SECTION 1: Adjuvant therapy

James Larkin:

Hi, everybody, and welcome to this post ASCO skin cancer round table discussion with the VJOncology. My name’s James Larkin. I’m a Medical Oncologist at The Royal Marsden in London, in the UK. We’ve identified a few different areas to talk about based on the exciting data we’ve seen recently at ASCO. And those are adjuvant and neoadjuvant, metastatic long-term followup, frontline metastatic, the very important PD-1 refractory space. And then potentially if there’s time, other highlights that we think they might be of interest. As well as talking about ASCO, we’ll be trying to incorporate the other recent data that we’ve seen published and presented in the literature in the last six to 12 months. So it is my great pleasure, I should say, to be joined today by esteemed colleagues from around the world. You really need no introduction. But nevertheless, I will make some introductions. We have Dr. Arance from Spain.

Ana Arance:

Hello.

James Larkin:

Hi, Ana. Dr. Ascierto from Italy.

Paolo Ascierto:

Hello, James. Hi.

James Larkin:

Yeah, and we have Dr. Amaria joining us from the US.

Rodabe Amaria:

Hello. Good morning, or evening.

James Larkin:

Yeah, early afternoon in London. Anyway, so welcome, everybody. Look forward to a great discussion. And I think what I’d like to do if I may, Dr. Amaria is actually start with you in terms of adjuvant and neoadjuvant. I mean there seems to be quite a lot happening in this space at the moment, and we’ve seen some really interesting data at ASCO. And actually in the last six to 12 months, we’ve seen some other important data. So perhaps I could ask you to start by giving us your take really overall and how the new data kind of fits into what we should be thinking about in clinic?

Rodabe Amaria:

Sure. So one of the major adjuvant updates from ASCO was the S1404 study, which was basically the randomized study of pembro versus standard of care, which could have included high-dose ipi or interferon in the study. And what you see here is that the pembro outperforms the standard of care, as we would expect in terms of progression-free survival, but there was no overall survival benefit seen. And actually this data is very complimentary to the CheckMate 238, the curves basically overlap and similar studies, findings, you basically see improvement in progression-free survival, but no change in overall survival, and that is undoubtedly due to crossover to the other lines of therapy once patients progress. Really no other differences with safety signals with this study, I think this really just highlights what we already knew from the CheckMate 238 study.

I do think that there’s been, as you alluded to, a lot of updates in adjuvant therapy. We clearly have both adjuvant PD-1 regimens showing RFS benefits. We have high-dose ipi, which is not necessarily widely used anymore due to the toxicity. We have very clear data with the COMBI-AD study, with the dabrafenib-trametinib over placebo showing both RFS benefits as well as overall survival benefits. But the other thing to remember of course is the CheckMate 915 study, which was presented at AACR this year. And that study did not meet its primary endpoint, ipi and nivo was not necessarily better than nivo for the entire intent-to-treat population or the PD-L1 positives. And we should discuss this, but there’s a number of reasons why and I really just think it’s the way that they did the dosing of the ipi. The low-dose every six weeks is not something we traditionally use in melanoma, and I think that’s what led to the finding from that study.

James Larkin:

Yeah, that’s a great summary to start us off with. So, maybe I’ll just ask a few questions and see what people think. I mean, not many of the modern or more modern trials have shown an OS benefit for adjuvant therapy. And do we think that’s because as you say, the patients are actually, there’s crossover in the metastatic setting and that’s the reason for it? But if it weren’t for that, actually we would be looking at an OS benefit? And it’s a complicated question of course, but sometimes particularly with regulatory approvals and sometimes with reimbursement we have these kinds of problems with adjuvant treatment. People say, “Well, actually, great. We see an RFS benefit that’s clear, why isn’t there an OS benefit?” That might mean that it’s more difficult to reimburse. So what about a Spanish or Italian perspective, I’d be curious?

Ana Arance:

So I agree with you, James. So we can assume that probably the subsequent treatments have an effect on overall survival, but I’m not sure if this this is due to all subsequent treatments. Are we compromising the treatment in the metastatic setting? Do we have to analyze that data in a different way, checking for the progression-free survival following this first progression? Just to be able to measure the benefit, so I don’t have a clear explanation. Because in the metastatic setting, we have been able to show a survival benefit even with subsequent therapies. Why cannot demonstrate that in the adjuvant setting? Do we have to analyze that data in a different matter, stop at the time of progression and check overall survival or PFS2 from there?

So, I don’t know. And the most important question, are we compromising treatment in the metastatic setting? Now we have many, many patients progressing on adjuvant immunotherapy and also in adjuvant therapy. And this is really a clinical problem, that maybe we can build later on with the other results from ASCO. So, how do we treat these patients now? I don’t have a straight answer, I have more questions that I would like to share with all of you.

