Exon 20 insertions in NSCLC - ESMO 2020

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Published: 25 Sep 2020
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Dr Alex Spira, Prof Benjamin Besse, Prof Michael Thomas and Dr Antonio Passaro

Dr Alex Spira, Prof Benjamin Besse, Dr Antonio Passaro and Prof Michael Thomas discuss the state of play for the treatment of non small cell lung cancer expressing exon 20 EGFR mutations. 

Unlike EGFR L858R point mutation or exon 19 deletions, which represent the majority of EGFR mutations in NSCLC, low frequency EGFR exon 20 insertion mutations are associated with de novo resistance to targeted EGFR inhibitors and correlate with a poor patient prognosis.

The panel discuss challenges in treatment, their current practice, novel therapies and look towards the future for this hard to tackle cancer.

This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).

AS: Hi, my name is Dr Alex Spira with Virginia Cancer Specialists and US Oncology Research.  We’re here today with ecancer with my guests, Dr Benjamin Besse, Dr Michael Thomas and Dr Antonio Passaro to talk about exon 20 insertions in non-small cell lung cancer. This has been a very difficult area because, while we’ve known about them for many years, there have been no drugs that have targeted this mutation. That being said, there has been a lot of data with new drug development specifically targeting EGFR exon 20 insertions. This year at ESMO there was an update on a lot of this data and we’re going to be focussing on that today. Dr Besse, do you want to talk a little bit about the history of this and why it’s so important and some of the challenges we faced in the past?

BB: Exon 20 insertion has been very difficult to target so far. When we talk about exon 20 we will refer to two main categories of genes: EGFR exon 20, where the usual drugs, the classical inhibitors, first, second or third generation, are fully active, and exon 20 of HER2 where it’s completely different from the amplification we can find in breast cancer. Both are quite rare, between 1-2% of non-small cell lung cancer, both are related to light or never smoking. Then all the usual TKIs have been tested without success but there is clearly a new wave of treatment now for these two alterations.

AS: In my practice I see this about 5% of the time, maybe a little bit more, a little bit less. As you said, it’s clearly present in more non-smokers than smokers so they tend to be younger with this. I tend to treat these patients with standard chemotherapy, sometimes with immunotherapy. Dr Thomas, how do you usually treat these patients and do you notice anything special or different than I have just talked about?

MT: Well, as Benjamin Bess already mentioned, those patients have a rare prevalence ranging between 0.5-1%. If you focus on EGFR exon 20 insertions those are 10% of the total, or at least 5%, of the total population with EGFR alterations which is this number. You have to detect those patients first so it’s important that you have an adequate testing strategy in place. To give an answer to your question, for the time being I would reflect on the last twelve months, there only have been trials in place that we have participated in to transfer patients to respective compounds but if it is not possible then usually we employ plain chemotherapy, often combination platinum-based with pemetrexed and then we experience response rates ranging from 25-30% and a median PFS of 5 months, something like that.

AS: As you mentioned, there has been a lot of excitement about a lot of clinical studies. The three major drugs that we’ve seen so far are poziotinib, mobocertinib, formerly known as TAK-788, and amivantamab as well, all of which are in clinical studies and all of which have shown a lot of promise for them. Dr Passaro, can you talk a little bit about your experience and how you treat these patients as well and then we can talk about some of the newer abstracts that we’ve had as well? There’s also data, I should point out, not at ESMO but previously, with higher doses of osimertinib as well.

AP: In the last years all of us have treated patients with exon 20 insertion with the standard tyrosine kinase inhibitors, more with afatinib but with no good improvement in efficacy endpoint but was the only evaluation option in clinical practice. This was a real need for all thoracic oncology in client practice. In the last years we saw very different kinds of tyrosine kinase inhibitors, so new agents that are coming up step by step, but the first need for us is that we have to identify the real target for exon 20 insertion that is very, very different from the other mutations of EGFR. We have a permanent active confirmation that they reduce the activity of the different kinds of tyrosine kinases. So this year we saw different presentations, also in ASCO and ESMO, that presented the activity of different tyrosine kinase inhibitors. One of the most interesting was the data that presented the double dosage of osimertinib presented in ASCO of this year. This was very interesting with an activity of a median progression free survival only in about 20% of 9 months and more but it’s interesting to look forward. On the other hand, we have a different kind of specific tyrosine kinase inhibitor today under evaluation and the data presented at ESMO is very, very interesting.

AS: So the higher doses of osimertinib you talk about and refer to presented at ASCO was a small study of 10-20 patients as I recall.

AP: 21.

AS: Thank you, so a small number of patients. It did show some response rates. Have you ever used that for a patient since it’s an FDA approved drug? Have you ever given it to somebody that you cannot get on a study?

AP: No, we don’t use in clinical practice osimertinib for exon 20. I don’t know the real effect in this kind of patients.

