Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, a friend and colleague, Dr. Tian Zhang, who is an Assistant Professor of Medicine and a GU medical oncologist at the Duke Cancer Institute in North Carolina. Thank you so much for being here with us today, Tian.

Tian Zhang: Thank you so much for having me. I'm excited to talk with you.

Alicia Morgans: Wonderful. So, I wanted to talk with you about your PDIGREE trial and, of course, also a little bit about the evolution of how we got to PDIGREE and where things stand now in the landscape of kidney cancer. Can you tell us a little bit about it, please?

Tian Zhang: Sure, absolutely. So as you know and as our listeners know, the landscape for kidney cancer really has changed dramatically over the last two to three years. PDIGREE itself has been open since May of 2019, and at the time of study opening, pembrolizumab and axitinib, as well as avelumab/axitinib combinations had just been approved. And now over the last past 18 months, they've been integrated into first-line treatment guidelines and practice patterns. But we think PDIGREE has more relevance now than ever, and we've had pretty steady enrollment and accrual, even through 2020 COVID times.

Alicia Morgans: Could you tell me anything about how things have changed or any developments related to CheckMate 9ER, reported at ESMO 2020? Did that impact anything?

Tian Zhang: Absolutely. So CheckMate 9ER is particularly relevant to PDIGREE because it did report on the efficacy of the combination of cabozantinib with nivolumab. And at ESMO 2020, Dr. Choueiri showed us that CheckMate 9ER had an improvement compared against sunitinib for patients with metastatic renal cell carcinoma in the first-line setting. The overall survival hazard ratio was 0.6 and progression-free survival hazard ratio was 0.51, both of which were statistically significant. And of note, cabozantinib nivolumab had an objective response rate that was around 55.7%, compared to just about 27% for sunitinib.

Building on CheckMate 214, which was the combination of ipilimumab nivolumab in this upfront setting, as well as CheckMate 9ER combination of cabozantinib/nivolumab, PDIGREE is enrolling patients with metastatic kidney cancer, no prior treatments, as well as IMDC intermediate and poor-risk disease. All patients are treated with induction ipilimumab/nivolumab every three weeks for up to four cycles. Then depending on their post-induction responses, then they're randomized to either nivolumab or nivolumab with cabozantinib. Patients who are randomized to these cohorts are treated until disease progression, unacceptable toxicities, or complete responses at one year.

While the primary endpoint is the three-year overall survival, we have key secondary endpoints around progression-free survival, objective responses, as well as the complete response at one year. And of note, this is the first, I think, kidney cancer trial that has prospectively discontinued treatments based on complete responses. I think that's a clinically meaningful endpoint as well. So building on the primary endpoint of three-year overall survival, our statistics are calculated and the sample size needed to randomize is 696. Then accounting for the differences in responses as well as dropout for toxicity, our potential number needed to randomize is about 1,046. So we have a ways to go, but it is enrolling quite well and steadily.

Alicia Morgans: That's fantastic. Can you tell us how many patients currently are enrolled?

Tian Zhang: Sure. As of December 2020, we're almost around 300 patients enrolled. Many of them are still in the induction phase, but we're excited. We're enrolling pretty steadily and each month we're seeing 20 to 30 patients come on. This is a really great testament to the NCTN network of clinical sites in terms of keeping up with the accrual rates.

Alicia Morgans: Absolutely, and we'll make sure that we have the clinicaltrials.gov information on the site that you wrote today so that people can take a look and certainly send patients to a nearby open center if they don't have it open where they are. Really, this is a phenomenal study, as you mentioned, I think particularly because of this planned discontinuation. We always want to try to limit our patients from having toxicities. If they're not necessary for disease control, why would we want to continue therapy? So a fantastic design and we are well on our way to getting the answers that we need for our patients. Part of this whole process though, of course, is adapting if we need to, to ensure that we continue to maintain feasibility of the study and, of course, update as the landscape changes. There were a couple of amendments I think that you've been working on or at least one amendment. Can you tell us a little bit about that, please?