James Larkin:

Yeah, I think it’s the same for all of us. Paolo, how about you? What do you think about these thorny questions?

Paolo Ascierto:

Yeah, I agree that the post-progression treatment side is something that affect the overall survival. But the EORTC trial with the ipi was a positive trial, we have seen relapse-free survival advantage. And then overall survival, yes, it’s true that at that time we had probably limited options post-progression. But this is of course an interesting trial and we should take in mind that in the CheckMate 238 and in the SWOG 1404, the control arm was an active control arm. So, I believe that the crucial trial will be the KEYNOTE-054. Because in that trial, there is also the possibility to get a crossover in the placebo arm. Really we’ll see if this crossover will affect overall survival, and then the question if we need to treat patients earlier or later will be an interesting question. But I agree with Ana, that at the end of day we don’t have the treatment available now. We should look probably to other endpoint, maybe even the distant metastasis-free survival, so something different.

James Larkin:

Yeah, that’s a beautiful segue, Paolo. Thank you, into the KETNOTE-054. I think it’s probably a good chance to talk about it now, the kind of Lex Eggermont now-or-later strategy. And we saw some data obviously at ASCO this year, what do people think about those data? Small numbers, a bit too early, any thoughts from anybody on how we should interpret that?

Rodabe Amaria:

I mean I think the data to me, I was most intrigued by the crossover data, right? Obviously there were small numbers of patients. But what I was disconcerted to see was the one out of nine patients basically with measurable metastatic disease, when they were rechallenged with pembro had a response. That’s definitely different than what we’ve seen in some of the other crossover data that’s been presented. And so to me, it’s very unclear. And I think clinically, I’m not as good results with rechallenge. But again, I think this is an area that needs further study and bigger patient numbers.

James Larkin:

And just to be clear on that point, we’re talking about rechallenge in the metastatic setting-

Rodabe Amaria:

At this point.

James Larkin:

With a single-agent anti-PD-1 in someone who’s previously … I mean certainly that’s my experience and I think most of the data point us in that direction as well. So Paolo and Ana, KEYNOTE-054 at ASCO, is that helping us or is it still pretty unclear?

Ana Arance:

Well, to be frank-

Paolo Ascierto:

Ana is first.

Ana Arance:

For me it’s unclear. First because we don’t have all the data, probably that there must have been patients who have been treated outside KEYNOTE-054 with anti-PD-1 alone or in combination. So it will be interesting if the EORTC would collect all these, all this information. Also in the placebo arm it’s curious to me that these patient that receive placebo, and then when they have been treated with pembro with anti-PD-1 that PFS is similar. It does not look like in the treatment arm, it’s much lower. So if at three years … I don’t know remember exact numbers with pembro, relapse-free survival is around 60% in the control arm. In the placebo arm for patients who were treated with pembro on relapse is around 30%, why? So, it means to me that it’s not very convenient to delay treatment.

But it’s the same, I think we don’t have the full picture with all the patients. Many people, a group of patients have been treated without … within KETNOTE-054. But what happen with the patient who receive anti-PD-1 probably or other outside the trial? So this is one of the comments that I may have, but I don’t know the right answer.

James Larkin:

No, I mean I think that’s a good point though actually. Paolo, how about you?

Paolo Ascierto:

No, James, I believe that we have seen interesting data. But that’s it, stop. So, we need of course more interesting data. We are waiting for overall survival, probably we will need also to see the five-years relapse-free survival. These are something like an interim analysis. Yes, with interesting data, but not nothing more.

James Larkin:

Okay. So listen, I’ve got two more things I want to talk about before we go on to neoadjuvant. So the first question is for all of you, why was CheckMate 915 negative? We’ve already had an allusion to that. And of course we’re speculating, we don’t have a manuscript and so on and so forth. But I mean frankly, it was disappointing, right? For all of us in the field to see the curves so clearly overlapping. Is it ipi dosage? Is it less treatment, is it more steroids? What do people think? There’s no right answer, right?

Paolo Ascierto:

So James, we did an interesting trial in metastatic melanoma with ipi 10 compared to ipi three mgs per kgs. And in melanoma we now know, it’s really clear that the dosage may make the difference. And as Roda said, so that’s it.

James Larkin:

So ipi dose for you, Paolo? That’s the-

Paolo Ascierto:

Well, looking also that the IMMUNED study, the German study, we have seen a very interesting separation. Yes, it’s a Phase II randomized trial, small number of patients. But the hazard ratios was really low and with an important difference. Yes, in my opinion is the ipi dosage. Because the ipi dosage and the schedule, this is the schedule that’s used for the lung cancer. So, we cannot use the same schedule for the different cancer. We know that in melanoma, the dosage make the difference.