AS: No, similarly here, we have not used it and obviously there are limitations about what is reimbursed. So one of the older drugs that has been out for a long time is poziotinib. The phase I has been out for quite some time, originally done with Dr Heymach at MD Anderson. We recently had an update from this at ASCO this year. Dr Besse, do you want to talk a little bit about poziotinib, I don’t know if you have personal experience? It’s had a very long journey with a lot of changes over time so can you talk a little bit about that? We also had one of the abstracts, one of the updates from the ZENITH20 study at ESMO this year.

BB: Yes, I used poziotinib within a clinical trial initially, as you said, on single centre small dataset. We saw response rates around 40%, so very encouraging, some degrees of toxicities. But it’s always the same, when it’s a highly trained centre management of the toxicities is quite aggressive and it’s the same for the phase I – when  you escalate the dose in highly specialised centres you can maybe go a bit high but since the patients are seen all the time and they are aggressively managed it’s tolerable. Now when they moved to a phase II in more centres the results were much more disappointing. At ESMO they reported the data on 90 patients and the response rate was only 14% which is clearly lower than expected. In R2 it was 25% with a PFS of 5.5 months. Clearly one of the main issues is the grade 3/4 toxicities and the report at this point was 26% diarrhoea grade 3/4. You have to remember that diarrhoea that is grade 3 is more than seven stools a day so it’s really something that is not compatible with a good quality of life. So, all these toxicities are dose dependent, as per any TKI; you can decrease the dose but maybe decrease the efficacy. And probably part of the issue with this drug is probably the dose that was tested in phase II was not adequate or at least the scheme, maybe an escalation of the dose in the phase II would have been more appropriate.

AS: I agree completely, Dr Besse. I think one of the interesting things is when this started as the single centre phase I study the response rates were incredibly high and the excitement… I think it was at World Lung a few years ago in Toronto, everybody was incredibly excited. I think it suffers from one of the classic early phase I studies where we picked the perfectly healthy patients with incredibly close monitoring. You’re smiling so it looks like you’re agreeing with me. This is an old drug, so this is an old drug that was taken off the shelf and repurposed. Do you think it’s because the drug is less effective over time or do you think it’s the toxicity that is limiting how much we can give and that’s more of an issue? Or we can’t tell?

BB: Difficult to say. What is clear is that it’s not sparing the wildtype EGFR so it’s induced toxicity. What we know, because all the TKIs for EGFR have the same toxicity because it’s class toxicity, we know that, for example, a drug like erlotinib that is not at all active in exon 20 insertions can be used at 150, this is the standard dose and this is the dose you use when you start. But we have done some phase II and some phase III where in patients that are chronically exposed to this dose you can escalate up to 300 which is much more than the maximum tolerated dose that was found in phase I. It’s really tricky with these EGFR inhibitors, it’s clear that when the patients are exposed chronically you can escalate more safely the dose. So I think the drug is clearly active, it has shown that, but maybe because of this dose reduction we have not found the perfect balance between efficacy and toxicity.

AS: It’s interesting because right now that study has been going on for quite some time and now they’re re-exploring b.i.d. dosing. So what we’re seeing is just a classic… it’s going to be tough to come up with an optimal dose. Moving on to the next one, Dr Thomas, there have also been updates regarding what used to be TAK-788 that I think was given the name of mobocertinib earlier in the year. That was specifically designed to target EGFR exon 20. Can you talk a little bit about that?

MT: Yes, we were aware of mobocertinib already last ASCO, last year, there has been a presentation on the compound. This has been on 28 patients with an exon 20 insertion. There it has been reported that it results in a response rate which is maturing which is 43%, which has been 43%. Patients experience progression free survival of 7.3 months. Again here the toxicity that had to be dealt with has been diarrhoea as well. So they have been reporting, at least in the updated results and updated toxicity reports in addition of this trial, of grade 3/4 diarrhoea in the range of something like 10% which is, of course, important, which then again requires dose reduction and management strategies in those patients. But the efficacy with the response rate of 43%, a PFS of 7.3 months, is better than, for instance, that which could be shown with plain chemotherapy. At least there has been no direct head-to-head comparison yet, respective trials are underway currently. But if you check back to cohort data, for instance, going into the databases, then you can see there that response with chemo is 25-30% and PFS is something around 5 months. So at least from those phase I/II data you get the impression that this compound should be superior than combination chemotherapy. But we have to wait for the phase III trial results on that.

