ASCO 2024
Latest advances in NSCLC
Dr Enriqueta Felip – Vall d’Hebron University Hospital, Barcelona, Spain
Dr Alex Spira – Virginia Cancer Specialists Research Institute, Fairfax, USA
Dr Antonio Passaro – European Institute of Oncology, Milan, Italy
Dr Alfredo Addeo – University Hospital of Geneva, Genva, Switzerland
EF: Hello from Chicago. My name is Enriqueta Felip, and I’m very pleased to participate in this round table discussion together with Dr Alex Spira, Dr Antonio Passaro and Dr Alfredo Addeo . Today we are going to discuss the latest advances presented here in Chicago about the EGFR mutation situation. We have seen a large number of trials with results that probably are practice changing. Perhaps I will start to ask you about the MARIPOSA trial – Antonio, what do you think about MARIPOSA, could you please give us your insights?
AP: So, as a recap, MARIPOSA is a phase III trial that evaluated the first line setting for patients naïve for treatment with a common alteration, the combination of amivantamab plus lazertinib versus osimertinib alone. The presentation that you present here in the ASCO was an evaluation of a high-risk patient population. So I think a very interesting evaluation, particularly also for our patients. When the investigators evaluated the presence of TP53 or ctDNA they all saw clinical characteristic as a brain liver. So globally the results confirm that the combination of amivantamab/lazertinib is globally highly effective compared to the standard across all the subgroups, including this high-risk population. So we know that TP53 is very common in our clinics – more than 50% – so I think these results are very interesting. Consider also the changing landscape, so we have a different option first line – osimertinib alone, the FLAURA-2 combination and here MARIPOSA. So I think very, very important data considering the position in the clinical setting.
EF: Alex?
AS: I agree completely. It’s interesting, I don’t think any of us is surprised by that. This is basically looking at either people with bulky disease or high-risk disease and those are all the high risk features. The only thing that didn’t come out was there any one thing in particular and there wasn’t. These are all the things that we were associated with. I think it gives us a little bit more comfort in treating patients with combination versus single agent osimertinib; if they have any of these features then maybe they do better. I wonder, do you guys think it’s going to be a game changer? The big question is what are you going to use for aggressive or intensification of therapy, is it going to be FLAURA-2, is it going to be amivantamab/lazertinib or is everybody going to get osimertinib. This has been a big thing that we’ve heard over the last couple of days with a lot of differing opinions.
AA: I think, if I may jump in, your question is very valuable. How are we going to select the patients? I think we have the answer, necessarily, by this study. This study is just proving that the combination of drugs is incredibly effective even in a high risk group. I’m sure the vast majority of the patients, or some of the patients, I won’t say the vast majority of the patients, some of the patients might get away just with osimertinib; who they are going to be is not that easy to identify. Also, as you mentioned, also for the FLAURA-2 study with the chemotherapy, so something else to throw in. But the study definitely showed that, as we were expecting, the high risk population definitely few, the combination is clearly much better than the osimertinib for sure.
EF: And I think it’s important in all high-risk subgroups there is a clear benefit, statistically significant, with the combination of amivantamab plus lazertinib compared with osimertinib. It was in patients with brain metastases, liver metastases, patients with p53 co-mutation and also patients with ctDNA. So in those subgroups there is this advantage. In the same session there was a very important presentation by Dr Leigh about the formulation, the subcutaneous formulation. This probably will change also, again, the way that we prescribe amivantamab.
AS: The biggest challenge with amivantamab is not only toxicity but those infusion-related reactions on day one. It’s also a very time consuming regimen. Basically PALOMA-3 showed that you can give sub-Q amivantamab, it can be done within minutes versus hours and the risk of infusion related reactions are down dramatically. So, from a practical standpoint, it gets rid of all the complaints about it. It doesn’t still get rid of all the side effects, you still have the risk of DVT prophylaxis but it was down. But, to me, I’ve sat on a couple of ad boards, as we all probably have, there was a survival difference. We’re all shrugging our shoulders, I don’t think anybody expected it but it’s there. To me, that’s important to see. My thought was if that was a phase III randomised clinical study of two different drugs that would be an approved drug. So, to me, that’s a very important thing; I guess nobody can figure out why it’s happening. What do you guys think?