James Larkin:

Yeah, and we could actually spend the whole time talking about ipi dosage. Couldn’t we, if we wanted to? But we’re not going to. Ana, any other comments? Or Roda, from you on this?

Ana Arance:

We have to remember that this trial had three arms. One arm with ipi monotherapy. And one of the results of the CheckMate 238 were made public, patients who were in the ipi arm were allowed to receive anti-PD-1. So, I don’t know exactly if this is going to be discussed in a future publication or if it was discussed in the presentation. I don’t know if these patients, that have they been analyzed? Have they been included in the pembro … sorry, in the anti-PD-1 group? Because there was this third arm with ipi and patients who were allowed. Because everyone have exhibited in this trial and we added nivo, anti-PD-1 to these patients once the data from CheckMate 238 were … I don’t know if that also has had an influence on the data, apart from the dosage. But I agree with Paolo, that may have influence a lot.

James Larkin:

Yeah, I mean that’s a good point, isn’t it? I mean I think it was a small number of patients, wasn’t it? Who got ipi 10 mono before the trial design was amended, but it’s an important point. Right, so if there’s nothing else on that, I’m going to ask a final question adjuvant question. Which is, will we see a positive signal in high-risk stage II for adjuvant checkpoint inhibitor therapy? Again, there’s no right answer.

Rodabe Amaria:

I think we will. It’s just going to take a while, right? So I mean I think the studies were smart and that they picked the highest group of patients, that IIB, IIC patients. We know those IIC patients can have as high relapse rates as IIIA patients, right? So in trials that allow IIIAs, you should honestly allow the IICs as well. I think there will be a positive signal, I think it’s just obviously going to take time for relapse events.

James Larkin:

Yeah. How are you voting, Ana and Paolo, on this question?

Paolo Ascierto:

So James, you remember the BRIM8. In the BRIM8 we had a cohort with IIC, with vemurafenib single-agent it was positive in that cohort.

James Larkin:

Absolutely.

Paolo Ascierto:

So I believe it’s, if I should bet, I will bet on the positive results with the checkpoint inhibitor in the IIB and C. The IIB, it’s a little bit tricky compared to IIC. But looking the data from the BRIM-8 time points-

James Larkin:

I always mention exactly the same thing, Paolo. Maybe arguably the most interesting part of BRIM-8, but I probably shouldn’t say that. Right, Ana, what do you think?

Ana Arance:

Well, I don’t have much to say. I agree with all of you. So let’s see, let’s see with these trials.

SECTION 2: Neoadjuvant therapy

James Larkin:

It might not be that long, but we’ll see. Okay, very good, very good. So neoadjuvant, right, and I’m going to go back to you now. Actually this is a major of interest for you and of expertise as well, so let’s move to neoadjuvant. I’d love to hear your thoughts.

Rodabe Amaria:

So I mean, we’ve come a long way in neoadjuvant. Obviously neoadjuvant immunotherapy is really an active area of interest. I think the data from the OpACIN-neo study is really the new standard of care, with the ipi one mg per kg and nivo three mgs per kg. That is two doses prior to surgery and then no mandatory adjuvant phase, that’s really where we are in neoadjuvant therapy in melanoma. And so the study that we conducted at MD Anderson using the nivolumab with the anti-LAG-3 antibody, relatlimab, the idea was to see if we could find a regimen with similar efficacy, but perhaps a lower side effect profile. And we gave these two doses in the neoadjuvant setting. To me, I think we had very comparable efficacy data. I think we had something like overall response rate, 57%, path CR rate I think 59%, a good number of major pathologic responses as well.

So to me, the clinical data looks very similar. And obviously the patients that are having the major pathologic responses and path CRs are not having relapse events, as we’ve seen in other neoadjuvant studies. But I think the highlight was that this was a much easier study for me to manage personally, having done an ipi-nivo neoadjuvant study and having to deal with a lot of toxicities. Really the toxicity rate was pretty minimal in the neoadjuvant. And when we started to have toxicities, it was more in the adjuvant setting, because we traditionally have neoadjuvant and adjuvant phases to our trials. So with repeated doses, we were having more toxicities. But again, this was happening six months into adjuvant therapy. Neoadjuvant-wise, I think it’s a really well tolerated regimen with very similar results as we saw in the OpACIN-neo studies.

James Larkin:

Yeah. And do you think that might be a regimen that we’re sort of moving towards, in the adjuvant and neoadjuvant setting? And what about randomized trials, comparing one with the other? What about that question for let’s say, people who’re a bit more conservative about this?

Rodabe Amaria:

In general, as we’re going to talk about the RELATIVITY study, I think this is really potentially a paradigm shift. I feel like with the toxicity not being high with this combination regimen, it opens up use of this in various phases, whether it’s neoadjuvant, adjuvant and metastatic, so I think we’re just going to see more and more data with this combination coming out in future.

