Pauline Funchain, MD and Paolo A. Ascierto, MD, on Advanced Melanoma: Results From the RELATIVITY-048 Trial

Thank you for joining us today at Paolo. We are so excited to talk to you about Relativity 048. So we just want to introduce the topic and can you just tell us about what question this trial is meant to answer and how you designed the trial? First of all, thank you for inviting me. The question was to add ipilimumab to nivolumab [inaudible 00:00:33]. The schedule is nivolumab, the classical 4/8 in milligram every four weeks, [inaudible 00:00:37] 1/16 milligram every four weeks. Ipilimumab was added, a dosage of one [inaudible 00:00:45] every eight weeks because the concern is about toxicity. We had those finding for the phase one, this was the question. And the O48, it's a large trial, not only melanoma, solid tumor. And then we have the expansion code and here we presented the data for the expansion code related to 46 patients treated with advanced melanoma. So a smaller cohort, but still we were very excited to hear the results. So can you summarize the results? Absolutely, yes, you're right. Excited results. So the prominent point was of course safety because this is a phase one of two, but the response rate was a co-primary... Response is per [inaudible 00:01:24]. How was the response rate? 59% with the 17% of complete response, 70% stable disease, 15 progression disease. If you look to the central revenue, similar, 57 response rate, 22 complete response more, 20% stable disease, 11% progression. Disease control rate, similar, 72% investigator, 76% central value. Progression-free survival, interesting. Three and four years PFS rate, 52%. If you compare with those 67 and the 47, was a little bit more than 30% for both, so 20% more. Overall survival, three and four years rate, 72%. Again, if you compare with those 67, 47, a little bit more than 50, 20% more. Very similar. Of course we can not compare this clinical trial because all the data should be interpreted with caution, but it's really intriguing. Yeah, I totally agree. I mean those numbers are very similar if not in certain ways a little better. But do you think that, that has to do with... It's a different time than 067, right? So how do you interpret those numbers over time? Yeah, it's difficult. This is the problem. When you compare the different... I enrolled several patients, the feeling is really good. So from my point of view, the addition of CTL4 to nivolumab increased the memory effect of the patients, increased the possibility to get the long-term benefit. And the safety, that is the primary point, still interesting because if you look, the data are comparable with the data of IPINIVO for instance. So grade three and four adverse event, 39%, the percentage of patients with discontinue for toxicity, 41% [inaudible 00:03:32] grade, 22% with three and four to that for one for the diarrhea and [inaudible 00:03:40] the other one from myositis, immune related. Myocarditis, when we talk about [inaudible 00:03:46] three, we should look to make [inaudible 00:03:48] only to patients grade two. So in general, the safety [inaudible 00:03:52]. I mean the safety does seem a little bit better than IPINIVO. What do you think in terms of where this lands, right? So IPINIVO, triplet, do you think these will end up being very preliminary, but when you see these and you see these patients, do you see this being in different clinical scenarios? Do you see this as something that might replace IPINIVO? So I believe that we should consider that now we have several possibility for melanoma. As far as the metastatic disease, is different for the patients who got metastasis without any treatment before or the patients who fail a previous adjuvant. And then we learn more patients who fail a previous neoadjuvant and adjuvant as fast. Then we have some patients with bad disease, very elevated LDH. And if you look the response rate in patients with more than two upper limit of normal LDH, 56% of response rate. The patients with liver [inaudible 00:04:57] 50% of response rate with the triple. So I believe with this kind of patients, so-called bad patients or the patients who were previously treated, the triple may have sense. Yeah, it was especially interesting, the brain mets, the two out of three. So two thirds, it makes you think about those poor risk patients. Yeah. Few patients with brain met were all three. The response rate was good, but I believe we need a larger quarter of patients. So last question, if I can, do you think at some point we would need to increase the IPI dose on this or have room to increase the IPI dose or do you think this is going to be where triplet will stand? No, this was part of the discussion of during the presentation, if you remember the data from the phase one IPINIVO, the best court in terms of response was NIVO three, IPI three, but with a lot of toxicity. So to add IPI three to NIVO, the 480, it's something like three [inaudible 00:04:46]. We are concerned, but I believe that we can work on the timing because IPI was given every eight weeks. Probably we can try to look every four or six weeks. This probably may be good. So I mean, we are very excited to see a larger cohort. Thank you so much for talking to us about these data. We were waiting to see these results, so thanks for spending the time with us. It was my pleasure. Thank you, Pauline.