AS: Hi, I’m Dr Alex Spira with Virginia Cancer Specialists and US Oncology Research. Today, I’m joined by my colleagues to talk about EGFR exon 20 insertions and some of the new data that came out at ESMO.
EF: My name is Enriqueta Felip, I’m a medical oncologist working at Vall d’Hebron University in Barcelona in Spain.
JS: Hi, I’m Dr Joshua Sabari, I’m a thoracic medical oncologist at NYU Langone Health Perlmutter Cancer Center in New York. Really excited to be here.
AS: Josh and Enriqueta, it’s great to have you guys here. So it’s been a fantastic ESMO hearing about these exon 20 insertions and amivantamab. I’ll just start with the background in the field. Obviously we’ve had mobocertinib and amivantamab in the second line and we heard a lot about some new data now in the frontline setting. So, Josh, I know you’re one of the authors so why don’t you start the conversation?
JS: Yes, so first off EGFR exon 20 insertion mutations, as we know, are uncommon, occur in maybe 1-2% of patients with lung cancer, maybe 10% of EGFR mutations as a whole and really hard to diagnose them if we’re using PCR-based assays, so NGS broad panel is what we recommend. As you mentioned, the data for amivantamab in the second line was quite impressive but so was the data for mobocertinib in the second-line setting. So this is trying to take that agent, amivantamab, and study it in the front line. So the PAPILLON trial randomised phase III study of amivantamab plus chemotherapy versus chemotherapy alone and this is treatment naïve patients in the frontline setting. I thought the data was practice changing. This is a regimen that led to a doubling in the median progression free survival. The overall survival is still immature but, regardless of that, two-thirds of patients in the chemo alone arm crossed over to receive amivantamab and there is still significant looking difference in the survival trend right now. So I think this is exciting, it’s practice changing. What are some of your concerns, though, with the addition of amivantamab to chemotherapy in the frontline setting?
AS: I think some of the current concerns, obviously, are toxicity, number one. These are obviously different side effects combining but most of the patients would have gotten it anyhow and we obviously learned a lot from the mobocertinib world that side effects are a big thing and, in fact, in the United States mobocertinib has just been pulled from the market. So, Enriqueta, what are your thoughts? What do you think about the toxicity and then I’ll ask you both are you going to give it?
EF: No, I think the study, as mentioned, is practice changing. I think it’s important to say that we need testing. This is especially important perhaps in Europe, now we need testing, we need NGS and we need also liquid biopsy because, for me, the study is clearly positive now so it’s changing the standard of care in a group of patients that we know that EGFR TKIs are not effective. So, for me, the results are amazing so it’s doubling the progression free survival for our patients. But, yes, there is a need to manage the toxicity. But, again, we have teams, we have to work all together with the nurses. For me, nurses have a clear role in the management of these infusion reactions that the patient has and also to have the [inaudible] to treat skin toxicity and mucositis. But, yes, I think when we work altogether this toxicity is manageable.
AS: So, Josh, what concerns you most about the side effects? There’s rash, there’s a little bit of GI side effects, it’s an EGFR drug and obviously infusion reactions. What are your thoughts and how do you manage those, especially infusion reactions?
JS: Yes, so the infusion related reactions you see commonly, 60-70% of patients. I think actually on the PAPILLON trial a little bit lower than what we saw in the earlier development. We’re more used to managing this, we split the dose, cycle 1 day 1 and cycle 1 day 2, we also premedicate with steroids, dexamethasone, antipyretics and antihistamines. That really does mitigate the toxicity of IRR. We don’t see IRR, the infusion related reaction, after cycle 1 day 1 generally. So it’s something that happens, you educate the patient, like you mentioned. You educate your staff, your team, and you don’t see it become a major issue. We’re also moving to a subcutaneous formulation, as you know, the PALOMA trials where that will dramatically reduce the risk of this infusion related reaction. The IRR, to me, is not something that is clinically an issue but in community if you haven’t given the medicine before that might be an area of concern. For me it’s the more long-term toxicities, things like rash, the potential low rates of diarrhoea and also VTE, venous thromboembolism, we saw at a slightly higher rate in this patient population.
EF: I think it’s important that the infusion reactions are predictable. As you mentioned, it’s in the first cycle only so we can predict and it’s really the situation in which perhaps we are recommending to give this treatment, the first one, in the morning when all the staff are in the right hospital. But then we know that it’s not happening again. So I think this is important.
