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Pedro Barata: Hi, I'm Pedro Barata. I'm a GU medical oncologist, and Assistant Professor of Medicine at Tulane medical school in New Orleans, Louisiana. It's a fantastic pleasure for me to be joined by Dr. Cristina Suárez. She's an MD PhD medical oncologist at the Vall d'Hebron University, and also Vall d'Hebron Institute of Oncology in Barcelona. Dr. Suárez, thank you so much for joining us this morning.

Cristina Suárez: Thanks for the invitation.

Pedro Barata: And by the way, I start by congratulate you on great job presenting at this ASCO at Chicago. Of course, you were able to present it virtually, you were in route, but what an elegant way to deliver on a very important topic. So just as a reminder, you did show us very interesting data between depth of response and outcomes. Which is part of an exploratory analysis of CheckMate 9ER. Right?

So, for folks out there, CheckMate 9ER basically established cabo/nivo as one standard of care for patients with advanced renal cell carcinoma, in line with the other combination regimens out there. Right?

So today, we're going to be talking a little bit cabo/nivo with Dr. Suárez's insights. So maybe I should start by asking you if you'd like to summarize for us, perhaps, the highlights that you'd like to make on the data you presented at Chicago.

Cristina Suárez: So, yeah. That was a post hoc analysis from the, as you mentioned, the CheckMate 9ER trial, that compared cabo/nivo versus sunitinib, and demonstrated an improvement in progression free survival, overall survival, and overall response rate. So this exploratory depth of response analysis, included patients who had baseline and available post baseline best overall response. And patients were categorized into six depth of response subgroups, based on the overall response rate, complete response, a complete response subgroup. Then, we had three groups based on partial response with different tumor reduction thresholds. PR1, with a reduction as a group of PR1, with a tumor reduction of at least 80%. PR2, with a tumor reduction of at least 80%, but then less. 60%, sorry, but less than 80%. And PR3, with a tumor reduction of less than 60%. Then we had an unstable disease subgroup and a progressive disease subgroup. And for each, and response subgroup, we analyze the progression free survival and the overall survival.

I have to say that, we did this at the six month post randomization landmark. So the six months post randomization landmark was set as time zero for this analysis. And then, the first thing we saw is that, at this landmark, more patients were alive in the nivo/cabo arm. There was 293 first versus 253 in the sunitinib arm. And of these patients, a greater proportion of patients in the nivo/cabo arm, had complete response PR1, or PR2. And when combined, also higher percentage of patients in the nivo/cabo arm had a greater reduction of 60%. And in addition, what's also important to mention, only 5% of patients in the nivolumab/cabozantinib arm had progression disease as best response, versus 15% in the sunitinib arm.

So when we analyzed the relationship with the outcomes, we saw that, in both treatment arms, deeper responses led to improvements in progression free survival. And this relationship, this improvement, was not necessarily linear in the nivo/cabo arm. And we also analyzed the relationship of this depth of response with the overall survival. And again, as similar to PFS, increasingly deeper responses generally led to improved overall survival in both treatment arms. And it's interesting to say that, the overall survival curves, and the results of overall survival in the complete response group and the PR1 subgroups were very similar. And I would say that, that's a more or less a summary of what we presented at ASCO this year.

Pedro Barata: Oh, this is great. I was looking at your data, right. And I was thinking, we kind of saw that, the depth of response, as well. We've seen these data from Dr. Reini and others on CheckMate. Right?

Cristina Suárez: Yeah.

Pedro Barata: Which really highlights, it seems like it does highlight the importance of response. Right?

Cristina Suárez: Yeah.

Pedro Barata: I guess, a follow up question. What you just presented to us would be, you mentioned the at six months. Right? The landmark analysis.

Cristina Suárez: Yeah.

Pedro Barata: We've seen over time, right, with more mature follow up for all these trials-

Cristina Suárez: Yeah.

Pedro Barata: ... that some of the responses change. So for instance, as you are an investigator you know, a lot of times, you have these very good partial responses. So over time, some will become complete responses, for example. The response rate can change over time, with more follow up. So I guess, the question I would have for you is, would you predict that with a much longer follow up time for CheckMate 9ER, would you predict the results to be different? Or in reality, you think all the data is going the same direction that, depth of response seems indeed to be associated with PFS in overall survival? What are your thoughts?

Cristina Suárez: So, yeah. I think no, the results wouldn't be. Maybe we can have, the numbers can slightly change. But as you mentioned, with longer follow up, the complete responses, or the potential of response, usually increases. Another thing we saw in the trial, and have seen in other trials, as you mentioned, is that, that percentage, or that the magnitude of the response, has a direct relationship with the median duration of the response. So what we usually see, the better response you have, the direction used to be longer. So I guess that, the numbers maybe increase a little bit, but they are not going to be, I don't expect big changes with longer follow up.

Pedro Barata: Got it. No, that's great. Thank you for that point. And I guess, the other question that we always think about, when we conduct these large trials, we got to wait for progression free survival. We got to wait for overall survival. Right? So it looks like this depth of response correlates very nicely, or has a strong association rather said, with those outcomes. So are we ready to start incorporating depth of response as kind of an important endpoint in the trials we conduct from now on?

Cristina Suárez: So yes. I think we should consider to include as a secondary endpoint, or at least, at an exploratory endpoint. And in fact, we have overall response rate as a secondary endpoint. But maybe we should start to considering doing, divide this response into subgroups. I don't know if we need so many subgroups that as we use in this exploratory, in this post hoc analysis, exploratory analysis. But maybe we should consider different shrinkage points for tumor reductions when we analyze the outcomes.

Pedro Barata: So, in other words, for the honest, I think you raised such a great point that it looks, it seems like the big group of patients, that includes complete responders and partial responders, is indeed a heterogeneous group, as well. Right? So it sounds like it's very different to have someone who had a 35% tumor shrinkage, versus someone-

Cristina Suárez: Yeah.

Pedro Barata: ... who had 85 or 90% or more. Right?

Cristina Suárez: Yeah.

Pedro Barata: Yeah. I know those are great, great points.

Cristina Suárez: Yeah. That's the point. I fully agree with that. Yeah.

Pedro Barata: Right. So I guess, one final question that I have for you, and thank you for being generous with us is, really, what kind of analysis are you thinking on doing, moving forward for CheckMate 9ER. Right? Are you planning on doing the same kind of analysis with a longer follow up? You are debating with the other PI's about where you're going to present. Because of course, everybody wants to see mature follow up at four or five years of follow up. Right? To provide data about what happens in the long terms, and whether or not these patients who are nicely responding had a very deeper response to cabo/nivo, for instance, how do they perform over time? Do you agree with that? Or, what are your thoughts?

Cristina Suárez: Yeah. And I guess that, we always need in all these trials, it's always interesting to have the longest follow up we can. And in fact, the CheckMate 214 trial, is showing how patients with a longer follow up, some of them maintain complete responses. So yes, I think that it's very interesting, and we will, I'm sure we will do longer follow up, and with of all those patients in the segment nine year as well.

Pedro Barata: Awesome. Well, Dr. Suárez, it has been a pleasure to chat about your data as post ASCO. So thank you so much again for taking the time and walk us through giving your editorial comments on the data you just presented. Thank you. And I hope to see you soon.

Cristina Suárez: Thank you. Thanks for the invitation. And I hope to see you soon too.

Pedro Barata: Bye-bye.

Cristina Suárez: Bye.