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Lung Cancer Session with leading UK thoracic experts Sanjay Popat, Alastair Greystoke, Anna Minchom and Riyaz Shah

EGFR exon 20 insertions and how to manage patients in the UK

In the first roundtable in a series of Lung Cancer Sessions organized by VJOncology and the British Thoracic Oncology Group (BTOG), leading UK thoracic experts Sanjay Popat, Alastair Greystoke, Anna Minchom and Riyaz Shah will discuss the identification of EGFR exon 20 insertions and how to manage patients in the UK, based on the recent decisions made by NICE on the use of amivantamab and mobocertinib.

Part 1: Current treatment options for EGFR exon 20 mutations 

‘There are two key drugs that are of interest here. One is an antibody called amivantamab, which has a license and this is a bispecific monoclonal antibody that hits EGFR and MET…the other drug is mobocertinib, so this like osimertinib…this is a tyrosine kinase inhibitor and it’s an irreversible orally bioavailable TKI which has a license.’

‘This is quite interesting. In oncology we are used to seeing really big, randomized phase three studies. The drugs that we use only get available on the NHS in really big studies and here two drugs…with a label, based on very small studies’

Riyaz Shah

Part 2: Managing patients according to real-world evidence – response rates and potential toxicities 

‘…Real-world evidence is pretty important in this patient group. As we said, they’re rare patients. You’re unlikely to get large, randomized control trials by which you’re going to get direct comparison. So real-world evidence is pulling the data from patients who are receiving standard of care’

‘…What you can learn from that, as you say, is about what people are using and certainly from data sets I’ve seen, it’s pretty split across in a post platinum era using either chemotherapy likely taxanes or even platinum re-challenge or as you say, immune oncology drugs, so immunotherapies.’

Anna Minchom

Part 3: Identifying EGFR exon 20 insertions 

‘This is where oncologists need to be really careful because if you’re sending testing for your patients, what genes get tested for so you can see if your patient’s being tested adequately for a RET fusion or a ROS1 fusion.

The problem is you need to actually look at the technology that’s been used because if it’s been done with a sort of EGFR, PCR like a single gene test or even a point of care device, a lot of these insertions may be missed so studies have suggested you might miss 40 to 50% of these patients if you’re using one of the older technologies.’

Alastair Greystoke

 

Full Transcript

Sanjay Popat:

Well, hello everyone and welcome to this first of several lung cancer sessions hosted by VJ Oncology and the British Thoracic Oncology Group, BTOG. I’m delighted to invite you to this session which will be focusing on the controversial and relatively novel area of EGFR exon 20 insertions in advanced non-small cell lung cancer. My name’s Sanjay Popat, I’m consultant medical oncologist at the Royal Marsden Hospital and I’m joined by three legends in their lifetime, three experts who know this area incredibly well. My colleague Dr. Alistair Greystoke, who’s at the University of Newcastle, Dr. Riyaz Shah, who’s at the Kent Cancer Center, and my colleague Dr. Anna Minchom who’s at the Royal Marsden Hospital, all medical oncology consultants. So we’re going to kick off asking about exon 20 insertions. Alistair, we hear about this term. What are these exon 20 insertions? What does this mean?

Alastair Greystoke:

Yeah, so I think we’re most used to the sort of classic sensitizing mutations of the 15 pace pair deletion in exon 19 and L858R and some of us may have seen on reports over the years EGFR exon 20 insertion is as a resistance mechanism to our standard TKIs and our hopes raised and then they fell again. They’re relatively uncommon, we’ll talk about it, it does partly depend on how you test, but maybe 5% of EGFR mutations have this insertion in exon 20 and what it does is it sort of activates in a different manner, but it activates the EGFR receptor but in a way that the classic first, second, and probably third generation EGFR inhibitors don’t block and leads to cancer in that sort of mechanism as we used to, as a sort of activating optogene.

Sanjay Popat:

And if you find an exon 20 insertion, what does it actually look like on the report? Does the report actually stay EGFR exon 20 insertion or not? Or do we have to interpret it? How do we, in the melee of the report, pick this up?

