AA: Hello everyone and welcome to this ecancer expert discussion today on the EGFR data presented at the ESMO 2025 from Berlin. My name is Alfredo Addeo, I’m a medical oncologist at the University Hospital of Geneva. I’m going to be chairing this interesting session with my colleagues where we will discuss some of the data presented; some of the data that are going to be presented at ESMO may have an immediate impact on your daily practice. So I will let my colleagues introduce themselves starting with you, please.
PT: Hello, I am Pascale Tomasini, I’m a thoracic oncologist from Marseille in France.
AM: My name is Dr Anna Minchom, I’m a consultant medical oncologist from the Royal Marsden in the UK.
NG: I am Nicolas Girard, thoracic oncologist at Institut Curie in Paris.
AA: Perfect. So we are seeing some interesting data and starting with the first line, of course, there was a lot of noise after the presentation already of the data from the FLAURA2. We have seen the publication in New England with this overall survival. So the first question is for you, Pascale, and see whether you want to give your thoughts about the impact on the overall survival data we are seeing with FLAURA2 and whether you think there are any subgroups of patients that might benefit. We have seen some presentations at ESMO trying to identify perhaps the patients that might benefit a bit more from a more intense treatment, what are your thoughts?
PT: Yes, two days ago we heard about the overall survival data from FLAURA2 in some different subgroups. The conclusion was that the combination of osimertinib and chemotherapy seems to be better than osimertinib alone in terms of overall survival among all the bad prognosis subgroups, meaning patients with brain metastases, ctDNA positive or also TP53 mutations. There may be a discussion for this TP53 mutation, I don’t know if you want to discuss about that, but the combination was superior among all subgroups with bad prognoses and the intensification, giving chemotherapy in addition to osimertinib, may be a good option for these patients.
AA: Yes, maybe that’s one of the limitations in reality, meaning that since in every subgroup there is a benefit, therefore it gets a little bit difficult. But there are some caveats and maybe Nicolas you want to perhaps point out that there are a few caveats?
NG: Yes, because intensification works for the patients with expected poor outcome, that’s true. But in patients with expected good outcome should you intensify with chemotherapy? This is the question. Earlier some data released about FLAURA2 showed that magnitude of benefit of chemo plus osimertinib versus osimertinib was actually even more important in patients with at least three metastatic sites when in patients with less than three metastatic sites the magnitude of benefit was actually lower. This is subgroup analysis, this is exploratory for sure, but the way I am envisioning the selection of patients for intensification with chemotherapy, probably the patients with more aggressive disease – CNS metastasis as you mentioned, maybe some ctDNA positive and so on, which is associated with aggressiveness – are those patients requiring intensification possibly with chemotherapy? The other way to intensify versus osimertinib is the MARIPOSA regimen with amivantamab plus lazertinib and we also showed the recent publication in The New England Journal of Medicine for overall survival, a hazard ratio of 0.75, more than 12 months’ benefit versus osimertinib and it remains chemo free. We had also some data in those patients with poor predicted outcome showing that, again, the benefit is observed in all patients whatever the subset of patients. So the first question is should I intensify and we still see some discussions around that and some physicians say, OK, I prefer osimertinib. Well, to me this is the first time I see that in oncology. We have two clinical trials – MARIPOSA, FLAURA2 – showing that intensifying versus osimertinib monotherapy is associated with a more prolonged PFS, a more prolonged overall survival. So, to me, intensification is the standard of care, MARIPOSA or FLAURA2, and maybe some patients I can de-escalate to osimertinib because of absence of [GBDT] to intensification and so on. But, to me, and this is in line with ESMO clinical practice guidelines, to consider the MARIPOSA regimen and the FLAURA2 regimen as standard of care.
AA: So we definitely have at least three options but let’s add something more to the equation because we have seen also the NorthStar presentation. It’s a phase II study but it’s an interesting one where they use another way of intensifying, that’s radiotherapy, which we’ve been using, I’m sure, in our clinical practice every day. The question is should we use it at progression, as we normally do, should we use it to intensify, perhaps? And we’ve seen the data showing in this phase II that the patients who got this radiotherapy or surgery, so a local treatment, they got quite an impressive progression free survival, to be honest. We don’t have the overall survival. So, Anna, what is your take about those data and do you think it is practice changing, it is practice confirming for whoever is doing it, because there are people already doing this?