James Larkin:

Okay, great. Thank you very much for those insights, right. Ana and Paolo, what’s your take on neoadjuvant? Is it standard of care already? Have we seen enough data, all sorts of things we could ask about?

Ana Arance:

Well, I think it’s a very interesting approach to exploring in melanoma, is different from other tumor types. I am one of the ones that is for randomized studies to compare adjuvant versus neoadjuvant, I don’t think it’s a standard. I think these studies, these neoadjuvant studies needs to be plan or given within the context of a clinical trial. And I think it’s a very interesting pathway or a type of trial to follow. But I have a question for Roda, that many times has asked myself. Because in my environment, let’s say like this, we don’t have that many patient that are going to be candidates for a neoadjuvant strategy looking at clinically palpable or radiologically-evident novel disease. Which one is the percentage of patient that have been included, for example in your, in the study of nivolumab plus the anti-LAG-3? That first diagnosis was with this clinically-detectable novel disease, have you have a look at that? Or how many patient were relapses, recurrences following an initial diagnosis?

Rodabe Amaria:

Yeah, most of these patients are de novo clinical stage III disease. And I would estimate that that’s probably 10% to 15% of patients that we see at MD Anderson come in this way with … maybe it’s different in different areas, but this is the population. So it is limited, these are a small number of patients. But obviously having a bigger group of patients that come into your institution, it makes it possible to find these patients.

Ana Arance:

Okay, that was my impression. That in novel disease, it was that 15% maximum or 20% of the patient. But this is going high, we are usually more used to this maybe at 10% of the patients and 15% of the patient are de novo cases. Is because at some point-

Rodabe Amaria:

The other thing that I-

Ana Arance:

[crosstalk]-

Rodabe Amaria:

Will see more and more of is as we’re using more and more adjuvant therapy and we’re having in-field nodal recurrences, because people are not having completion in nodal dissections, this is bringing in a new population of patients. That I think would be eligible for neoadjuvant trials, even though they’ve had prior adjuvant therapy.

Ana Arance:

Yes, and I agree really. And maybe you, do we know if the biology or the … of these tumors de novo? And the ones that they are relapses, recurrences? It’s something that I think, I don’t know if the biology is the same?

Rodabe Amaria:

No, it’s not. And I will say that I have had a couple of patients, we allowed a couple patients on this trial that had had say, prior BRAF/MEK and progressed. They did terribly, right? So, they didn’t do well. So it’s the biology is absolutely different with these patients that had had a prior adjuvant therapy and progressed, and then obviously the de novo patients.

James Larkin:

Yeah. And I mean I think that it speaks to the importance actually of the neoadjuvant setting that we’ve got these refractory patients, massive unmet need. And actually you can do small studies with translation and so on and so forth, which may really give us a lot of insights I think. Paolo, what’s your take on neoadjuvant?

Paolo Ascierto:

A couple of short comment. The first, neoadjuvant at the moment may not be considered something right in a standard of care. And we need the clinical trial very soon, we will have our Phase III, the NADINA trial that Christian Blank is designing. Should start very soon, with the comparison with the neoadjuvant and the adjuvant. But there is also another important comment about research, because the neoadjuvant study are window of opportunity study. So this, it’s something important in development. So the data that Roda is showing about this combination, it’s a clear example about the power of the new combination, that we can check with pathological complete response. Yes, it’s a small cohort of patients, probably we need also to know the LAG-3-positive, maybe that there was a comment about the median size. But if will not be the 66% or major pathologic response, may be 50%. Surely this is a very interesting combination. Then we will discuss about the metastatic setting now, very soon. But is it the study that we should do, with the new combination to look to the power? To look to the safety, to look to the translational research and other things?

SECTION 3: Metastatic skin cancer

James Larkin:

Yeah. Thanks, Paolo. I think those are all great points. So I think we’re going to move on and that’s actually another nice segue, and talk about some of the metastatic data now. And I think maybe, Paolo, I’m going to sort of ask you to lead this part of the discussion. Maybe it’s best to talk about the RELATIVITY data first, because we’ve just been talking about LAG-3. And of course you and I and others were involved a few years ago now, when we were first looking at this. So, it’s great to see a positive Phase III. Then maybe after that, talk about some of the longer term follow-up data for some of our established regimens. Paolo, over to you.

Paolo Ascierto:

So that four years ago, we were seeing the first data about these combination. And what we have seen that at the time about, its most interesting part was the safety profile. That, well, we had important confirmation in the neoadjuvant setting with Roda in the RELATIVITY. So this is interesting combination, and mainly also for the safety profile. At the time we have seen the data and with interesting data in the patients who previously failed anti-PD-1, now is in first-line, an interesting study. I treated more than 150 patients with this combination, and this look really interesting. But if I look the data of RELATIVITY, I’m not so excited I have to say. And I will explain the reason, as far as this is the first time that I see a clinical trial when we see progression-free survival but not other response rate. We don’t know the percentage of complete response, partial response. It’s really strange.