Alastair Greystoke:

Yeah, so hopefully if you’re a genomics laboratory lab, which is where most of these will be picked up, if you are working in the English environment, they should highlight that this is known as an EGFR exon 20 insertion but that they do have to give sort of genomic nomenclature and as you’ll hear, there’s a number of different insertions out there. They are some of the most common ones, but in general what you’ll see is they’ll say insertion or INS or duplication, which means say just say DUP and often these will be free extra base pairs and somewhere between the six, 762 to 774, that’s right, I always have to check myself mark but that’s the exon 20 and that’s where you see them and there’s some that are particularly common and you’ll get used to seeing, but often these will, well they should normally be multiples of free numbers or free letters rather that shows the free base pairs that are being inserted or six base pairs, most commonly free [inaudible 00:03:14] and it should say insertion or duplication.

Sanjay Popat:

And how are these patients currently being treated? I mean our current commissioning for osimertinib in England just says EGFR mutation, so is that what we should be doing first line? What are these patients currently getting?

Alastair Greystoke:

Well, so it’s not sensitizing and osimertinib is standard dose as very limited activity in these. Again, you will see, if you’re go into the literature, that there’s some of that called proximal, which are some of the more rare ones that are in the actual C helix themselves and they may be more responsive to some of the standard tyrosine kinase inhibitors and some of the new ones that we may talk about. But most of the them are more distally and these don’t respond to osimertinib. Osimertinib is for this classic sensitizing EGFR mutations, that was what [inaudible 00:04:10] in flora and so in my practice, certainly up to date and we can talk about whether it’s the right thing to do or not. I’ve tended to just treat it as that in the first line setting as a resistance mechanism EGFR and I treat them as wild-type in the first line setting.

Sanjay Popat:

And so they’re treated with chemo, platinum doublet chemotherapy, platinum and pemetrexed as per standard.

Alastair Greystoke:

Yes, correct.

Sanjay Popat:

Yep. Okay. And Riyaz, do we have any drugs specifically that might target these mutations? What have you got our past leave?

Riyaz Shah:

Yeah, so basically there are two key drugs that are of interest here. One is an antibody called amivantamab, which has a license and this is a bispecific monoclonal antibody that hits EGFR and met. And so that drug has an FDA label and it has an EMA label and the labels are for exon 20 insertion patients in the post platinum setting only. The other drug is mobocertinib, so this like osimertinib, afatinib, all the ibs, this is a tyrosine kinase inhibitor and it’s an irreversible orally bioavailable TKI which has a license.

Now this bit’s quite tricky because in the FDA it is licensed in exactly the same space as amivantamab. The UK, now that we’re not linked to EMA, also has a label, but in EMA the application was withdrawn, the EMA asked some questions of the manufacturer questioning the response rate being a bit low and the manufacturer basically withdrew the application. So there is an odd, unusual approval system. So amivantamab FDA EMA approved, mobocertinib, just FDA approved in our NICE system. CDF reimbursement is just for mobocertinib.

Sanjay Popat:

And so can I just clarify, we have MHRE approval for mobo and we have NHS commissioning through CDF4 mobo in England so we are allowed to use mobo, prescribe it as of today and that’s-

Riyaz Shah:

Through Project Orbis so it’s been on label for some time-

Sanjay Popat:

Okay.

Riyaz Shah:

… now, maybe even up to a year, I can’t quite remember but quite some time.

Sanjay Popat:

And just remind us what is the indication?

Riyaz Shah:

So the indication for both drugs is in a patient who has a stage four patient with, it doesn’t actually say that in the label, but an advanced disease, the patient with a known exon 20 insertion in EGFR post platinum.

Sanjay Popat:

Okay. So we using it effectively in the second line setting. You start off with first line-

Riyaz Shah:

Assuming they haven’t had a first line conventional EGFR inhibitor, the conventional thinking what would be that these patients would’ve had first line chemo or chemo-IO. There’s a discussion to have around that and then this would then be introduced as the second line treatment.

Sanjay Popat:

Okay. And what is the approval based on? What is the efficacy and what’s the sort of toxicity that we see?