AS: Some of the interesting things, and we’ll get back to this in a second, there is clearly a real toxicity here in grade 3/4, as Dr Besse pointed out, and grade 3/4 toxicity is still really difficult. People, I do think, did better with some dose reductions. I think the starting dose was 160 and came down to 120 over time. So there is some interesting data there and they are also reporting, and we’ll talk about it in a minute, on some of the first-line data compared with chemotherapy as well. One of the important things, for me the take-home messages, we’re all used to EGFR inhibitors with response rates measured significantly greater than 50% with not a lot of toxicity and PFS and DFS measured in the 1-2 year timeframe. I think, as a class, we haven’t seen that. Not that these are bad drugs but it’s an important take-home message that the current first generation of these drugs is not going to be as good as osimertinib for regular EGFR mutations. Dr Passaro, do you want to talk a little bit, and this has not been a big discussion at ESMO this year, but if amivantamab is a monoclonal, so it’s a different mechanism of action. Do you want to touch base a little bit about that? I think there were some data at ASCO and hopefully there will be updated data forthcoming as well.

AP: Maybe at the present time amivantamab is one of the most interesting for the exon 20 insertion but it’s a very different kind of drug; it’s a fully human anti-EGFR MET antibody. The data presented this year at ASCO was very, very interesting with an overall response rate more than 35%, about 35-40%, with a median progression free survival of about 18 months. So this data was balanced with a rate of grade 3 or more toxicity of about 35% and, of course, these data are intriguing if we consider the possibility to use this drug in clinical practice. This is a very interesting drug at the present time, it’s under development also in the first line setting. It’s in the combination setting also for EGFR positive disease.

AS: As you discussed, it’s a different mechanism of action which is a challenge. The other two drugs we talked about previously are oral so having IV is going to be a little bit more of a challenge. There are some patients that did get infusion related reactions. That drug was filed in the United States at least for breakthrough approval so it seems to be a very exciting drug as well. There’s obviously a lot going on in the field. Also at ESMO this year there were a few other compounds that were talked about, one is CLN, there are also some updates on Tarlox as well. So there have been a few other molecules as well in there so it appears to be a very interesting and deep area. Rather than delve into that into huge detail… and there’s also a drug from Daiichi also that has been showing some interesting pre-clinical activity as well. What I thought we would spend some time on today, really, is where do you think these drugs are going? As I mentioned before, and I’m seeing some smiles on some people’s faces, these drugs don’t appear to be as active as osimertinib so the question ultimately is mostly studies are in the second line and at ESMO there is a clinical trial in progress comparing mobocertinib with chemotherapy in the first line setting. Do you think these drugs will be relegated to second line? Do you think they’ll be done in the first line setting? Do you think they will be combined? Dr Besse, it will be interesting to hear your comments and we can have a little bit more of an open discussion since there’s clearly not a lot of data on any of these approaches right now. How do you think these drugs are going to end up?

BB: As Michael said, the data that we have from the efficacy of platinum-based chemotherapy is not amazing. In EGFR exon 19, exon 21, the activity of the chemotherapy is a bit better than accepted so those patients are mostly light or never smokers so they have few comorbidities so you can treat them easily with chemo. Even if it’s mostly light or never smokers it seems that the activity of the chemo is a bit lower on exon 20. So the design of the mobocertinib trial is fair, the data that we have with the drug, the PFS that is 7.3 months in pre-treated patients, for me, is enough to go first line. As you said, you will not expect the PFS of 18 months like you have with osimertinib but, again, we’re talking about platinum-based chemotherapy where toxicity is quite significant. Let’s see but it will not be the same toxicity. I think the duration of response of TAK is 13 months, or mobocertinib I mean, so we might have the chance to have a positive trial. To be honest, I would completely agree to use such a drug up front. As Antonio said also, the amivantamab is a completely different category with a quite different toxicity profile. But, again, it’s a molecular abnormality for which there is a huge unmet need. These drugs will really make it as single agent first line.

AS: For me, thinking about it, there’s the nice thing about having an oral therapy which is what many of our patients would like, assuming it gets approved. But the response rate from first line carbo/pem is pretty high, it’s 65%. We don’t have a lot of good first line data yet for any of these drugs but it may even be higher so there’s going to be a big yin and yang, as they say, as to what people would like to do and then obviously there’s the reality. Dr Thomas, what are your thoughts? And I guess another question is do you think ultimately, I know these studies are ongoing, at least in phase I, do you think they would be combined with chemotherapy? So do you think there is a role for that and is that something you would be interested in seeing data on?

MT: As already emphasised, we know that this first line trial with mobocertinib in comparison to chemotherapy is coming and there will be this comparison. I would agree with Benjamin that it’s a worthwhile comparison strategy and would expect that there is a superiority of this oral compound. With respect to your question, to combine that type of TKI with chemo, I don’t know if this is a good idea because we see the side effects with diarrhoea grade 3/4 ranging in this 10% range. If you employ chemo here in addition you would have to concisely do the dosing, dose reduction, if diarrhoea is experienced and you have neutropenia, then you have a breakdown of the mucosal barrier, patients might be prone to infection. So here I would really have concerns to do here a combination strategy. With respect to this TKI I think there should be different opportunities, different strategies, if a combination is considered. In terms of the antibody, amivantamab, here combination with chemo might work because we don’t see this side effect of diarrhoea in this extent as is given in mobocertinib so here it could be a strategy .Potentially it could increase or could contribute conceptually to the efficacy due to the potential ADCC activity amivantamab might exert or chemotherapy might contribute to a different antigen release and so on and so on. So here it could be a strategy to go into this direction, though so far from my side to this question.