AS: Yes, I laugh that you say that, Enriqueta, because what we do in our clinic whenever… I always tell my patients there’s always going to be an infusion reaction and when there is one I always say it’s got to be an amivantamab patient because you could pretty much rely on it. I think the nurses are so tuned into it they call you for anything. I think the patient is going to have one and obviously we can manage through, but I agree, we can manage it pretty much that way. Is there anybody you wouldn’t give this cocktail to? Or this is going to be for everybody, by and large? By the same thing, is there anybody you wouldn’t give the chemo part to and just the targeted agent? There’s been a big push – targeted agents should be given, we know that from the EGFR world, the ALK world. In exon 20 it was always both of these drugs, mobocertinib was taken off, were given in the second line. Would you think about is there anybody you wouldn’t give it to and then, secondly, is there anybody you wouldn’t give the chemo part and just give the targeted part to?
EF: I think when you have a treatment that is improving outcomes, it is better to give it first. For sure, we have to discuss with the patients the options that we have, but for me the results are clear and I would recommend to give this combination in first line. It’s true that the situation is that we are giving chemotherapy plus amivantamab in this target; we have other clinical trials ongoing that we are analysing in first line TKIs, for example. Furmonertinib that is a new compound and TKI that is also analysed as monotherapy in first line. But you have the results of a phase III trial that is giving a combination of chemo plus amivantamab, this study is positive. Although we can discuss for sure, and the patient is the most important, I think this is the practice-changing trial and this would be our standard.
JS: Also the question depends on what is your current standard of care – is it chemotherapy alone, platinum doublet, or are you using chemotherapy with immunotherapy in the front line? I’m not a major believer in using a PD-1 or PD-L1 inhibitor in this patient population so, for me, I agree with you, amivantamab plus chemo becomes my standard of care in all EGFR exon 20 insertion mutant patients. I would not give a patient just amivantamab alone – we don’t have sufficient data in the front line. In the second line the data, though, look quite good – 40% response rates or so and progression free survival around that 7-8 month range. But, as you mentioned, there are so many new therapies. You mentioned furmonertinib, there’s also sunvozertinib, we saw data at this meeting here where we’re seeing in the later line setting 70% response rates. So moving that also into the front line. So, how do you predict the future, Alex, here? How do you think it’s going to look in the next 3-5 years?
AS: It’s amazing, it’s getting complicated, right? We’re going to have a whole slew of new drugs coming down clinical studies. So I don’t know where the field is going to take us. We’re going to have other drugs being looked at in the first line, other drugs in the second line, clearly there’s a lot of new drugs coming out there. Furmonertinib has a front-line study that’s coming that’s versus chemo right now. It kind of begs the question – that’s versus chemo, we learned from FLAURA2 that if you add chemo on to a really good EGFR inhibitor for the typical ones you still do better. So maybe we should be considering them all and some of these are just not even viable concepts anymore. So I think there’s a lot to be talked about. For me, the biggest concern about all this, and we can get to where we’re going to go, is brain metastases. The amivantamab, they didn’t look at it that closely but we all think because it’s a monoclonal you’re not going to get a lot of good central nervous system penetration. Now, there are anecdotal reports going there but, for me, that’s the biggest limitation. So there are a few new drugs coming down the pipeline, BLU-451 or ORIC-114, that are really looking at the CNS penetrance of these drugs and are really focussing that, of course first in the second-line setting. So let me ask you, is that a super-important thing to do? How do you manage brain metastases and do you think there’s a role because clearly the developmental path has got a lot more complicated? So, Josh, I’ll start with you.
JS: I think brain metastases are common, upwards of 30-40% of our patients with EGFR exon 20 insertion mutant disease will develop brain metastases over their lifetime. It’s an unmet need, clearly. Amivantamab, I agree with you, I don’t see great intracranial activity. There have been responses documented but it’s a large molecule so the question really is do you need a small molecule, a TKI? I do agree that the BLU-451 data early on, we saw some data on ORIC-114 here as well, that’s going to be a huge battleground. That’s one limitation of the PAPILLON trial, it did not enrol patients who had active untreated CNS metastases. It was well balanced, 20% or so in each group, chemo versus amivantamab and chemo, but these were all treated patients and I think they had a four week washout. So we’d look to see the data, the subset analysis of those who had brain metastases, to see how they do and also look at CNS recurrence down the road as well. But for right now, as we stand, I think that there is a significant unmet need. I personally would radiate patients who have CNS metastases up front, I’m curious what you would do.
