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Pedro Barata: Hi there. I'm Pedro Barata, a GU oncologist at University Hospitals Seidman Cancer Center in Cleveland, Ohio. It's such a pleasure, Dr. Tannir, to have you again. So Dr. Tannir is a world-renowned expert in kidney cancer. Super well respected, has conducted many important trials in the field of GU, particularly kidney cancer; you've helped shape the field. And I'm very, very happy to be here talking to you today about another outstanding presentation you did this time, and a long, long follow-up, eight years, on the CheckMate-214. The first Phase III trial we've seen with an IO-based approach. In this case, ipilimumab and nivolumab. It was quite remarkable. It did change how we manage patients with advanced renal cell carcinoma.

So Dr. Tannir, thank you for joining us. I would ask if you could update the audience, who have not had the chance to actually be there for your presentation, can you summarize briefly? Because we've shown this new data. Can you summarize briefly the highlights on the efficacy part regarding ipi/nivo for patients with advanced RCC in CheckMate-214?

Nizar Tannir: Thank you, Pedro. First of all, thank you for the invitation, and to be here with you for having a nice fireside conversation chat about this data.

As you know, CheckMate-214 was the first Phase III trial in first-line therapy of patients with advanced clear cell RCC. It was the first to show overall survival for patients with intermediate risk, poor risk, again selected by the IMDC criteria. It is the only trial in first-line therapy that has past five years of follow-up. And so now, this year, we have eight years minimum follow-up. And to be exact, 99.1-month median follow-up for the study.

And just to review quickly for patients, for physicians or practitioners who may not be, again, to remind about the co-primary endpoints in the design. So this was a more than 1000 patient Phase III trial of nivo/ipi versus sunitinib in patients with clear cell RCC.

The three co-primary endpoints for the study were overall survival, progression-free survival, and objective response rate in the intermediate-poor risk IMDC patient population. So that was the three co-primary endpoints.

The secondary endpoints were the same in ITT, intent to treat.

And the third endpoint was exploratory, again, efficacy outcomes in patients with favorable disease. So what we have observed now with eight years median follow-up is, the hazard ratio between the two treatment arms has remained stable over the past eight years. So at the first primary analysis, 17 months, median follow-up 30 months, 42 months, 48 months, five years, and now eight years. That hazard ratio for OS between the two treatment arms has remained stable. And for patients with intermediate risk, poor risk, it is 0.69. What does it mean? It means that there is a 31% reduction in the risk of death for patients who are treated with nivo/ipi compared to sunitinib. And for the ITT, that hazard ratio is 0.72. There's no trial that can have that claim, that over time the hazard ratio has remained stable.

So that was the most impressive, important, I would say, take-home key message for CheckMate-214.

Pedro Barata: So let me follow up on that, because this is a remarkable summary, thank you for that. One thing that caught my eye and caught a lot of folks in the audience's side, which is very important when we put this data into context, is really the tail of the curve, right?

Nizar Tannir: Yes.

Pedro Barata: So in other words, these patients who receive ipi/nivo, some of them are actually off systemic therapy. They complete the four cycles of ipi, they completed perhaps two years, some patients less, some patients more, of nivolumab. But the reality is, we see about a quarter or so of patients who actually remain without progression.

Nizar Tannir: Yes.

Pedro Barata: And we talk about an eight-year follow-up.

Nizar Tannir: Yes.

Pedro Barata: That is remarkable.

Nizar Tannir: Yes.

Pedro Barata: So I would like you, what are your thoughts when you put this into perspective? How important is that to patients, and how important is that to actually treating physicians out there?

Nizar Tannir: That's a very good question and point you're bringing up, Pedro. I think, again, when we look at the impact of any therapy on patients and patients' outcomes, is that tail at the end of the curve, as that's obviously, people will look at the beginning, at the early, I mean. Are the two curves close together, or is there a separation from early on when you're looking at progression-free survival or overall survival? When you look at progression-free survival between the two treatment arms, and you look at over time, at 90 months there is already a tail or a shoulder at the end of the curve, with a quarter of the patients alive and progression-free. So those patients were treated with just nivo/ipi and haven't had any other therapy. And they seem, and if this trend continues, which I have a feeling it will continue with further follow-up when we again analyze the 10 years, it will, above 20%, we will have that plateau, that tail at end of curve. So patients, alive and progression-free.

Then when you look at the duration of response, which is the other important key data point here from the CheckMate-214, duration of response with sunitinib, the control arm comparator, and duration of response with nivo/ipi. Impressive for patients with intermediate risk and poor risk. Duration of response, 82.8 months median duration of response, versus 19.5 months median duration of response with sunitinib. So to round them up, 83 months versus 20 months, that's median.

And when you look at the responders, you look at the responders and you look at over time, what happened to the responders? And these are patients who achieve a CR or a PR. And you start, there were 180 patients who responded to nivo/ipi out of the 425 who had intermediate risk, poor risk. 180 treated with nivo/ipi. And over time, at 90 months, that landmark, 50% of those responders continue to maintain the response.