AP: Do we still have an evaluation that maybe the use of subcutaneous injection is more effective through the lymph nodes and through the lymphatic system? But this is an evaluation that we are evaluating currently to the data. But I think that globally these are very impressive data, considering the clinical impact in the future. Because we know that IV amivantamab is a little bit difficult considering the infusion reaction but the data are very, very impressive. We have only 12% infusion reaction in the PALOMA-3 and we know that yesterday that there is an application on EMA to immediately approve the subcutaneous injection in the first line. So another step forward for the applicability of this kind of kind of combination in the clinical setting.
AA: I totally agree, I think the subcutaneous is definitely going to make a huge difference for all the reasons you have just mentioned. Again, the overall survival, progression free survival improvement, even if it needs to be taken with caution, is of course something that is reassuring. So not only the pharmacokinetics but also the efficacy is pretty much the same.
AS: My only other thought is the thing I like best about all these studies is we really just changed focus to quality of life for patients. Ten years ago it was just about active drugs and getting active drugs, every single talk we’re hearing right now – what is quality of life and what are we doing to our patients? Before PALOMA-3 came out the biggest criticism, as we all said in MARIPOSA, is that it’s toxicity, same with FLAURA-2. The fact that we’re thinking about that is a big step forward. And PALOMA-3 fixes some of it, a lot of it, not all of it.
EF: We have seen also during ASCO that this combination is also active in CNS. Any ideas?
AA: I think this is something that is very reassuring also. So we saw it even at the ESMO before when we saw some data before with MARIPOSA-2 and MARIPOSA. Anyway, there is a combination, we know lazertinib works very well, we know amivantamab seems to have some intracranial activity which is something that before seeing the data I wouldn’t have said, to be honest, because I thought a monoclonal antibody was never going to have great intracranial activity. There is some intracranial activity so that’s definitely a very active drug. And now the toxicity is going to be a concern. My point is more about the more we use the more we become familiar with the drug because, to be honest, the infusion reaction was a bit of a concern, now we seem to be dealing with that. Skin rash is another concern but I think it’s just a matter of becoming more familiar. That, perhaps, is one of the things that sometimes pushes us to use a bit more chemo in the FLAURA because we are familiar with the schedule. But I think it’s just a matter of becoming more familiar with amivantamab, to be honest. This is my take.
EF: Another trial also showed us the results of the combination in patients with atypical, non-typical EGFR mutations, excluding EGFR exon 20 insertions.
AA: That honestly is a great one for the EGFR uncommon mutations. First of all they recruited about 105 patients, if I’m not mistaken, which is huge so I think it must have taken years to get that. Also what was really impressive to me, the efficacy for sure, and the progression free survival which was quite a long progression free survival. It was about 18 months, something like that. So it was something that we’d never seen before. Again, uncommon, we all know it’s very heterogeneous so all together clearly there are subgroups that might do even quite well with osimertinib or afatinib which are two other drugs that have indication for that. But definitely the combination showed very, very good results in a very difficult setting because in the uncommon generally we don’t see the same results as we see in the sensitising.
AP: I thought it was impressive that the benefit within a typical mutation was around 20 months and when we discuss about afatinib or osimertinib it’s quite effective. So the benefits are lower than 10 months generally. So I think that the results were impressive considering the potential to give to our patients a real new standard of care. Of course, these subgroups are a very, very small group of patients but I know that the companies and the authors are working to convalidate the results and to allow the use of amivantamab/lazertinib also in these particular patients that are not so rare when we use NGS analysis for the evaluation in the clinic.
AA: Definitely not rare at all.
AS: I think it’s a huge step forward. At least in the United States we’ve been stuck with afatinib or osimertinib off label and it never quite felt good. I’ll speak for myself but I’m sure you all agree, afatinib is not our favourite drug, it’s been very tough on the label dose. So it’s nice to get some new data here and we’ll hopefully be able to give something to our patients with more data that works and improve outcomes there.
AP: I couldn’t agree more. I think this is… and also with the subcutaneous formulation there is going to be a massive change.
AS: It’s hard to believe that we’ve sat for so many years without a really good approval, of osimertinib and all of these others, numerous TKIs as we all know. Nothing has made it past afatinib for approval in the US and it’s nice to have that.