AS: Dr Passaro, do you have any thoughts? Would you like to see this in first line, second line? How do you think this is all going to play out? It’s interesting because a lot of it is also going to be dependent upon how these drugs get approved. We actually have, certainly in the case of amivantamab and mobocertinib, two drugs that are probably relatively close in the development process. Poziotinib, I’m not sure, it appears to be very good but they are still obviously having some dosing issues. So there are going to be a lot of moving parts. Part of it will be which one gets to the finish line first, at least here in the United States, and then secondarily how are people going to be thinking about all these things as well. Certainly I think most of us think it’s going to be approved in the second line setting first but then how do people approach it and where’s the development path. So I’d be curious to your thoughts.

AP: Yes, the history of EGFR positive disease from the BR.21 in the wildtype disease from the study of Frances Shepherd shows starting from the second line and moving on the first. Of course mobocertinib and amivantamab maybe have the power to move into first line and we need, of course, data from the first line also to understand the possibility of the sequence of treatment. Because one of the important things for patients with exon 20 that is coming out from the study of poziotinib is that more than 60% of pre-treated patients received immunotherapy and immunotherapy raises the risk of pneumonitis in these kinds of patients. This is very, very important for our clinical practice. So we have, of course, to try to move these drugs into the first line setting if activity is confirmed and also to improve the sequence line for the future.

AS: All great points and I think we’re all very much on the same page and it’s a fascinating time. We’re almost out of time so I’ll just ask for some parting thoughts from everybody. My thoughts are very simple – we have a lot of great drugs and promise for something five years ago we didn’t even have a single drug for, so how exciting is that? For me, the take-home message is if you don’t test you can’t treat. We always forget that the most important thing is to test your patients, whether or not from the tumour sample or liquid biopsies, and that’s a completely separate discussion. But testing rates, no matter where you are, even in the United States where we think we’re great, are still not where they should be. So we must be testing for these and not only that but identifying the appropriate mutations. I’ve seen many patients see EGFR mutations and the doctors, I’ve seen them in second opinions, treated with osimertinib because all they see is EGFR.  So it’s important to understand what we’re testing for and to test and then clinical trials. We have a lot of drugs that we’ve never had before and the only way we’re going to get to the finish line is by getting these patients on clinical studies. For me that’s the most important thing. I’ll go in order, Dr Besse, any parting thoughts?

BB: I agree. What we can say is that exon 20 EGFR, exon 20 HE2, are targets and we have drugs. But, as we said, it’s the beginning of the story. We might find in the future, like osimertinib does on exon 19 and exon 21, drugs that are more specific for exon 20 and less potent on the wildtype EGFR. So to get, let’s say, more friendly drugs. It’s the beginning of the story but the drugs and the efficacy is there.

AS: Dr Thomas, parting thoughts?

MT: Yes, I really would emphasise as well testing matters and testing is key. It’s important to do it nowadays in a concise manner, to have the information which could allocate patients to appropriate treatments. Here, I think if it’s affordable and available NGS testing, DNA based and RNA based, is very good. You receive information on gene fusions if you do RNA NGS and if you do DNA NGS you have information on mutations, insertions and all those alterations, as we have seen now. It’s very exciting, just in this tiny population of exon 20 insertion patients which is 0.5-0.7% of the total population, we now have several compounds which will come in place, or potentially come in place. The next step then is to better understand, for instance, microenvironment properties, sequencing strategies or combination strategies. This will be a very exciting field and very exciting avenue in the next 5-10 years which we’ll see in thoracic oncology and particularly in those genetically driven diseases.

AS: Dr Passaro, any thoughts?

AP: I think that we need to crack the target. We have very different kinds of agents but we need to test our patients. So this is the same indication for patients with uncommon mutations with EGFR that in the last years increased in rate in our clinical practice only because we use NGS analysis or better testing analysis. So we have to test our patients, of course, we have to enrol our patients in clinical trials. This is the time for all of us to improve the rate in clinical trials of our patients for improving efficacy and quality of life of our patients.

AS: He said it best and I think I’ll just end with test and put patients on clinical studies. Those are the best things we can all do and if that’s the only take-home message we get to our audience I think that’s a great thing. So on behalf of Dr Besse, Dr Thomas, Dr Passaro, I’m Dr Alex Spira and thank you to our friends at ecancer for this presentation.