Pedro Barata: Right.

Nizar Tannir: And I think that's the other take-home message, that in addition to the stability of the hazard ratio, the tail at end of the curve for the PFS, that probability of 25% alive and progression-free.

Pedro Barata: Right.

Nizar Tannir: And the duration of response, the impressive 83 months median. And again, the hazard ratio for duration of response, the difference between the two treatment arms, was 0.48, with a tight, narrow, 95% confidence interval.

Pedro Barata: I agree. I mean, those are impressive results, right? It sounds like if you respond, and I bet if you start looking at the kind of partial responses, right? You have the complete responders, meaning you don't see disease anymore in the scans. And if you look at the deep responses, meaning the very good PRs, partial responses, with much shrinkage, 80%, 90%, etc.; I predict that the chances of you remaining with that response are very high, to your point. I think that means a lot to patients.

What is your advice? What are your thoughts that you can offer to the folks hearing us out about, here's a situation where I think ipi/nivo makes a lot of sense, for the reasons that you want to point out. And in this situation, it's completely appropriate, and perhaps I would tend to favor an IO TKI for these other reasons. Do you have an algorithm in your mind? How do you approach those patients coming to see you?

Nizar Tannir: Well, I mean, it's the most important question. As they say, the $64,000 question. How can we select which therapy to give to patients? I mean, if we knew with a biomarker, whether it's a tissue-based biomarker or a blood-borne biomarker, if we knew which patient would respond to nivo/ipi, which patient would respond to an IO TKI, obviously, that is what's needed, right? We don't have that. And it's unfortunate. I mean, for decades, high-dose IL-2, Steve Rosenberg and his colleagues at the NCI for decades tried to. And the Cytokine Working Group, Mike Atkins and David McDermott and their colleagues, tried to come up with a signature, a biomarker, to really know which patients are best to respond to high-dose IL-2. And the same thing.

Now here is, I'm going to say that the protocol, the CheckMate-214, when we wrote the protocol back almost 10 years ago or longer, we stipulated that patients should get the first four cycles of induction with both agents, then get the scans. Now in practice, how do I select therapy for my patients? Who do I give nivo/ipi to, and when do I do the scans? The argument that proponents of IO TKI, an anti-PD-1 plus a TKI, have is that there is a high progressive disease rate with nivo/ipi, which is true.

Pedro Barata: Right.

Nizar Tannir: It's 19% in patients with intermediate, poor risk. And they say you have only one shot at the goal. If you give nivo/ipi to a patient and they don't respond, and they, unfortunately, their condition deteriorates, you may not get a second chance to treat them with something else. Well, we are looking at this data, and we will be coming up with a percentage of patients from the CheckMate-214 who had progressive disease as their best overall response to see how many actually went to a second line.

Pedro Barata: True.

Nizar Tannir: I can speak of my practice at MD Anderson, and I tell you, very rarely, extremely rarely, do I give a patient nivo/ipi, and if they don't respond, I don't have a chance to give them a second line.

Pedro Barata: Okay.

Nizar Tannir: So I do scans every two cycles.

Pedro Barata: Gotcha.

Nizar Tannir: And if a patient has progressive disease or stays symptomatic, we change therapy quickly.

Pedro Barata: Right. Because you're not seeing those responses where you know it's more likely to benefit.

Nizar Tannir: Yes. So you'll have a chance to go to a second line. Remember, if we treat a patient with nivo/ipi and they don't respond, then we're talking about palliative care.

Pedro Barata: Right.

Nizar Tannir: Then we've got to give them a TKI. And so, really that's why I think-

Pedro Barata: And the mindset changes, right? The rules change.

Nizar Tannir: If we are judicious in selecting the appropriate patient for the appropriate therapy, I think we can treat our patients sequentially. And if they do not respond to the nivo/ipi, we have a chance to give them second-line and third-line. And I, at MD Anderson, my patients go through multiple lines, even if they have poor risk at the initial presentation.

Pedro Barata: Got it. That's a fantastic way to kind of break it down. Because we have, again, our community who is dealing with all these IO, and so that's, thank you for offering what you are doing in practice. And also, it's very refreshing to hear that the research around CheckMate-214 is not over.

Nizar Tannir: Absolutely not.

Pedro Barata: And it sounds like we're going to have more and more interesting data coming up from that, which is remarkable. I thank you so much for this robust discussion.

Nizar Tannir: Well, thank you as well.

Pedro Barata: It's always a pleasure. Always learn every time I talk to you.

Nizar Tannir: Oh, well thank you, Pedro.

Pedro Barata: And so thank you for taking the time.

Nizar Tannir: Appreciate the opportunity to be here with you. And hopefully, this conversation will inform and help our patients make the right decisions. And their treating physicians to be comfortable with the support from the data that we presented at ASCO GU this year.

Pedro Barata: Well, congratulations, Nizar.

Nizar Tannir: Thank you.

Pedro Barata: Thank you so much.

Nizar Tannir: Thank you, Pedro.