EF: I think the management of brain metastases is really important. It’s true that for these patients with EGFR exon 20 insertions we are using to treat the patients with stereotactic radiotherapy in the brain when there are lesions. Also, yes, patients are receiving also chemotherapy that has some activity in the CNS. Again, I think there is a need for the sequence of a number of strategies and, of course, we have now chemo plus amivantamab but there are at least TKIs that are now in development that are active in CNS and could be important to analyse also the best sequence in this patient population.
JS: You brought up a really important point I want to double click on a little bit. The concept of do you need chemo in the front line, can you just use a TKI versus chemotherapy? It’s a really interesting question, it depends on how good the activity is in the second- and third-line setting. With mobocertinib we initially saw 43% response rates and then unfortunately it came down into that 20% range. The EXCLAIM-2, as you mentioned, which was mobocertinib versus chemotherapy, we saw in the press release was a negative trial. So we’ll need to see that full dataset but mobocertinib, as you mentioned, is now pulled. So I do worry about single agent TKI in the frontline setting – are we moving too quickly? But if you have 70-80% response rates for a TKI, I think that will beat out chemotherapy in the frontline.
AS: Yes, you talked about sunvozertinib there, they were reporting really high response rates. You remind me of the days of poziotinib, though. The first study in poziotinib had a 70% response rate at MD Anderson and we all thought it was going to be the greatest thing.
JS: Right, it just kept on going down.
AS: And it kept on going down. I think it ended up at 17% with a very narrow therapeutic index so it’s gone away for the most part.
JS: So toxicity is important. For you, Alex, how do you think about the difference between an IV infusion EGFR/MET bispecific versus an EGFR BDAD TKI tox-wise? Because these are totally different types of agents.
AS: It’s a great question and, for me, we’ve done a lot of these ad boards and people have asked us. For me, when I compare it when mobocertinib was approved versus amivantamab, most of us in the room sat around and said, ‘We like amivantamab better because of the toxicity.’ But that’s of course not the real world patient that’s sitting in front of you who has got to come in for the treatment, deal with the infusions, deal with the side effects of that and the time. I think if you looked a lot of patients in the real world who were given mobocertinib, despite the fact a lot of KOLs, knowledge leaders, were really pushing people towards amivantamab. I think there’s going to be a huge desire still to find an oral drug in this scenario. So we’re all looking for an easy thing, that’s why people as we debate the typical EGFR mutations, Tagrisso versus the others, it’s going to come down to not just benefit but it will come down to quality of life, side effects as well as time within the clinic. Here, though, if you look at the second-line response rates, and will have to see how sunvozertinib plays out, but, for me, all the amivantamab and the mobocertinib in the second line just didn’t have enough to cut it as a second-line drug, for whatever reason. We probably just don’t understand. So I think in the frontline it’s going to probably be given with chemo and I asked the question but I’m going to follow along the trials. So what do you think is going to happen? We have a lot of new drugs coming down the pipe, so this year we heard about BLU, we talked about sunvozertinib, we talked about ORIC, we talked about furmonertinib, there’s actually new ones coming down to clinic – this company called Scorpion has a new drug as well. It’s actually almost more trials than patients right now, so you wonder. So what do you think? How do you think, Enriqueta, the field is going evolve? This is a big guess, right, what do you think is going to happen?
EF: I think we have a new standard and we need to build from this new standard that is first line chemotherapy plus amivantamab. It is not easy to develop clinical trials in this subset population because it’s an uncommon molecular alteration and represents probably only 10% of all patients with EGFR mutations. On the other hand, I think that this mutation is probably less sensitive when we compare to sensitising mutations. So I am seeing probably the future first chemo plus amivantamab, amivantamab has a unique mechanism of action, and then to have tyrosine kinase inhibitors with a higher potency and also CNS activity in patients previously treated with this chemo plus amivantamab combination.