Riyaz Shah:

So both drugs have been… So this is quite interesting. In oncology we are used to seeing really big randomized phase three studies. Our drug, the drugs that we use only get available on the NHS in really big studies and here two drugs are potentially, well one of them is approved, but two drugs with a label, based on very small studies, basically phase one dose escalation and then dose expansion cohorts two studies, one called CHRYSALIS and the other one called EXCLAIM that’s documented the MTD, documented the activity, both powered for response rate and I mean I think we’re going, through the course of this discussion talk in detail about the efficacy, but two very similar studies and I would call them essentially phase 1B/ phase 2 studies.

Sanjay Popat:

And this is because they’re in an accelerated approval paradigm with the US FDA isn’t it?

Riyaz Shah:

Correct.

Sanjay Popat:

And Anna, Riyaz has been talking about amivantamab, I know you’ve been using it in the trial. So how does amivantamab work compared to what we normally think about with monoclonal antibodies and how do you administer it?

Anna Minchom:

So it’s a bispecific antibody. So in simple terms it’s two antibodies in a construct together, which has Riyaz says, targets both EGFR and met on the cancer cell surface. So it is quite unusual in terms of drugs that we use in lung cancer. It’s got a variety of different proposed mechanisms, some you’d expect such as ligand binding and also endocytosis and degradation of that bound receptor and also some sort of immune mediated proposed mechanisms of action. So how do we use it? Well, it’s intravenous. We can talk through the dose escalation portion of the study, which it gave us a recommended phase 2 dose, which is dose banded according to weight above and below 80 kilos.

And then it’s administered in quite an unusual way. I’m sure many people are using it in the UK now, you have a dose, but it’s split on day one and day two, so a half dose on day one and day two of first cycle and that’s to get around this issue of infusion-related reactions which are quite prevalent in the trial, both fairly low grade and vast majority. After your split dose on day one and day two the drug is given weekly for the fair cycle, which is 28 days and after that is given fortnightly so essentially got a bit of a loading period for that first cycle of treatment.

Sanjay Popat:

And with the infusion reactions, is that, how do we manage that? I mean is that something that you need to supervise personally? Do you need to train your nurses for that? How does that work?

Anna Minchom:

Well they’re very predictable in some ways in that over 90%, I think it’s 94% or something in the trial, occur on that first day. After that there’s about 4% on the second day and then diminishing these smaller, small incidents of infusion reactions after that. So it’s partly about counseling of patients to say, you know, are quite likely to have the infusion in the first day. This is what it might feel like, this is how we treat it so they’re prepared and also staff training. The practical aspects of it is slow infusion times that’s sort of clearly described how you can increase your infusion if your reactions aren’t occurring and then pre-medication with steroids, antihistamines, antipyretics.

Sanjay Popat:

And what is the natural history of these patients? So if we weren’t using mobocertinib which Riyaz has talked about, and we weren’t using amivantamab, which you’ve talked about, they’d presumably be getting either a taxane or IO, I’d have thought. I always thought that taxanes were what people were getting but I know Ali, you and I have had a sort of different chat and some of the feedback we’ve had from people around the country when it comes to the NICE submission was that actually there’s a wide diversity of treatments that people are giving. What happens to these patients normally after progression on platinum?

Alastair Greystoke:

I think the first thing to say is that these patients have a poor prognosis in the absence of targeted treatments, probably both in terms of platinum doublet chemotherapy, but definitely in terms of single agent immunotherapy. And I think that’s now been pretty well documented. Unfortunately, I think, because a lot of people see that these patients don’t have a classic EGFR mutation where we do tend to avoid immunotherapy and they think well they’re hoping that these patients might do well with immunotherapy and that they’ll have less side effects with immunotherapy than a taxane, I think many people just treat them as they would a wild-type patient and go forward with second line immunotherapy, which I think the data would support us is the wrong thing to do but I think unfortunately a number of people would do it.

Sanjay Popat:

Yeah, I tend to agree. I mean the data, I mean, it’s basically like having an EGRF mutant patient without a drug right?

Alastair Greystoke:

Yeah.