AP: And the approval of afatinib for atypical mutation was a subgroup, a very, very small number of patients with the three major uncommon, not all the uncommon, mutations. So I think these data are very robust in the setting that is the rare setting and I’m very happy.
EF: Coming back to the activity in sensitising mutations, we have seen in the plenary session the results of the LAURA trial in stage 3, that is another scenario. What do you think about this?
AS: I don’t think there’s a surprise here. We know osimertinib in the adjuvant setting for surgery works incredibly well, those curves are great. LAURA echoes the same thing, you need to give it in patients stage 3 that were not resected. My only criticism, I think [10:33] is indefinite treatment with osimertinib. We’ve never seen a trial of indefinite anything for a curable malignancy and that’s a big step forward. I think we’ll have to see what practice patterns are. I think there are going to be two schools of thought – stage 3 lung cancer is bad and maybe you should give it indefinitely because there could be a lifelong recurrence. But in the same token, in my mind, patients when they’re treated even with very good drugs, and osimertinib is incredibly well tolerated, checkpoint inhibitors for metastatic disease in patients we cure are incredibly well tolerated, but when they stop the drug my patients always say, ‘I didn’t realise I felt bad until I stopped the drug.’
AP: Until you stop it, yeah.
AS: I probably would probably stop it over time after discussion. I’m curious what you guys would do.
AP: I completely agree. I think that the LAURA trial, this positive, completely positive, a hazard ratio less than 0.20, the major understanding is that also in a potential curative setting now we need to treat our patients with anti-progression treatments. So this is new for stage 3b when all our knowledge confirms that it is a potentially curative setting. I think it’s very interesting. So it’s the first in class trial with a TKI here and I think it was very interesting, the discussion, [?? 11:47] data suggests using all the TKIs for different kinds of alterations in the future in this particular setting. So very interesting and this is the line after the ADAURA trial that has confirmed that maybe in EGFR mutant non-small cell lung cancer, regardless of stage, you need to use a dedicated track.
AA: And I think, going back to the LAURA which, of course, is a super-positive study, one of these probably will be a bit provocative, I wondered do we need to give chemo-RT given the data. Stage 3 patients, they do so badly with the chemo-RT, in the chemo-RT arm, that it makes you question is this really adding a lot first of all. Of course it is, but being provocative you do wonder; the results are so bad that you do wonder if there’s any value. The second thing, and this is perhaps my limitation for the study, I think the fact that all the patients get a PET scan before going in the study, I wonder how many stage 4 were in the study and therefore there were no… of course they were relapsing very early. But, again, overall it’s a very positive study and it’s going to be challenging, of course, to keep up osimertinib for ever. That’s going to be very difficult.
AS: I’m personally surprised that, at least in the United States, the FDA said that was a good design. It’s such a paradigm shift – lifelong therapy for curable disease. I agree, it’s a horrible disease, stage 3 EGFR mutated lung cancer, but a 40-year old, does that mean you take it for 50 years?
AA: Good point.
EF: I found also another study interesting, analysing the consolidation stereotactic ablative radiotherapy. Patients with stage 4 disease treated with EGFR TKIs with osimertinib. So I think the treatment of oligoprogression was radiotherapy but here it’s consolidation. Is this your standard practice in patients with EGFR mutation stage 4?
AA: It’s not my standard practice. I have a few cases where I might consider some consolidation radiotherapy but it’s definitely not standard practice. Something I’ve done a few times for specific situations but it’s not something I would call standard of care for me.
AP: The same for me but I think that this kind of trial is required, because all of us treat these kinds of patients sometimes with [?? 13:54] in clinic and we have no clear understanding of the performance or the efficacy and long-term efficacy. So the trial was well conducted, the patients were really well analysed and also discussed and I think the results are not impressive because we know but now we have some data to discuss also with our patients because the addition of radiotherapy in the early stage is a key but also metastatic disease with a low [?? 14:17] disease is a great opportunity.
AS: I agree as well. I think the practicality is what is oligometastatic disease and how many lesions. I think if you ask radiation oncologists ten, in all ten sites.
AA: Because it’s feasible, it’s feasible.
