Pedro Barata: Hi and welcome. My name is Pedro Barata. I'm a GU Medical Oncologist and Associate Professor of Medicine at Tulane Medical School in New Orleans, Louisiana. It is my pleasure to be joined today by Professor Marc-Oliver Grimm. He's a Professor in the Department of Neurology in Jena, Germany, in the Jena University Hospital. Professor Grimm, welcome.

Marc-Oliver Grimm: Yeah, my pleasure to be here.

Pedro Barata: By the way, congratulations on your work you just presented at his ESMO this year in Paris. You did present the data, the final results, of the very, very interesting study, in my opinion, TITAN-RCC, which basically explores this tailored approach of NIVO and IPI/NIVO, with IPI/NIVO being explored in a salvage manner. But instead of me summarizing the study, perhaps I would ask you that question. Can you briefly summarize for us what is the study design, the endpoints of interest, and basically tell us a little bit about the rationale to bringing ipilimumab as a salvage approach for patients with advanced RCC.

Marc-Oliver Grimm: Actually, TITAN-RCC was designed many years ago, and at this time, NIVO/IPI was not approved as a first-line treatment. The pivotal trial CheckMate 214 was still running and I was one of the investigators, and while we were very much impressed by the complete remission rates and long-term remissions we saw, we were also impressed by the toxicity of NIVO/IPI as a combination. That's why we asked, in TITAN, the question whether we could start with NIVO, provide NIVO induction for eight or even 16 weeks in kidney cancer, and only in patients who don't respond to NIVO, that they are exposed to NIVO/IPI. So not as a rescue strategy more or less, but as an intensified immunotherapy. So we wanted to decrease toxicity and to increase, compared to NIVO monotherapy, the efficacy.

Marc-Oliver Grimm: The trial was powered for the endpoint objective response rate, as a response rate based on NIVO on the one hand for the responders initially, and NIVO/IPI for those who do not respond. So those patients who were stable or were progressing, they received NIVO/IPI, as you said, as a rescue strategy. Actually, it was also possible to receive NIVO/IPI later during the trial. So, patients who did respond initially to NIVO monotherapy, they were allowed, when they progressed during NIVO monotherapy after initial response, to receive NIVO/IPI then actually as the salvage strategy. The trial had two different cohorts, one first-line cohort and one second-line cohort. The results are a bit different in these two cohorts. If you see the approval or the approvals we have at the moment, which is NIVO/IPI in front line for intermediate and poor-risk and NIVO monotherapy in the second line.

Pedro Barata: No, that's great. Thank you for that. It will be quite interesting. It's quite interesting, actually, I invite everybody to go through your data for these final analysis, because it does stress out the points that you're making. Actually, if I may, as a follow-up question, can you tell us what are the key points or the take-home messages you'd like for the audience to take out of these final analysis of the data? If you can give us an overview of that for the two cohorts, it would be great.

Marc-Oliver Grimm: Okay, let's talk, I think, line by line because as I said, these were two different completely independent cohorts with independent statistical assumptions. If we look at the front-line setting we observed with NIVO, with and without, based on the design I just mentioned, NIVO/IPI, an objective response rate of 36% in intermediate and poor-risk patients, which were included. Mainly this was an inclusion criteria to intermediate or poor. So this is close, but not quite the same as what we have seen with NIVO/IPI starting early on just at the beginning. If you look at the median overall survival and median PFS, median PFS was 6 months and median overall survival is 36.1 months. So it's, again, lower, as what we would expect with NIVO/IPI upfront.

Marc-Oliver Grimm: If we look on the second-line cohort with NIVO, with and without NIVO/IPI, we observed 32% objective response rate, which is a bit more as what we would expect, but not a significant difference. However, if we look at the median overall survival, this is 33.7 months as a median, so that's not bad and appears a bit more compared to NIVO monotherapy, what we usually apply in the second-line setting.

Marc-Oliver Grimm: In summary, what we see that the effectivity parameters, objective response rate, overall survival in particular, suggests inferiority to NIVO/IPI starting right away in the front-line setting. If we compare in the second-line setting to what we have approved NIVO monotherapy, we see better efficacy parameters. So in summary, I think the trial shows that NIVO/IPI should be given upfront in first line and may add some additional benefit in the second-line treatment.

Pedro Barata: That's a fantastic response. Thank you for that, because it seems indeed to be a differential activity. I have to assume, can you remind us if the second-line cohort allowed or did not allow for a prior checkpoint? In other words, this would be patients that were treated like we did in the phase III nivolumab. So post, usually, TKI in the frontline. Just to clarify that point, were we're not talking about patients who progress on a prior PD-1 or PD-L1 inhibitor. Is that right?

Marc-Oliver Grimm: That's correct. On the other hand, we had these patients who received late immunotherapy boosts. So they were on NIVO, responded initially, and then they received a later NIVO/IPI escalation of immunotherapy. In these patients, we also saw some responses, 18% in the second-line cohort achieved a partial response for a late boost. If we consider they were all progressing, another 36% were stable at least for some time, although it was not for a long time and the numbers are definitely small, the number of patients we observed.

Pedro Barata: Right. Fantastic. I do believe that your trial just present at ESMO really highlights the importance of CTLA-4 inhibition, in this case with IPIlimumab. It reminds us that the addition of CTLA-4 to a PD-1 actually makes sense. As we talk, I'm thinking about the long-term follow-up data with CheckMate 214 with NIVO/IPI. Now we have 5 years and that benefit that we saw seems to be there. And so I think your trial helps to tell the story, that, indeed, we should consider the addition of a CTLA-4 to PD-1.

Pedro Barata: I want to provoke you a little bit, and here's a provocative question for you. We saw data at ESMO with triple therapy, it's a positive trial, in this case with a COSMIC-313 and CABO/IPI/NIVO versus IPI/NIVO, and more to come. There's a number of large trials exploring triple therapy in the advanced RCC setting. I'd like to ask you what your thoughts about a CTLA-4 inhibition in that setting, knowing, keeping in mind your data, data from other trials out there, do you think that all triple therapies should include a CTLA-4 inhibition, should explore different mechanism of action beyond PD-1/CTLA-4 combo? What are your thoughts about bringing the CTLA-four front-line, or waiting for patients who progress?

Marc-Oliver Grimm: Well, if we talk about the front-line setting, I strongly believe that we should start with NIVO/IPI combination upfront, because what we have seen during the trial is that, obviously during the short induction period with minimal monotherapy, we lost some patients because they were not able to achieve a response or they were not able to achieve a long-term response, at least with NIVO/IPI afterwards, otherwise it cannot be explained why the remission rate appears a bit lower and the overall survival is considerably lower compared to NIVO/IPI upfront. So I think in the front line, it is of key importance to start with both drugs. And on the long run, I think that is the main aspect of IPI that we see the tail of the curve, which we have not seen yet with any TKI/PD-1 checkpoint inhibitor combination. I think that's a matter of ipilimumab, and so I'm actually a strong believer that we will only see this tail of the curve with IPI in the combination.

Pedro Barata: If I may add, similarly to what we see in other solid tumors. I'm thinking a melanoma as a classical example.

Marc-Oliver Grimm: Sure. Yeah.

Pedro Barata: That's fantastic. Professor Grimm, I feel like we could spend all day talking about this. I have to congratulate you again for the great presentation you did at ESMO. Thank you for that, we're looking forward to the paper, and thank you for joining us today and I'm looking forward to talking to you with more updates soon.

Marc-Oliver Grimm: Thank you.

Pedro Barata: Thank you.