AM: It was a fascinating presentation and this you could describe as intensification because it was after 12 weeks of treatment of osimertinib and patients who were having local consolidative therapy. That was actually a range, so there were surgical procedures such as lobectomy as well as the radiotherapy procedures as well. As you say, patients who had successful treatment with this LCT had improved prognosis compared to those who did not. This ethos of trying to intensify therapies certainly fits with what many clinicians are doing as standard practice, though an alternative way of doing that is to think about oligometastatic progression and there are many trials which hopefully will read out looking at, for example, radiotherapy for oligometastatic progression. So that is when patients have progressed on, for example, osimertinib. I think with the NorthStar we have a very heterogenous group of procedures which were planned so it’s quite difficult to interpret that directly into clinical practice and it’s progression free survival. I would love to see what the overall survival data would translate.
NG: It is expected that PFS will be better because actually you are treating the target.
AM: Yes, you’re removing…
NG: So OS in this kind of trial is probably the primary endpoint, but hard to measure.
AA: I’ve got to say, I agree though it’s true it’s a phase II study so it’s quite normal to see. We all design studies, we know how difficult it is when you get overall survival as an endpoint because it’s a larger study, you need a larger sample size. But it’s intriguing and they are also pointing out that there are many possible options, which is good, so it’s not just drugs but also in first line we have now at least two more options in first line, so osimertinib, we have the MARIPOSA regimen, the FLAURA2, but we also have to bear in mind that sometimes local treatments are also of value. Again, multidisciplinary, altogether we need the surgeon, we need radiotherapy, we are one team, it’s not just medical oncology with new fancy drugs, which is good. So first line definitely quite exciting. Now we are going to see the presentation later on about some second-line data. Again, as you all know, once we move to the second-line data it’s complicated. So when a patient progresses historically after osimertinib, yes, we do a biopsy, yes we do look for further targets but it’s always very challenging. We have some regimens already, we have the MARIPOSA-2 with the combination of chemo/amivantamab that showed progression free survival, we’re still waiting for the final overall survival, it’s not mature yet. But we’re going to see the ADC that’s going to be presented today, the OptiTROP-Lung04 study with sacituzumab TMT. I say TMT to avoid problems by saying the name. So it's a very fancy ADC with a specific linker, it’s an anti-TROP2 but might not be exactly the same as the other anti-TROP2s that we have seen so far. So, again, starting with you, we know that the overall survival is positive, we know progression free survival is positive, so it’s not just PFS, OS. It is an Asian study. Of course we are waiting for the discussion which I’ve seen some data but we don’t know the nitty gritty of the data. What are your thoughts? Is it practice changing or did you think you need a confirmatory study? What is your impression?
PT: We heard a lot about this new sacituzumab TMT, as you said, in ASCO already but not in this specific population of EGFR mutant non-small cell lung cancer. It might not be the same as the one, the anti-TROP2 that we already know. But it may be an interesting option for these patients. The issue with this trial is that the control arm was chemotherapy only and not chemotherapy plus amivantamab which is the new standard now. So to be practice changing it has to confirm that it’s better than what we do have now with chemotherapy and amivantamab. And also it’s not as easy in terms of toxicity, so this also has to be balanced with the standard.
AA: So I just want to know what your thoughts are but, Anna, if you want to have a go at it and say is it really…? But we need to bear in mind that when the study was designed of course the standard was chemotherapy. There are many places where the standard is still chemotherapy, not everybody has access to chemo/amivantamab. So it might be a standard of care for many other hospitals or in centres in Europe, what is your take on this?
AM: I think we don’t know what the standard of care is yet, certainly we don’t have access to MARIPOSA-2. So our standard is, at present, chemotherapy. But as we move into the FLAURA2 and MARIPOSA era we’re going to have to see what that standard of care looks like and I think we are going to be looking at standard of care hopefully according to resistance mechanisms. I don’t think we’re going to touch on MET targeting in the second-line setting today. But what you can say about this ADC is that it is an active drug, whether it meets the barriers for what will ultimately become standard of care in these patients remains to be seen but as a target certainly TROP2 is extremely interesting in this patient group.
