the three month mark.

Alicia Morgans: Fantastic. So, if patients have a complete response say after some of these treatments, do these patients stay on therapy or have you built in discontinuation for those patients?

Tian Zhang: Yeah, Alicia, I think this is one of the first trials we have in kidney cancer where we've actively built in a discontinuation for complete responses and we've done that for patients who have complete responses at one year. So, whether that's on the nivolumab monotherapy or randomized to the nivolumab with cabozantinib combination. Everyone who has a complete response at one year, we're asking patients to discontinue treatment. And this is really important because we really haven't had a lot of studies looking at discontinuation of these immunotherapies, most studies are treatment until progression of disease and we all know that toxicities form immunotherapies can occur at any point along the way and even up to a few months after stopping therapy.

So, I think it's really important to think about how long we're keeping patients on treatment and how long is enough to sustain those treatment responses. And so we do discontinue treatments also if patients have another progression of disease or unacceptable toxicity but the one I'm really excited about the endpoint the complete responses at one year.

Alicia Morgans: Like I said earlier, I think that that's really a really important and also fantastic and unusual aspect of this trial and as people are listening I think that's one of the things that patients will also be most interested in. And we are all interested in not exposing patients to extra treatment that they don't need, so really a critically important question. Some of the other important things that you're answering are going to be coming out of correlative, so what other markers or different tissue based or other assessments are you doing to really just continue to make this study more valuable for us as we interpret the results?

Tian Zhang: Right, so we currently plan a number of tissue-based markers such as PDL-1 status and because cabozantinib targets the MET receptor, we'll look at met as well. We're thinking about doing DNA sequencing for things like tumor mutational burden and neoantigen load and if that could predict for responses, we will eventually do things like RNA sequencing for gene expression profiling and immune subtyping and really think about how these patients fit into predicting for responses to immunotherapies. And then finally, we're thinking about doing tumor infiltrating lymphocyte evaluation for regulatory T cells and effector CD8 T cells.

From a circulating plasma marker's perspective, we're looking at IL-6 based on prior work that's been done in the cooperative groups as well as through industry studies as well as other cytokines or angiokines that are in the bloodstream. We'll look at germline DNA and also evaluate circulating tumor DNA and then finally we're collecting peripheral blood, mononuclear cells to profile the peripheral immune cell phenotypes of these patients.

We're collecting a variety of quality of life for surveys for these patients for our own treatment and hoping that these patients have similar quality of life on combination treatments versus immunotherapy alone. And then finally we will be centralizing imaging studies to look at other qualities for predicting treatment responses to these immunotherapies.

Alicia Morgans: Great, so I think everyone listening I'm hopeful, clinicians, patients alike, will be interested in potentially getting involved in this trial if they have metastatic clear cell kidney cancer. How many patients do you need and how do patients get involved if they are interested? Do they have to come to Duke for this trial?

Tian Zhang: Absolutely not. This is a cooperative group trial sponsored by the CTEP program and NCTN. It will be posted to the NCTN website next week, May 9th is our target date and we are looking for a large number of patients for this study. We need to randomize right around 700 patients to meet our primary endpoint of evaluating and improving three year overall survival and to do this we will have some drop out from the complete responders and progressive disease patients and so we're projecting a number around 1000 to enroll for this trial to be successful. And to do that we really need the engagement of everyone in the community who will open these cooperative group trials as well as academic centers.

And patients can get involved by really asking their medical oncologists whether this is an option and if there might be a center close by that does enroll patients in cooperative group trials. PDIGREE will be open and it's already been approved through these the central IRB and also the CTEP program and so I really hope that it will be available quite broadly to enroll patients with clear cell kidney cancer.

Alicia Morgans: Absolutely. So just really to emphasize that this is a cooperative group clinical trial which means that it's open at many sites. Hopefully, at least in the many 10s of sites if not 100 sites or more across the country supported by the National Cancer Institute. A coming together of oncologists and patients across the country to answer these question for our patients, large trial. If you're eligible or if you want to see if you're eligible, or if you are a physician and you have patients who might fit this category or fit these criteria, think about reaching out. Find a place near you because in most settings there is going to be a center pretty close, at least reasonably close, we hope, where you can get involved in this trial.

I think it's a smart study. I think it's answering questions that are critically important to these patients and it's not all about can we throw the kitchen sink at you, but it's really about how do we tailor these treatments to the responses that we see. And then how do we use the correlative science to predict in the future, predict who these patients are going to be before they even start treatment. So, this is really important work but it's going to take a lot of work, clinician work, patient work, 1000 patients that we have to look at to try to get the 700 who need to be randomized.

So, let's get going. And thank you so much, Tian, for sharing your insights on this trial and for your work putting it together. Do you have a closing thought or closing message to the folks who are listening?

Tian Zhang: I just really appreciate being able to engage and talk with everyone and certainly I am available if anyone has any questions about this trial and the timelines but I'm hoping will be activated soon and we will be able to start recruiting patients in the near future.

Alicia Morgans: Great. So this is the PDIGREE trial, look for it on clinicaltrials.gov, look at it on the NCTN's interface and try to think about this study for all the patients listening and for the clinicians, get your patients on this trial. It's really an important one. Thank you for your time, Tian, and have a good day everybody.