Sanjay Popat:

A single agent IO does next to nothing in terms of PFS and response rate for that patient so I was quite surprised when I saw that. Now Anna, you’ve done a bit of work in real world outcomes of patients with exon 20, very nice publications you’ve been involved with, as of you Alastair, but Anna, maybe you can tell us about what we’ve learned from these about what happens to these patients. I mean is it as good as the exon 19 deletions? Or is it a different kettle of fish?

Anna Minchom:

Yeah, I mean I think real world evidence is pretty important in this patient group. As we said, they’re rare patients. You’re unlikely to get large, randomized control trials by which you’re going to get direct comparison. So real world evidence is pulling the data from patients who are receiving standard of care, the US is often a playground for this and that was very large data sets that are accessible but of course looking at the UK, experience is also, is really important for our local population.

There is obviously drawbacks with using retrospective non trial data but nevertheless it provides a useful correlate and you can really look at, as you say, we’ve had some publications looking at first of all comparators to study populations so are the group who have exon 20 who are treated with standard of care getting better or worse outcomes than those treated within a trial, such as amivantamab trial, CHRYSALIS trial to which you try and match a population as near as possible in terms of post platinum and performance data, some would like.

And what you can learn from that, as you say, is about what people are using and certainly from data sets I’ve seen, it’s pretty split across in a post platinum era using either chemotherapy likely taxanes or even platinum re-challenge or as you say, immune oncology drugs, so immunotherapies.

Sanjay Popat:

So we now have exon 20 specific drugs. That’s basically what we’re saying, we have two drugs with different regulatory approvals. In terms of the NHS, amivantamab is not NHS reimbursed at least in England, but mobocertinib is, so Anna, what’s the activity? Can you speak to the response rates, et cetera about ami? Are we seeing with ami the same thing as we are seeing with osimertinib for example?

Anna Minchom:

No, that would be great.

Sanjay Popat:

Okay.

Anna Minchom:

No, so I think the responses are not to the level that you get with TKIs in the common EGFR mutations. So from the CHRYSALIS data, which as Riyaz says, was a relatively small study, just over 80 patients in this efficacy group. Response rates are 40%, median duration response was 11.1 months and PFS was just over eight months. So certainly, and again going back to a real world evidence, that appears to be better than the alternatives but not at the dizzy heights of osimertinib being common in EGFR mutations.

Sanjay Popat:

Yeah, okay. So activity not as good as we’d see with [inaudible 00:16:42], probably not as good as we’d see with IO mono and certainly nowhere near as we’d love to see with a TKI for a typical target approach and Riyaz, with mobo now, so mobo is NHS reimbursed, you can prescribe it today within the CDF guidelines, what sort of activity should you and your colleagues be expecting to see with that? What did EXCLAIM say about efficacy?

Riyaz Shah:

Well you know that’s actually quite an interesting question because you get different numbers depending what document you look at. It’s a slightly complex situation. There was a dose expansion, dose escalation, dose expansion cohort and then there was a separate EXCLAIM thing that happened in a few countries called EXCLAIM and the publication mixes patients from both of these into some sort of conglomerate group and they report response rates for different subgroups differently. And if you then look at, there’ve been different presentations and different regulatory documents, all quote slightly different response rates at different cuts but ballpark figures, investigator-assessed response rates of about 25, 26% so a bit low really. Investigator assessed a bit higher, 34, 35% in that order, but the thing that’s interesting for me is duration of response in the study was about 15 months longer than amivantamab but you know, PFS not very good, seven months so nothing, exactly as Anna said, not a blockbuster drug, not an osimertinib, but more of a sotorasib shall we say.

Sanjay Popat:

Yeah. So yeah, step in the right direction, but it’s not the-

Riyaz Shah:

Yeah.

Sanjay Popat:

… new, it’s not going to completely set the earth on fire straight away, but actually way better than what we’ve got at the moment. I mean that’s my interpretation of the data. Now one of the challenges that we have is that these patients behave like EGFR mutant patients. They are your typical never smoking, light, ex-light smoker patients. They get brain mets like EGFR mutant patients. What do we know about the brain activity of these drugs. Riyaz, do you want to go into that?