AA: I totally agree and, again, Nicolas, now we have highly likely a possible new standard, don’t you think that using an old ADC will heavily depend on what you have done before, meaning if you use osimertinib first line it could make sense to say I’ll do second line ADC? But if you use chemo/osimertinib or maybe amivantamab/lazertinib, would that have a role on whether you would use an ADC as a second line?
NG: That’s a very important question. We know that patients with EGFR mutations are fit patients so we can also consider re-challenge with chemotherapy in those patients. Even after FLAURA2 we know that the duration, the actual duration, of chemo is not 24 months, most of the patients are discontinuing the chemotherapy component before and continuing on osimertinib. We know that the mechanism of resistance, the molecular history of the disease, is not changed with FLAURA2. With MARIPOSA we see a completely different resistance mechanism because we are preventing the emergence of the MET-related resistance mechanisms. TROP2 is very interesting for sure – sacituzumab tirumotecan is actually effective in the third-line setting, we saw that at ASCO; in the second-line setting we see that during this meeting. There are some ongoing trials with datopotamab deruxtecan, the TROPION 14 and 15 programmes, so we will have confirmatory data for sure. One point in the management of those patients is probably the need to continue the EGFR pathway inhibition. We saw that with the COMPEL trial, an academic trial, probably some imperfect trial, but showing that after osimertinib when you move to chemo the continuation of osimertinib is actually bringing some additional benefit. We have the same thing in cohort 7 of PALOMA-2 with the continuation of amivantamab post-MARIPOSA when you start chemotherapy, so moving from MARIPOSA to MARIPOSA-2. So continuation of EGFR inhibition is clearly leading to another step in the incremental benefit of survival. So switch and maybe re-challenge with EGFR inhibitors or continuation of EGFR inhibition, this is another concept that we need to integrate into sequencing.
AA: I definitely agree with you and historically our colleagues from the States, they always said they would use the inhibition of the EGFR component and we were a bit sceptical. To be honest, in my practice at least, I’ll be using it; certainly for brain patients with brain mets I’m always a bit worried to completely stop an anti-EGFR.
NG: But COMPEL was conducted in patients with non-CNS mets.
AA: Absolutely, and also was positive.
NG: So this even more a question.
AA: Totally, I’m totally with you. So it’s incredible how things are evolving so quickly and how many options we’re going to have. We haven’t talked about toxicity, toxicity is also going to play an important role, what toxicity added previous, what is methodological toxicity, and also patient preference – whether the patients want to come back every three weeks or weekly at the beginning. All these things might have a…
AM: And healthcare preference as well – subcutaneous, intravenous.
AA: The subcutaneous is another interesting story. We’re very much hoping to have soon access to subcutaneous amivantamab.
NG: During this meeting we saw the data from PALOMA-2 post-osimertinib, so chemo plus amivantamab, like in MARIPOSA-2 but with amivantamab subcutaneous, producing similar benefit as in the MARIPOSA trial. So probably subcutaneous will change not only the patient pathway, the organisation, and so on, it may also be associated with a better safety profile – less infusion-related reaction and possibly less cutaneous side effects.
AA: I think for the infusion reaction for sure it’s going to be… and also it’s going to be a relief for the burden on the chemo suite because, of course, it’s going to shorten the infusion time and you’re not going to have a reaction, which is really good. For the last few minutes of our conversation now I’m going to switch a little bit. We’ll stay in EGFR but we’re going to switch to the uncommon and the exon 20 insertion which I don’t know for you but for me are always a bit of a difficult and challenging cases for several reasons but first of all because we don’t have many options because it’s a rare event and rare mutation. Therefore it’s something that we need to detect properly and we keep saying NGS, don’t do the single gene analysis – you may risk to miss some of the uncommon. So, starting with you Nicolas, there were two presentations, one in second line, on two compounds – zipalertinib and [??] or furmonertinib – they are already being developed in Asia, in China in particular. They have already been used, furmonertinib is already used even for common EGFR. So there was some data on second line and also intracranial activity. Again, good activity, I don’t say overwhelming activity, but what are your takes about all of them? Two of them, whether there’s any difference, whether you think it’s definitely good data, compelling data, whether they’re convincing enough as a second line in this setting. What are also your takes on what you do for uncommon, what you do for exon 20 insertion? Lots of questions.
