Pedro Barata: Hi, I'm Pedro Barata. I'm a GU medical oncologist and a director of the clinical research program for Advanced GU Tumors at University Hospital Seidman Cancer Center in Cleveland. I'm very, very happy to be joined by Dr. Michael Atkins. Dr. Atkins is a giant in the field of GU. He's also the deputy director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.

Dr. Atkins, welcome. Thank you for joining us today.

Michael Atkins: Thank you, Dr. Barata. It's a pleasure to be here.

Pedro Barata: Thank you so much. And this is an exciting ASCO GU. I think we have a lot of important data presented during this meeting, and I congratulate you for the outstanding presentation you did. Again, on, to me, an important study into many out there, a very important study that you help conducting, regarding the role of salvage ipi nivo for patients on upfront immunotherapy for treatment-naive advanced renal cell carcinoma. So we're really talking about HCRN GU16-260, specifically with cohort A. Before we go into exactly what you presented us during ASCO GU, maybe it'll be a good time, if you could allow us, or remind us, rather, what the design of that study was. How do you put it together? Because it's out there, but some folks might have missed it.

Michael Atkins: Sure. So the HCRN GU 16-260 trial was a trial of nivo monotherapy followed by nivo ipi boost in patients who didn't respond. On this trial, all patients got nivo monotherapy, which we called part A, and those with a PR or CR received a maximum of 96 weeks. And those who had progressive disease or stable disease at 48 weeks could receive a nivo ipi boost, followed by nivo monotherapy for a maximum of an additional 60 weeks, and we called that part B.

In this particular analysis, we were presenting a little bit of updated clinical data, and then we described a novel endpoint, which was treatment-free survival. Treatment-free survival in this study began when treatment was stopped for toxicity, progressive disease or treatment completion and ended with the start of subsequent therapy or death. And so we looked at the 128 clear cell patients, and we had a median follow-up of about 37.7 months, and we wanted to see what the actual treatment-free survival was in this particular study, which was unique because it had a defined treatment stoppage time compared to the, for example, the CheckMate 214 study where patients could continue on therapy, and therefore we wanted to see the real opportunity for maximizing TFS in this particular trial.

Once again, we defined TFS as the area between the Kaplan-Meier curves for time from registration to protocol therapy cessation and time from registration to the subsequent treatment initiation or death. So that area between those curves was TFS, both estimated from a 36-month mean time. So we looked at a three-year time and we looked at averages, and we also were able to look at the time either on or off treatment with grade 3+ toxicity.

Pedro Barata: Got it. That's a great summary. Thank you for that. To your point, it is really important. We talk about IO-based combos in the frontline. And oftentimes, first of all, longer follow-up is important to really assess what's going on with these patients, which you were providing with three years or so of follow-up. It starts to be pretty good to assess those kinds of endpoints and also, kudos to bring up a novel endpoint. And we do care about that. Treatment-free survival is something that has meaning to treating physicians also to patients. So tell us a little bit about the findings you presented in regards to treatment-free survival.

Michael Atkins: Sure. Well, I'll start with the updated, more traditional analysis that I presented, which was in this study we called the regimen part A and part B as one regimen, and therefore tumor response in either part A or part B was included as a regimen response. The overall response rate was 36% with 58%, or 22 of 38 patients, with favorable risk responding, and 27%, or 24 of 90 patients, with intermediate or poor risk responding. And the three-year endpoints from the Kaplan-Meier curves showed that 68% of all patients, and 97% of all favorable risk patients, essentially all except one patient remained alive, and 38% of all patients were alive and subsequent treatment-free and no patients were still on protocol therapy at three years. We then looked at the mean months under or between the Kaplan-Meier curves and the percent those months represented of a 36-month total period.

And for the whole group, the mean overall survival was about 30 months, which consisted of time on protocol treatment of approximately 11.5 months, TFS time of approximately 9.5 months, and survival after the start of subsequent treatment of approximately nine months. So you add all those periods up and it gets to 30 months, and the mean time, either on or off therapy with grade 3+ toxicity, was pretty small, 0.6 months and 1.2 months respectively.

For the favorable risk patients, TFS was 12.9 months, or 36% of that 36-month period. And of note, approximately 40% of patients completed part A therapy the whole 96 weeks. And the overall survival area, which was a mean, was 99%, with the only death in the favorable risk patients occurring at 28 months. And for the intermediate and poor risk patients, TFS was eight months or 22% of the 36-month period. And this TFS for the various populations compared favorably to what was reported for CheckMate 214 at 36 months, which I think illustrates the impact of a designated treatment cessation time on the extent of treatment-free survival.

Pedro Barata: Wow. I think these results are really impactful. And I'm wondering if you were to chat with a treating physician in the community and you were to summarize this in use different words, what would be the take-home point from these findings, specifically with IO? Because in addition, you can say a lot of things. One of them is actually the IO is active, and clearly there's a benefit that patients are getting in the long run, but I'll let you use your words. How would you summarize the findings of specifically treatment-free survival, these unique and novel endpoint, to a treating physician out there in the community?

Michael Atkins: Yeah. So this regimen, which was nivo monotherapy, was salvage nivo ipi, which was designed to potentially reduce the toxicity by sparing people ipi who didn't need it, and also capping therapy in patients who were having a long-term response was active, and it resulted in substantial treatment-free survival and toxicity-free survival and treatment-free survival was increased and sustained following elective treatment cessation at this 96 to 108 weeks. And treatment-free survival over 36 months was greater than was seen in CheckMate 214, where there wasn't a defined treatment stop and toxicity full survival represents only a small percentage of both the on-treatment or treatment-free survival time. And so I would conclude that TFS captures valuable information not contained in the traditional trial endpoints, which could be used in the design of future immunotherapy-based protocols, not just in kidney cancer, but other diseases. And it was particularly noted in patients with favorable-risk disease, which further supports my ongoing mission to encourage the use of an immunotherapy-only regimen in this patient population.

Pedro Barata: Right. That's a great point. Dr. Atkins, congratulations again. I know this was a big effort from a lot of colleagues in the field, getting over 120 patients on this particular trial, and so I really think these results are important, and I'm glad that ASCO GU actually selected this work to be presented. I think it's very helpful. I really appreciate your time. Thank you for sitting down with us. Thank you for that. And keep doing great job. Great work. Thank you.

Michael Atkins: Thank you very much, Dr. Barata. I look forward to more participation on these podcasts.

Pedro Barata: Thank you.