And I’d like to also to look, so that the biomarker. Because we’re using only the data from the LAG-3 expression more than 1%, so the cut-off of 1%. I believe that it’s important also to look to a higher cut-off, to look to the co-expression of PD-L1 and LAG-3. Because I’m sure from the data, and some of you knows because you participated to the 020 trial, that in the LAG-3-positive we have seen a better response. Having say that, why I am so surprised about this data and not so excited? Because if you look at the control arm, the performance of nivolumab is not like the performance of pembro and nivo in the same setting. If it’s true like Jason Luke discuss, that the assessment was different. It was centralized in the RELATIVITY, it was based on investigator assessment in CheckMate 067.

If you look at the duration of the treatment, the median duration of treatment, the control arm is 4.9 months. That with nivo and pembro, we have seen a median duration in the arm of the treatment of about 11 months. So that the control arm performed not so well, I cannot say the why. Because if you look at the patients’ characteristic, I don’t see a characteristic that was really worse than others. And also if you look at the M1c and d, it’s 40%. It’s lower than the classical 60% that we have seen in clinical trial, yeah. Maybe the patients treated previously without an adjuvant, maybe some that … really I don’t know. But with an hazard ratio of 0.75, looking to progression-free survival I don’t know if this hazard ratio will translated in an overall survival benefit.

So, I’m strongly convinced that this is a very nice combination. The data that Roda presented, it’s confirm that it’s a powerful combination. I’m not sure that this combination will replace nivolumab and pembrolizumab monotherapy. We need a biomarker, we need to know which is the best patients for these combinations. Because ipi-nivo, from my point of view remain the first choice for the patients with elevated LDH, high tumor burden, brain met and mucosal melanoma. Having say that, we had an important confirmation where from the CheckMate 067 about the power of the ipi-nivo. Now we have a 6.5 years overall survival, and-

James Larkin:

Listen, Paolo. I’m going to stop there for a bit of discussion about relatlimab, because that you’ve made some excellent points there. I’m not privy to any insider knowledge, but I presume that the regulator accepted that statistical trial design without response rate. But I agree with you there, we want to see the response rate. And it kind of gives you confidence in the PFS if you see the response rates, so I think that’s one point. I want to ask you about safety though, Paolo, before I open it up with the others. So you alluded to that, but could you be more specific? Well, I’m going to be more specific now anyway. So I mean in the trial, I think there was quite careful monitoring for myocarditis. And I think, Roda, in your slides as well at ASCO, what you had one bullet point that myocarditis wasn’t much of an issue.

So in well conducted clinical trials which are carefully monitored, where you can mandate you know, where you can mandate troponin testing and all this sort of stuff, I think we can be pretty confident about safety. But let’s say there is a regulatory approval for the sake of discussion, fixed-dose combination, okay. It’s out there. Are we going to kind of be as confident about the safety monitoring? I mean myocarditis is a side effect that frightens me certainly, and I think frightens all of us. So what do you think about that, Paolo?

Paolo Ascierto:

So about the safety, we have ongoing still the 020. And the reason, because there was a lot of attention to the cardiac toxicity from the Phase I with the single agent. With relatlimab single-agent, because there were some side effect that then were translating in the combination. In the 020 with a higher attention to these kind of side effect, to look to the troponin, and you know very well because you also participated this trial. But now if we consider the 020, the different quarter, we have more than 1,000 patients treated with this combination. And it’s clear that looking at the safety profile, it’s a little bit more that the single-agent with the nivolumab. So we should look more at the data from the 020, that we have also the quarter with the flat dosage with both relatlimab and nivolumab even with the higher dosage. I believe that the safety profile, the toxicity that we have seen in the RELATIVITY study that were presented at ASCO is consistent with the data that we have seen in the 020 study.

James Larkin:

Okay, thanks, Paolo. Ana or Roda, can I move to you now? What did you think about the RELATIVITY study, what’s your gut feelings when you first see those data?

Rodabe Amaria:

So from my perspective, I have kind of a very different feeling than Paolo. I think this data is a little early, right? 12 months off, but I think very encouraging. And again skipping many steps ahead, if this does achieve regulatory approval, I would envision that this regimen could potentially replace single-agent nivo. So I’m not sure that single-agent nivo in the metastatic setting will have much of a role, I think this combination with its favorable safety profile could replace that. But I completely agree with Paolo-

James Larkin:

Very quickly, both, doing it single-agent nivo and single-agent pembro?