NG: So first line is the PAPILLON regimen, so chemo plus amivantamab. Clearly better than the sequencing so that’s the standard of care, it’s part of the ESMO clinical practice guidelines, NCCN guidelines. The question is second line and probably here the TKIs show high efficacy – zipalertinib something like 40% response rate, not only systemic but also CNS response, so that’s interesting data. We have seen sunvozertinib data as well, furmonertinib, so the TKIs show some efficacy. Zipalertinib and sunvozertinib are also evaluated right now in the first-line setting, either to replace chemo or in combination with chemo. So what will be the best sequencing strategy would obviously depend on the results versus chemotherapy but also we need to learn more about the resistance mechanisms to the TKI. Amivantamab we know may cover those resistance mechanisms but meanwhile preventing the resistance mechanism with amivantamab first line is probably better, we see that in MARIPOSA for common EGFR mutations. So lots of questions around the management of those patients.
AA: I agree. So Anna, going back to you, do you in your practice, if you have access to chemo/amivantamab, we do have access to chemo/amivantamab but I’ve got to be honest with you, I’m not sure why we manage to perform biopsy at progression all the time which is a bit challenging. Is this something that… what about you, is this something that you do in your practice, you tend to do? How helpful it is?
AM: Yes, we actually don’t have access to it. I have used it.
AA: I was suspecting that.
AM: Yes. So if we get some oral TKIs which… These are small studies, a very small number of patients, but look tolerable, oral. If these do come through into practice then they’ll be absolutely practice changing. And, yes, for those who have access to amivantamab/chemo resistance mechanisms are important but if we have access to it then this will be in a non-targeted population. So this is mechanisms…
AA: How about you?
PT: Sorry. In France we have access to chemo/amivantamab first line and we have a programme also, a national programme, to perform liquid biopsy at progression for all patients with chemo/amivantamab and EGFR exon 20 insertion. So we will see the results of this programme, saying that we want to explore the mechanisms of resistance and that would be interesting I guess.
AA: That would be very interesting. How about the uncommon, because again in the uncommon we might discuss but the label at the moment, at least in Europe, was with afatinib based on the lung study and pooled analysis. We have seen some data about osimertinib, we also see very good data from the CHRYSALIS-2 with the combination of amivantamab and lazertinib – 115 patients, I think, with a very long progression free survival – 18 months, never seen that before. So at the moment how would you treat a patient presenting with an uncommon knowing there may be an exon 21, it might be different from perhaps a PAK classical mutation? So what would you do in your practice?
PT: For now we do not have many options because the CHRYSALIS regimen is not validated and approved. But in the future many new TKIs, [??] TKIs are also developed in this population, so I’m hoping things will be moving also in this population in the near future. But for now we only have afatinib.
AA: Is it the same for you?
AM: Likewise. And they’re very complicated – although they’re rare there are many of them and there’s compound mutations. It’s very difficult in advance to know what the response rate is going to be.
AA: I agree.
NG: It’s important to perform NGS to identify those PAK mutations. Many of these are combined with L858R so if you do only L858R testing you will believe it’s L858R but it’s actually a combined mutation and there is a risk of disappointment if you use osimertinib alone. Maybe chemotherapy plus osimertinib, maybe MARIPOSA and probably these intensive regimens are working on some of those mutations but we need to generate some data.
AA: I totally agree. This is an area where as a community we have done an effort by collecting real-world data because also we need a lot of real-world data to see what we are doing in practice. So there’s still a lot to do but at least we can see that there is an interest. Last year at the World Lung Cancer Congress was also the furmonertinib presented in this uncommon and again showed some activity. The only problem we have with TKIs, as we all know, is more diarrhoea so GI toxicity might be a bit of a challenge. So thank you very much all of you for this fantastic exchange. I think we have covered quite a bit of the EGFR world presented at the ESMO so lots of exciting data. I think there’s a lot of potential practice changing or practice confirming data presented at ESMO 2025. So thank you very much for following us, have a great day. Thank you.