Riyaz Shah:

Yeah.

Sanjay Popat:

[inaudible 00:19:04] data?

Riyaz Shah:

So brain mets are highly prevalent in exon 20 insertion patients. Many of the patients are, the small number of patients I’ve looked after have had brain mets and all have, if they’ve not had them, have developed them so incredibly common. In the mobo study, we know 35% of patients going in had brain mets. We don’t really know what the intracranial response rates of these drugs are because they don’t report them in a straight… As a simple statistic and really highlighting how badly and non standardly brain mets get discussed and reported across clinical trials across the world.

So it’s actually really difficult to tease it out, but I think you generally get a sense that there are concerns. Obviously amivantamab, being a monoclonal antibody, it’s a big molecule, it’s unlikely to cross membranes. You would think mobo certainly being a TKI might obviously have an advantage there but when you look at the mobile data, one of the commonest sites of relapse in the patients in EXCLAIM was in the brain. Something like 40% of patients who progressed, progressed in the brain. We know that, we don’t actually know what the intracranial response rate separate from the extracranial response rate is. So there are concerns that these drugs are not hugely CNS active.

Sanjay Popat:

I think that’s right, so we don’t, the trials, that none of these trials have been designed in the same way the ALK studies have where you’re doing MRIs every six to eight weeks alongside the CT scans. So all we know is that the response rate in patients with brain mets, a whole body response rates is lower than patients without brain mets. Really giving us some idea that we are not in the world of osimertinib here, but we’re probably still, I would suggest, let’s not be too negative, in the world of docetaxel either. Anna, if I can just bring in the amu experience here. So Riyaz has been a bit disparaging about large molecule crossing the blood bone barrier, but we know that these molecules can cross the blood brain barrier right? So do we have any data with amivantamab and CNS efficacy or is this still a challenge as well?

Anna Minchom:

I think it’s definitely still a challenge. I mean I think if you are a betting person, you’d say it probably wouldn’t get through a blood brain barrier, but we don’t have any direct evidence biologically to support that. But inclusion for CHRYSALIS was you had to have, you couldn’t have active or untreated brain metastasis.

Sanjay Popat:

Yeah.

Anna Minchom:

So that limits our population hugely.

Sanjay Popat:

Yeah and Riyaz, I’ll come back to you about mobo, so if we are using this, we’ve got to be careful about the brain. So you’re going to give your patient platinum up front. Ideally you’re going to be really careful about your brain because you know that these patients are going to get brain mets at some point. You’re dealing with drugs which aren’t going to have great intracranial penetration. What’s the role of brain imaging in these patients? Should we be doing it routinely? Does it have a role in the same way as it does for others?

Riyaz Shah:

I think it’s absolutely critical and I think it’s critical for all EGFR mutation positive patients. I can’t insist because there are implications, as we know, on your ability to drive. I never insist that patients have brain imaging, but I very, very strongly suggest to them that if they want to see the outcomes that you see in international data sets of what kind of median survivals are being reported in Japan, US, other western economies where brain imaging is integral, the survivals are orders of magnitude longer than what we are seeing in the UK based on real world data presented at BETOG meetings in the past. And I think a lot of that is driven by intracranial management and if you don’t image the brain, you just don’t pick these things up at an early stage where they can be SRS. You can’t do preventative brain medicine if you like, you know?

Sanjay Popat:

Yeah. And so if we are using mobo, what are the adverse events that, you know, you should be counseling your patients about and Riyaz, what do you say to your patients when you are talking to them, taking them through the consent? What are you going to look out for and how do you mitigate against these adverse events?

Riyaz Shah:

Yeah, so mobocertinib is an EGFR anti-EGFR TKI so we know what the, we’ve been using all the EGFR inhibitors for a while so we’re very ofay with the kind of toxicity profile. I think it’s important to say mobocertinib, in my opinion, is a hot drug and what I mean by that is at its standard starting dose of one 60 milligrams a day, toxicity is very frequent. And in my experience, very few patients, I don’t actually think I’ve ever had a patient tolerate that dose for any length of time. Dose reductions are very common. There’s a whole, and a lot of it is standard EGFR stuff, so paronychia, rash, [inaudible 00:24:10]. But there are other things that are important to consider. ILD is something you need to watch out for. One of the main things with mobo that you need to be careful of is CNS, sorry, is cardiac toxicity. So QTC prolongation is something that is common and needs to be watched for quite carefully.