Tian Zhang: Sure. Our new protocol amendment was actually just approved by the central IRB and CTEP and we will likely be implementing and rolling this out in January of 2021. But the first major update was our implementation of iRECIST criteria. So with all immunotherapy trials in the Alliance, iRECIST criteria are being implemented to assess disease response and tumor response. This is a difference in criteria to assess for tumor response compared to the prior RECIST criteria, which were used really in the era of cytotoxic and targeted treatments. And so with immunotherapy, we know there's maybe some new lesions or some increasing lesions that represent potential pseudoprogression instead of true progression. And so the iRECIST criteria allow for that adjustment.

In PDIGREE, we did see patients early on with some mixed responses, but a new lesion, which on RECIST necessitated progression and treatment in the progressive disease cohort. But the patients were otherwise doing well and seem to have some benefit from their induction of ipilimumab/nivolumab. Our investigators said if the patients were on standard of care, we would continue immunotherapies. So by using iRECIST criteria and clinical stability, those patients would now be allowed to randomize and have a chance to obtain the combination of cabozantinib and nivolumab. So I think this is a win-win for our patients as well.

Alicia Morgans: Absolutely. I think PDIGREE, like many studies, has also had to adapt to the fact that we live in the COVID era, and we're trying to really ensure the safety of our patients, but we do need to continue progress in terms of clinical trials. So have there been any adjustments related to COVID for PDIGREE or in PDIGREE?

Tian Zhang: Sure, yeah. So early on during COVID times, we released a COVID memo to allow for telehealth visits and omission of physical exams. As we are eight months into the pandemic, we're still doing a lot of these changes in our oncology practices. And so we've implemented these telehealth visits, allowing for the omission of physical exams in the next amendment that's about to come up, and we're allowing also external lab results for patients to obtain local labs. Then as long as those are then sent to the main treating site and updated in the database, those will all be allowed. So I think this is a way to pivot and allow for the flexibility and the changes in oncology practice, as many of these patients are being treated in community centers, as well as in academic sites across the US.

Alicia Morgans: It's great, certainly, to keep our patients safe but really make sure that we adapt to the current situation, so that's wonderful that you're able to do that. I did want to give you the opportunity to mention one other thing that you're involved in. I know your hands are in so many different places. You're always busy, Tian, but you have been such an expert and a guiding force for us as a community when we think about immune-related adverse events and you're also a fantastic communicator. So I think you've started a podcast. Can you tell us a little bit about that?

Tian Zhang: Sure, thanks for the opportunity. Yeah. So we recently started a podcast with my co-host, Dr. Afreen Shariff. She's an endocrinologist at Duke, and we made this independent podcast really focused around immune-related adverse events and thinking about best management strategies. And so each episode will be dedicated to a different adverse event that we see commonly with immune therapies. We've released a couple now around thyroid toxicities and immune hypophysitis, and we have more to come after the holidays for rheumatic, GI, cardiac, and neurotoxicities. So we're really excited to talk through each of these and release a series of episodes, which we hope will be helpful for oncologists as well as other sub-specialists treating patients who develop immunotherapy-related adverse events. We have a website at checkpointnow.org, as well as the podcasts themselves are available on Apple as well as Spotify, and people can follow us on Twitter @CheckpointNowMD.

Alicia Morgans: Fantastic. Well, thank you so much for that. Keep up the good work, certainly, on educating all of us on how to best manage our patients and their immune-related toxicities, and keep up the great work with PDIGREE. We're all trying to get over the finish line. Only about 600 patients or so to go, we're almost there, or 700. I can see it, it's coming up. So thank you so much for sharing this, and I encourage everyone to get their patients to PDIGREE if they can. I think this study is really going to make a difference. Thank you for your time today, Dr. Zhang.

Tian Zhang: I really appreciate it. Thank you, Alicia.