Rodabe Amaria:

Yes, correct. Sorry, single-agent PD-1s is what I should say. But I agree with Paolo that ipi-nivo is still your go-to in people with elevated LDH, symptomatic disease, brain mets, right? So nobody’s going to replace that, I think. But in the people that you are in your clinic deciding, “Boy, I think this patient needs a single agent PD-1,” I think it would very easy to say, “Okay, instead of single-agent PD-1, I feel confident with this combination.” Regarding the myocarditis, in my experience I, you can see myocarditis from single-agent PD-1, right? To me, I didn’t see any bigger signals except that I had the check troponins. And to me, that was more of a hindrance than a benefit. At least with the troponin assays in my hospital, it was an issue.

So to me, I did not appreciate any crazy safety signals. What I thought was interesting is that we had a lot of people with … not a lot, a few people when they were having toxicities, they were having adrenal insufficiency. That was a toxicity that we saw over and over in the adjuvant phase of the protocol, but it really wasn’t any kind of myocarditis or cardiac toxicity.

James Larkin:

Okay, thank you very much. So Ana, I’m going to ask you about RELATIVITY now. Then we’ll go back to Paolo for some discussion of the longer term follow-up from CheckMate 067, and then perhaps we can come back a little bit to ipi nivo and how this all fits together. Ana, RELATIVITY?

Ana Arance:

Well, I cannot add too much. I agree with comments of both, with Paolo and with Roda. Yes, it’s surprise to me also that they only presented the PFS data and no data on objective response rate or overall survival. I hope that this is going to be presented in the near future. I agree that the safety profile is, in my opinion, excellent. I participated in the Phase III, this is my only experience, and we cannot make a difference between the nivo versus if the patients were in the nivo-rela. It’s true that they waited. A study has been conducted with this first part kind of Phase II and then recruitment has stopped for a period of time, and then again. So may have influence how the data have been presented, I don’t know. But I agree with Roda, that maybe with a longer follow-up and in the future that may be an alternative to anti-PD-1 monotherapy.

With regards to comparisons with ipi-nivo, I think the only thing and the only situation now that I would prefer ipi-nivo probably is in brain mets. Because for ipi-nivo we have study showing the activity of ipi-nivo in brain mets, at least two studies. We don’t have these data for nivo-rela. And the other situation, high LDH, M1c and d, these are opinion-based. This is a speculation. I think this is investigator or expert opinion, but probably you would favor with data and more evidence ipi-nivo on the brain metastases situation. And then let’s get more data, a longer follow-up, more data to be shown from this study.

James Larkin:

Thanks, Ana. Actually I’m going to ask about cheeky question before we go to talk about long-term followup of CheckMate 067. So if you were reviewing the data for the RELATIVITY study, for say New England Journal of Medicine, would you accept or reject it?

Ana Arance:

I think I would accept it. Because it’s the first one, I hope that I’m not confused, that is comparing a combination against an anti-PD-1 monotherapy.

James Larkin:

That’s clear. Paolo, Roda?

Rodabe Amaria:

Accept.

James Larkin:

Paolo?

Paolo Ascierto:

Data is data.

James Larkin:

Oh, very diplomatic. Okay, very good.

Paolo Ascierto:

Yeah.

James Larkin:

Right then, we’ve talked a bit about ipi-nivo. Paolo, so over to you. Long-term follow-up with CheckMate 067, is that still standard of care for most patients? And maybe a word about COLUMBUS long-term follow-up as well, if we’ve got a bit of time.

Paolo Ascierto:

Yeah. So two important confirmation, the CheckMate 067 and the COLUMBUS as you said. So the COLUMBUS, if you look at the combination of encorafenib and imatinib and if you look at the five-years overall survival data, are consistent with all the other two combinations. And there is the confirmation that encorafenib is the best and vemurafenib, these are with the data now at five years. And also with-

James Larkin:

Paolo, is it the best combination do you think or not?

Paolo Ascierto:

I cannot say this for the efficacy. Looking at the safety profile, the pyrexia and photosensitivity is something that can affect the quality of life and probably is better tolerated. So this is my personal opinion, of course. And the data showed that looking at the percentage of grade 3 and 4, the discontinuation rate are seen, but it is my personal feeling. The CheckMate 067, now we have the data at 6.5 years. That to confirm what you have seen previously, but we have an additional interesting data. Yes, it’s just a retrospective analysis, but this is the melanoma-specific survival. 56% at 6.5 years, so it’s an incredible result I have to say. Even with median overall survival, the highest, never seen in the field of metastatic melanoma, 72 months.

So what we want more from the CheckMate 067 now, after this data? I believe that after this we can clearly say that ipi-nivo, it’s an important treatment. But even nivolumab monotherapy performed very well, so this probably, it’s another message. Anti-PD-1 monotherapy, it’s an important treatment for our patients, for metastatic patients. And this is something that it’s important for the country where ipi-nivo not to reimbursed yet, like Italy for instance.