You need to be quite careful about the ejection fraction and I would probably do an echo at baseline and perhaps intermittently monitor a patient for the first few months they were starting on it. I would certainly do serial ECGs at the beginning. And the other thing that needs to be considered is drug interactions. So CYP3A inhibitors and inducers that will seriously affect the steady state level of mobocertinib and so that needs to be considered as well. So many patients require dose reductions. Dose reductions are relatively straightforward. The dose is 160, it’s a 40 milligram tablet or capsule. So you can go down in 40 increments. The SPC says to… Goes down to 80 and not below, but I’ve managed a patient on 40 once a day because they just couldn’t tolerate a higher dose.

Sanjay Popat:

And when do you see responses? Do they occur other TKIs quickly? Or are they like…?

Riyaz Shah:

Yeah, I think so. I mean it’s difficult because you don’t get the numbers of patients to really get a sense of that but my sense, when you look at the EXCLAIM data is the time to response was very quick. Within a cycle or two you’ll start seeing improvements on imaging if you image that frequently.

Sanjay Popat:

And Anna, are we seeing the same kinetics with ami? It works in a very different mechanism, right? It’s really talking about EGFR degradation from cell surface than this other sort of potentially immune mechanism as well. So are we getting rapid responses or is it a bit more nuanced?

Anna Minchom:

I think it feels similar in terms of when the response comes in if patients are going to respond. I’ve had symptomatic patients who’ve gone on and by the time you see them for their second cycle, they’re feeling an awful lot better from a disease point of view. So I mean as, like Riyaz says, it’s difficult to build up large numbers of patients to answer that fully, but I certainly think if patients are responding, they tend to respond early as well, yeah.

Sanjay Popat:

So Alison, we’ve got these new drugs, we’ve got access to drugs in the UK. We’ve heard about the efficacy, it is not as great as we’d like to see with osimertinib, right? But it’s definitely good stuff, right?

Alastair Greystoke:

Yeah.

Sanjay Popat:

And people will tell you that they get better very quickly, right?

Alastair Greystoke:

Yeah.

Sanjay Popat:

How are we going to find these patients? That’s the fundamental issue. What-

Alastair Greystoke:

Yeah-

Sanjay Popat:

… are we doing [inaudible 00:26:58]?

Alastair Greystoke:

This is where oncologists need to be really careful because if you’re sending testing for your patients, what genes get tested for so you can see if your patient’s being tested adequately for a RET fusion or a ROS1 fusion. The problem is you need to actually look at the technology that’s been used because if it’s been done with a sort of EGFR, PCR like a single gene test or even a point of care device, a lot of these insertions may be missed so studies have suggested you might miss 40 to 50% of these patients if you’re using one of the older technologies.

Now I think most places are moving to medium or large panels that will do next to initial from sequencing that will pick up a lot of these mutations but because we’re still struggling to get good turnaround times and waiting lists and everyone wants to get everyone on treatment quickly, a lot of places are using point of care devices or rapid gene testing and that will miss these patients and you won’t even know it because you’ll say, oh yeah, they’ve got EGF, they’ve been EGFR tested, there’s nothing there. So that’s really dangerous for us as oncologists. We need to look at what’s being done.

Sanjay Popat:

And we’ve got very good data really from many of these commercial NGS providers who’ve shown that if you look at the wide diversity of exon 20 insertions, many of which have only been uniquely reported once in a database, only a tiny number will have been picked up by a standard PCR right? So you’ll be missing those. You’ll be calling a patient EGFR wild-type when actually their exon 20 insertion and doing all sorts of treatment when you’re actually not giving them the right treatment. So I think what you’re saying to me is know the test that you’re doing and make sure that NGS, if possible, I think is a message that you’re saying. So what about liquid biopsies, right? Is this going to going to solve the problem or is this just going to create more problems, Ali?