JS: The fact that we’re talking about all these new second-line, third-line agents, does that need to then beat out amivantamab and chemotherapy or would you be satisfied with a sunvozertinib versus chemo or a furmonertinib versus chemo type study? It’s an interesting thing to think about in this world and is there any opportunity to combine amivantamab with one of these TKIs so you get the better brain penetration, you have the durability that you do see with amivantamab.
AS: That’s a great point. I think for me we’d all like to get to a chemo-free cocktail. But, then again, chemo, carboplatin pemetrexed, is not the end of the world and we’ve all given it. It’s a pretty well-tolerated chemo, you drop the platinum after four cycles if there’s not a shortage. So most people can actually tolerate chemotherapy pretty well. But there’s something theoretically nice about having a fully targeted approach. Another question, do you guys think about EGFR mutations in the exon 20 are complicated, right? There’s location, loops etc. Do we know enough and do you think about any of those mutation locations different or are we just lumping them all together?
EF: I think this is an important question and I think there is not enough evidence. As far as we know mobocertinib has results and has activity irrespective of the kind of mutation but I would like to see the same results with amivantamab now in the PAPILLON trial and know exactly the response rate, if the PFS is the same. As far as I know, the main issue is that there are a lot of mutations, different mutations, so it’s a heterogeneous group and probably it’s not easy to find.
JS: We talked at the beginning, using PCR you’ll miss half of these mutations in your practice. There are over a hundred EGFR exon 20 insertion mutations so you really need to do broad panel NGS. You agree, far loop, near loop, there are so many different locations. There was a really nice abstract here presented at ESMO looking at the different TKI and potential activation or activity in the different mutations and there is a concept there that maybe some small molecules work better in certain locations of mutations whereas amivantamab, we’ve shown on CHRYSALIS cohort D, has activity broadly but we have not seen that data yet from PAPILLON. I think that’s going to be a very important subset analysis to look at as well.
AS: That kind of makes sense, we have a small molecule that has to get into certain parts of it but you have a monoclonal antibody that just sits at the cell surface although we know it has multiple mechanisms of action, including this thing called trogocytosis that didn’t exist when I was a medical student. Do we know anything about resistance patterns? I don’t think we do yet and people haven’t really looked at that or do you know anything?
JS: For mobocertinib we looked at some of the data and there have been some reports of T790M emerging but that’s not something common that I’ve seen with amivantamab. But we don’t have any large subsets of patients with amivantamab so one of the things that I think is clear is, as good as the PAPILLON data is, these are not cures for our patients. So we do need to study how patients progress and what are the resistance mechanisms. So plasma and tissue NGS are going to be critically important here. That’s going to help us guide the next generation of therapies.
AS: Do we know anything? Back in the day when we had mobocertinib, and this just happened a few weeks ago, a lot of people would give the monoclonal and then give mobocertinib or backwards. In fact, in the United States it was on the NCCN guidelines and really in the absence of data you give one followed by the other. What do you think? How do you think that’s going to play out? Do you think there’s going to be a lot of… ? We have a little bit of hints about activity maybe in BLU and maybe in ORIC but do you think that’s going to be… how viable do you think it’s going to be, looking at, right now, after our conversation I think we can say most people are going to get amivantamab. But do you think there’s going to be a lot of activity with TKI after that? What are your thoughts?
EF: I think the mechanism of action is different so, yes, I expect some activity in patients previously treated with amivantamab. I think there is also an older antibody drug conjugate, it seems, and also during this ESMO there are presentations that are also active in patients with actionable genomic alterations after targeted agents. So if I have to predict something I think, yes, first the patients should receive chemo plus amivantamab then probably a TKI. That could be interesting to know the responses in patients previously treated with amivantamab and you have also the potential use of ADCs in this scenario.
AS: Yes, so there’s a lot of ADCs in development; there’s data about some of the TROP-2 drugs in patients with actionable genomic alterations. So there are going to be a lot of different options and it’s actually getting really complicated. There are going to be a lot of choices and we are experiencing this throughout the EGFR world where for the first time, due to the rapidity of drug development, there’s not going to be one standard choice. We’ve pretty much had limited choices for a long time but now you’re going to be open to a whole lot of things that doctors may in fact differ on and have to individualise it. So I want to thank you guys both for participating and I want to thank the audience. Thank you for listening to this ecancer segment. I hope you learned a lot about the emerging data, especially in PAPILLON as well as some of the emerging drugs in EGFR exon 20 insertions. Thank you.