AS: With stereotactic radiosurgery almost anything is feasible, right? I think we have to be realistic and come up with good numbers. I don’t think it’s a surprise here, if somebody has one bone met and it’s lighting up on a scan, sure, why not offer benefit to a patient. It does harken back to the day of consolidative radiotherapy for small cell lung cancer which everybody used and it’s kind of faded away in practice over time.
EF: Yes, and in the area of exon 20 insertions we also have data interesting in the meeting, sunvozertinib.
AA: Again, good data showing in pre-treated populations, so patients who were treated with platinum-based chemotherapy treatment that were also exposed to this drug there seems to be quite an effective response rate, it was in the order of 50%, I think it’s 53%, something like that. The toxicity, because this is the other point, so we have a good drug, now we have amivantamab. We had amivantamab already in second line, now we even have it in first line, but one of the concerns we do have when we use this drug is toxicity, particularly for the EGFR wildtype. The toxicity was quite manageable, I noticed that it was grade 1, grade 2 and mainly skin rash and diarrhoea, as you would expect. So something else popping out which is good. Now, we don’t know exactly what we’re going to do with this, it’s a bit early days, but the activity was quite good in my opinion.
AS: It’s amazing how we’ve moved past the days of poziotinib and mobocertinib. There are new drugs. I think the challenge is going to be it’s an embarrassment of riches and what do you do.
AA: And how do you use them?
AS: Obviously PAPILLON and amivantamab in the front line setting is what we’re all thinking about. We have sunvozertinib, we have zipalertinib, we have fermo and there’s others in clinical study as well. I think we’re not going to know what to do and there’s going to be almost too many choices with very subtle differences over time. I’m just glad we’re able to make TKIs now that are clearly not as bad on wildtype EGFR.
AA: Exactly and they’re also very effective.
AP: It was very interesting, the trial, that a [?? 16:03] patient with also amivantamab before and there was a confirmation that the use of TKI [?? 16:35] affected her. So I think this is a really key point for the future also because PAPILLON is very strong, more or less one year progression free survival and you have the ability to have a dedicated TKI to use after or before, in the future. I think it’s a very clinical opportunity for our patients, also for the science behind because amivantamab is a bispecific antibody, it’s not a TKI, and we have some evidence now that the combination or the sequence could be effective, looking to the future.
AS: Do you think we will see combinations of TKI and amivantamab instead of chemotherapy?
AP: Yes.
AS: To me that makes sense.
AP: Yes, also for me. So I think that is very potential. So amivantamab/lazertinib we know that is effective, is feasible, and I think also these new TKIs for exon 20, fermo, zipalertinib, sunvozertinib maybe are less toxic than third generation TKIs. The combination will be very, very interesting and so the problem may be today that we have a different company to interact and to make an agreement. But I think it’s a great opportunity for the future to try a combination with a selected TKI for exon 20 plus amivantamab.
EF: So very important trials presented here, practice changing. Perhaps I will ask you a few take-home messages from each of you?
AS: So, for me, every year I see lung cancer dominates these meetings. It’s great to be a thoracic oncologist if we get to keep doing this.
AA: It feels good.
AS: It is a reminder to me that no matter what we still need to do better, EGFR mutated lung cancer, the five-year survival is still low. So these are all great, it’s amazing, but I still think there’s always room for improvement for our patients, especially focussing on quality of life.
AP: For me, the first evaluation for the high-risk population, the biology. So biology first now. And then the atypical mutations. So this is, in my opinion, a step forward for patients that are considered rare in the clinic or rare according to the biology and now we have a very great opportunity for the future for this kind of combination of amivantamab plus lazertinib.
AA: Yes, for me, the take home message is definitely the uncommon atypical. I totally agree with you and they’re becoming less uncommon because we are detecting more and more. So definitely there is a need and I think we are definitely doing something about it. Again, I totally agree with you, very well with EGFR my only perhaps criticism or remark is the fact that perhaps we are trying to do precision oncology a bit unprecisely, meaning that we’re giving the drug to everybody for ever. That is a bit the opposite so we definitely need to work a lot more on how to determine the length of time we want to put those patients on and that’s something we need to do as soon as possible.
EF: So thank you, I think we have new opportunities for the patients. Thank you for all your comments and thank you all the people watching. Thank you.