James Larkin:

Yeah, thank you. I mean I think the reimbursement point is really an important point for patients, and we shouldn’t lose sight of that. Ana and Roda, what do you think about the CheckMate 067 6.5-year follow-up? Anything different from Paolo?

Rodabe Amaria:

No, I mean it confirms what we already know. This is a superior regimen, but basically it looks like it’s curing potentially 50% of patients. So I think in terms of how to improve on that is finding regimens that have the same efficacy, but with a lot less toxicity. We all know ipi-nivo is super toxic, it can be super toxic. So, that’s the way we go forward. But yeah, agreed, 10 years ago there was no regimen that improved overall survival and now we have this data which is potentially curing half of our metastatic patients.

James Larkin:

Thank you. Ana?

Ana Arance:

I don’t have much to add. Yes, it’s consisting of data that keep consisting a long time. And regarding to the data of COLUMBUS, I think this combination is similar in terms of efficacy to the other two combinations that we have available. They have a slightly different safety profile, some … and that depends on if you are used to use one combination more than the other, also the regulatory issues. But I think the three combinations, the data are quite consistent, so not much to tell.

SECTION 4: PD-1 refractory disease

James Larkin:

Thanks, Ana. I mean and I’d just make the point before we move on that as Paolo said, to show melanoma-specific survival, how about that? Considering where we were sort of 10 or 15 years ago, it’s a big deal I think. Okay, so the last segment’s going to be about the anti-PD-1 refractory space. Very, very important, I think arguably biggest unmet need at the moment in the disease. We’ve talked around it a little bit already. But we’ve got some data shown recently, Ana at ASCO. And I guess a couple of things at least in the oral session, one was the Leap data. I think lots of interesting question and discussions there, and some of that comes back a little bit to the kind of anti-PD-1 rechallenge thing. If you see what I mean, we’re really seeing something different there. Is lenva doing anything, is the biology of that drug important or not? I mean there’s all sorts of questions, and then the lifileucel data was the other one perhaps to think about. So Ana, over to you.

Ana Arance:

So as you have said, patients who have progressed on anti-PD-1 in the metastatic setting or in the adjuvant setting, I think this is a real big problem. I feel that it is a big problem, one of these same questions of patients that you have in clinic. And I think it’s very difficult. I’m sure all of you are participating in clinical trials. And I always say that all these clinical trials, they don’t compete among them. Because they have different inclusion criteria and different definitions to include patients, and we need more of these patients. I think it’s very interesting and nice that the data from the TILs have been published or presented in congress, the data of this pembro low-dose ipi have been published and the LEAP-004 have been shown also in congresses. Because there are many arms within clinical trials and trial that they have not been made public, because they have been closed. Because of futility, because of no activity.

So my main message is that it’s a very difficult group of patients to treat, that now we have many patients who have progressed on adjuvant anti-PD-1. Many times they have a small-volume disease, and they are in an excellent general condition. And there is no standard of care, I would say in my opinion, what to do in this situation. That all these trials are very heterogeneous among them, and they have different number of patients included. They are single arms, their definition or the order of operating those lines are different among them. For example LEAP-004, I think LEAP-004 is the one with the highest number of patient that have been included in this setting. Their response rate is 21% approximately, very well defined at least within the trial the type of patient that would be included. But also in terms of progression to anti-PD-1, because all the progression and all their responses were check by an independent committee. But the population of patients similar to the TILs trial, they have been heavily pretreated and they have received many lines.

One of the messages also from the trial, the duration of the response is less than a year. So I don’t think that we know what can we expect in this population in patients the who are resistant or they are refractory to anti-PD-1, which is the rate that we can expect in these patients. And what I envision is that maybe in the future we may have different treatment strategies for these patients. Because in the pembro-ipi they were treated, most of the them immediately after anti-PD-1 progression. In the LEAP-004, 60% of the patient had received two or more lines, something similar to what’s happened in the TILs trials. The response rate in the TILs trials is higher, but it’s a special treatment. And we have to agree that this is special treatment, it’s not for all patients. 36% of response rate is high.

But I have worked up my numbers, it’s approximately 55%, 60% of the patients of these responders that a response last for more than a year. While only are 40% or 30% of the patient in the LEAP-004 trial, their response last more than a year. So, that tell me that these patients are difficult. And also is my question, which response rate do we have to expect in this population of patients? 20%, 30% when in first-line we are getting with anti-PD-1 monotherapy 30% to 40%? What is … I have … and I think we have many questions. We need a randomized trial in this setting.