Alastair Greystoke:

It’s a really good question actually that. So often we had patients who we’ve picked them up on, you’d think because there is an insertion on duplication and ctDNA is a bit smaller that you might miss some but I had a look and in the mobocertinib trials they picked it up in about 75% of patients, which is probably what we reckon is about the sensitivity normally in the stage four setting. So probably you can pick it up by ctDNA, but again, as always with ctDNA, if you don’t pick something up, it doesn’t mean you haven’t missed it unless you’ve found another obvious driver which should be mutually exclusive. So just be a bit aware.

Sanjay Popat:

And Anna, we’ve got the genotypic technology, we’ve got the drugs available, we’ve talked about the efficacy and the patient management first line. Are we going to move to first line with these drugs? Tell us what’s going on in the ami space in the first line setting?

Anna Minchom:

So the first line ami trial that’s going on is Papillon.

Sanjay Popat:

Papillon, yeah.

Anna Minchom:

Which is comparing, it’s randomized and it’s comparing ami plus chemo versus chemo alone. So that’s not single agent ami, that’s in combined chemotherapy. I guess with a recognition that the single [inaudible 00:30:02] activity is okay but could be improved on. And the whys and wherefores of combining an EGFR inhibitor with a cytotoxic drug can be debated but those results will be very interesting to see.

Sanjay Popat:

So that tells me that the control arm is platinum doublet chemotherapy without IO.

Anna Minchom:

Sorry. Yes, exactly right.

Sanjay Popat:

And the interventional arm is chemotherapy platinum doublet chemotherapy with ami. So Alistair, that tells me that the FDA have recognized that platinum doublet chemotherapy is the regulatory standard for these patients and not chemo-IO. Do you agree with the FDA? Is that what we should be doing?

Alastair Greystoke:

Well I wouldn’t dream of arguing with the FDA. I think we don’t really know because certainly, so I had an EGFR exon 20 person who went into one of the chemo-IO studies because they were allowed in, they only excluded sensitizing EGFR mutation patients and these are so rare so I don’t think we really know that. I guess the question is do we think the IO adds anything and we don’t know. And also the second question then is if you’re giving IO in combination with your chemotherapy, is that going to impact on subsequent toxicity when you do want to give either imatinib or mobocertinib? And again, I guess we don’t know, but I would be worried about that. So I have an informed discussion or an uninformed discussion with patients at the moment and most of them, if fit, have chosen to have the immunotherapy, well small numbers, alongside it.

Sanjay Popat:

And Riyaz, where are we going with mobo out front? We’ve got single agent data in the post platinum setting. Are you able to speak about the mobo frontline trial?

Riyaz Shah:

So I know there is one, mobo versus chemo, and when you look it up on clinicaltrials.gov, it’s classified as an active trial, but an active trial that’s not recruiting. So it’s either completed accrual and is waiting for a readout. So I don’t really know much more than that.

Sanjay Popat:

Yeah, so the frontline trial is standard platinum chemotherapy as we’ve discussed before, the FDA has clearly recognized that as the control arm versus mobo mono so it’s not what the ami group have done in combining the drug with chemo. They’ve gone for mobo monotherapy versus platinum doublet chemotherapy and that trial has completed recruitment and we’re clearly all going to be waiting for the number of events to come through.

So I think this is going to be an exciting time period. We’ve got two frontline trials, we’ve got approved options, but we’ve got two great phase ones on the line, Anna and Alistair so there’s lots of activity coming through. Just give me a couple of lines, Ali, first about what are you quite excited about coming through? Because the way I view it is that mobo and ami are great, but they’re the sort of first wave, right?

Alastair Greystoke:

Yeah.

Sanjay Popat:

We’ve got the bigger drugs coming through. Ali.

Alastair Greystoke:

Yeah, so there’s a number of so many EGFR TKIs coming through from companies, some which are further forward in development than others and some that have presented some early data that suggests higher response rates than have been described in mobocertinib and amivantamab. A number of them have still reported this issue about hitting EGFR, so particularly DZD, which has now got a name, I think it’s some dasatinib or something, that’s still got very high rates of diarrhea and rash associated with it. So I’d like to see some of that are a bit easier to give. So there’s this new one, which is CLN081, which again, small numbers, the efficacy look pretty good and they’re not reporting the diarrhea or rash. So that’s probably the one I want to see a little bit more of.

Sanjay Popat:

Anna, is anything otherwise that is floating your boat in terms of drugs has Ali hit on the main contenders there for the crown?

Anna Minchom:

Yeah, I think those are the ones that we’ve seen a little bit of data about to get excited about, but there certainly are ones which are a little further behind. There’s BLU-451 and there’s another couple, but there are going to be starting, but they’re a little further back. But there’s certainly a pipeline of interesting drugs on their way.

Sanjay Popat:

I think this is going to be an extremely exciting area for the next few years. We are going to be really seeing the latest advances in medicinal chemistry coming through as the next generation EGFR inhibitors come through both biological agents and kinase inhibitors. Extremely interesting and it’s not over for ami as yet because I think, Anna, there are trials ongoing using a subcutaneous formulation as far as I’m aware, looking at clinicaltrials.gov so that those are enrolling, is that right?

Anna Minchom:

Yeah, that’s right. And I mean that’s an interesting approach given that the main issue is with infusion reactions and subcutaneous delivery and theory would potentially overcome some of those issues of delivery. So keep an eye for that data really.

Sanjay Popat:

Great. Well look, we’ve had a fantastic discussion. I think the key take home messages that I’ve learned is that EGFR exon 20 insertions are uncommon, but there. If you don’t do NGS, you won’t find them. They look like your typical EGFR mutant patient, but we haven’t got the kinase inhibitors that we’d like upfront as yet, those trials are still ongoing. We do have two licensed drugs in the post platinum setting, mobo and ami, although only mobo is prescribable in the NHS at the moment. There are loads of trials going on so please make sure that we find these patients and researchers king to try and improving the outcome of our patients. And with that, I’d like to thank our experts for giving up their time to speak and really helping us understand this field much better and to the audience, thank you for your attention and look forward to chatting to you further at the next of the VJ Oncology BTOG lung cancer sessions. Thank you.

The Lung Cancer Channel on VJOncology is supported by Takeda and AstraZeneca.

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Disclosures

Sanjay Popat

Personal financial interests:

    • Consultancy/Honoraria: Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, Guardant Health, Incyte, Janssen, Lilly , Merck KGaA, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, Xcovery
    • Leadership: Nil
    • Stock: Nil
    • Licencing: Nil
    • Direct funding: Elsevier


Institutional financial interests:

    • Institutional research funding: Amgen, AstraZeneca, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, GSK, Guardant Health, Janssen, Lilly, MSD, Novartis, Roche, Takeda, Trizel, Turning Point Therapeutics, Seattle Genetics


Non-financial interests:

    • Advisor: ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation
    • Board of directors: Mesothelioma Applied Research Foundation
    • Leadership: BTOG Steering Committee, ETOP Foundation Council

 

Alastair Greystoke

Consultancy and speaker fees: AstraZeneca, Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Janssen/ J and J, MSD, Novartis, Pfizer, Lilly, Takeda and Roche

Research Funding: AstraZeneca

Additional disclosures: Alastair Greystoke is the Clinical Lead for Cancer North East England Hull and Yorkshire Genomic Laboratory Hub. He is also a member of the National Test Directory Evaluation Working Group. Views expressed are personal.

 

Anna Minchom

Anna Minchom has served on advisory boards for Janssen Pharmaceuticals, Merck Pharmaceuticals, Takeda Pharmaceuticals and Genmab Pharmaceuticals. Has received honoraria from Chugai Pharmaceuticals, Novartis Oncology, Faron Pharmaceuticals, Bayer Pharmaceuticals and Janssen Pharmaceuticals. Has received expenses from Amgen Pharmaceuticals and LOXO Oncology.

 

Riyaz Shah

Riyaz Shah discloses links to Boehringer Ingelheim, AstraZeneca, Roche, BMS, MSD, Pfizer, Lilly, Novartis, Takeda, Bayer and Beigene.