James Larkin:

Thanks, Ana. So, that’s great. I got asked this stuff, where I presented the data actually for lifileucel about regulatory approval. Maybe you just answered it when you said you needed a randomized trial. I mean are those data strong enough for regulatory approval either in the US or in Europe, or not? And once you’ve answered that, I’m going to open to Paolo and Roda for their thoughts on this.

Ana Arance:

Well, I have always said, even for the LEAP-004 study that probably in the European context in this setting, we may need a randomized trial.

James Larkin:

And Ana, what’s the what’s the control arm? You just said there’s no standard of care, is it cytotoxic chemo?

Ana Arance:

No, well, it depends. I think it should be left to the investigators to choose, because maybe some patients come straight from anti-PD-1 corroboration. And then we know from the ipi-tilsotolimod that response rate following anti-PD-1 is 8%, in the context of an international randomized trial. So that it was an area, how difficult to treat are these patients? Or combination anti-PD-1 plus anti-CTLA-4, but I mean what has happened to the patient who have already receive anti … I think probably the control arm will need to be, will depend on the design of the trial. At which point you include the patients, just immediately after they have anti-PD-1 or after several lines, because that happens in real clinical practice. We, I have many patient who have received many lines of treatment. And maybe it will be to the choice of the investigator and could be anti-PD-1, the combination of anti-PD-1 plus anti-CTLA-4, even cytotoxic chemotherapy. Or usually they are combination, one of the drugs that they combine with the anti-PD-1, so I think this is open and it’s going to depend on the design of the trial at the time point where the patients are included.

James Larkin:

Okay, thanks, Ana. And listen, we’ve only got about five minutes left. So Paolo and Roda, two or three minutes each for your thoughts. And I’m anxious to hear what you think as well about regulatory approval, standard therapy, control arms, need for randomized data. Roda, do you want to go first, maybe a sort of US-type perspective?

Rodabe Amaria:

Well, I mean I like the LEAP-004 data. I think it’s great, focusing on PD-1-refractory patients. I loved that that trial had 55% of patients with elevated LDH, which really represents the patients that we need the best therapies for. As Ana pointed out, you’re not necessarily having a tail of the curve, right? It can work for a period of time, it stops working. It’s not necessarily as durable as we’ve seen with the TIL data. Which seems to have deepening responses every time they go back and look at the data, which we would expect from a traditional immunotherapy regimen. What I’ll say about the TIL data is agreed, it looks great. But as Ana said, this is a select patient population.

This is going to be, if it is regulatorily approved, I don’t think that will be the majority of patients who will go on to get TIL. I mean at least in our institution it’s, this is a very selected group of patients that go on to get this treatment. And I think the data looks very good, because these patients fit that very strict criteria. In actuality, I don’t know how effective this regimen will be. In terms of regulatory approval I think the TIL data is closer in the US than perhaps the LEAP, the lenvatinib data. The lenvatinib needs a randomized trial, I think that’s going to be a little harder to do with the TIL data. And based on that very robust overall response rate and the persisting duration of response in treated patients, I actually think it will get regulatory approval in the US at least.

James Larkin:

Thank you. Paolo, last couple or three minutes for you.

Paolo Ascierto:

No, yeah, so I will try to be really short. The first … second-line in metastatic melanoma, it’s now the phase where we need to do something. So, it’s a strong unmet need for this group of patients. And looking the data, are interesting. I agree that it’s in a small cohort of patients, but of course we need some sign to go in better trial and larger trial. It’s interesting the data about the LEAP-004 in the patients who failed anti-PD-1. Yes, it’s just 30 patients, but looks interesting. Also the data about the TIL and probably, James, I believe that we should look. This was a question that someone asked you for the pegylated IL-2. So now, we have a lot of pegylated IL-2. We have a clinical trial, and probably this is the right compound to combine with the TIL.

So, we’ll see. And about the regulatory issue, I believe that in Europe with this data we cannot get the approval and we need a randomized trial. And I agree with Ana, at the moment with no standard of care, the best, investigator choice should be the control arm for a trial in the second line.

James Larkin:

Okay, thank you very much. I suppose once minor notice that we’re no longer part of Europe anymore, at least from that perspective. So I don’t know what our regulatory situation is going to be in the next little while, but I guess we’ll find out. Okay. So listen, everybody, that was a lot of fun. You’re all smiling. We had a great discussion, we could’ve talked for much longer I think as well. Thank you very much, indeed. Thank you for joining us. I hope everyone’s found that informative and interesting, and we will end there.

Recording date: 30-June-2021; Webinar broadcast date: 28-July-2021; Feature publication date: 29-July-2021.

James Larkin:

Consultancy:

Iovance, Boston Biomedical, Pfizer, BMS, GSK, Novartis, Incyte, Immunocore, YKT Global, iOnctura, Apple Tree