EF: Hello everyone and welcome to this ecancer round-table to discuss the latest advances in patients with EGFR mutations. We are going to discuss the most important studies presented here in Chicago during the ASCO 2025. My name is Enriqueta Felip, I’m a medical oncologist working at Vall d’Hebron University Hospital and it’s a real honour for me to share this conversation with my two friends, please if you can introduce yourselves?
NG: I am Nicolas Girard, a thoracic oncologist at Institut Curie in Paris.
PT: And I am Pascale Tomasini, I’m also a thoracic oncologist in Marseille, France.
EF: So important papers discussed during this meeting. One of the papers that I think is important was presented by Dr Califano and analysed the baseline mechanisms of acquired resistance in patients included in the MARIPOSA-2 trial. Dr Tomasini, what are your key findings from this study and the take-home messages?
PT: This study showed that the MARIPOSA-2 regimen with amivantamab and chemotherapy induced a longer progression free survival in comparison with chemotherapy across all the resistance mechanisms groups, whatever the resistance mechanism is, dependent on EGFR or MET or independent on EGFR or MET. It’s also important to see that when the resistance mechanism is known the MARIPOSA-2 regimen is also better, with a longer progression free survival, than chemotherapy alone.
EF: So it’s important to analyse the mechanisms of acquired resistance probably but this mechanism has no impact in the treatment if we decided to give the MARIPOSA-2 schedule?
NG: That’s a very good point. From earlier in the year with amivantamab there was a sense that patients with MET overexpression or EGFR were the ones that had the most benefit. But in the setting of combination with chemo in the post-osimertinib setting we see this broad efficacy of the combination. Still I believe that it’s important to do a re-biopsy of the patients because maybe before moving to MARIPOSA-2 there is an opportunity for other strategies and transformation into small cell is also something that may be observed and that we need not to miss at the time of disease progression.
EF: And in your clinical practice how do you do it, doing re-biopsy, liquid biopsy, both, in patients with EGFR mutations after first-line treatment strategy?
PT: Both.
EF: Both.
PT: When possible we try to do tissue biopsy and when not possible liquid biopsy.
EF: There is another important trial also presented here that is focussed also in second line but in patients with MET amplification, an analysis of savolitinib plus osimertinib versus chemotherapy. Nicolas, what are your…?
NG: Well, that’s a very interesting study kind of mimicking the SAVANNAH study that was presented previously at ELCC. The question is if we have a MET amplification, which is a quite frequent mechanism of acquired resistance to osimertinib, can we treat the patient with savolitinib, a MET inhibitor, while continuing osimertinib? What is really interesting is that we have this efficacy of savolitinib in the second-line setting in this subset of patients. I agree that those patients should also be sensitive to amivantamab, maybe savolitinib could add one line of treatment in those patients, possibly moving them after to chemo plus amivantamab. It’s a way also to have a second line which is chemo free so I feel that we are prolonging the chemo-free interval in those patients.
EF: So in this second line scenario sequencing is also important and this offers a new opportunity to have the possibility of MARIPOSA-2 but also if the patient has a MET amplification this study may be also relevant.
NG: And probably it’s important to add several lines after the failure of first line. In EGFR mutant non-small cell lung cancer we know that first line is a major contributor for overall survival and then we have some incremental benefit with what we are doing. But adding several lines of treatment is probably also very important in those patients.
EF: Also amivantamab is also a crucial agent in the treatment of patients with EGFR mutations activating but also exon 20 insertion mutations. You, Nicolas, presented during the ELCC meeting the initial results of the COCOON trial that have been updated during this meeting at ASCO. What are they?
NG: So COCOON is first line, first line with a combination of amivantamab plus lazertinib, based on the MARIPOSA trial. We know that we have a benefit of amivantamab plus lazertinib versus osimertinib, not only in terms of PFS but also in terms of overall survival. COCOON assessed whether a prophylactic dermatologic management was able to reduce the incidence of grade 2 or higher cutaneous side effects that are more frequent with amivantamab/lazertinib as compared to osimertinib. We see a reduction in the risk of those grade 2 or higher adverse events during the first weeks of treatment, this is the main endpoint of COCOON, and during this ASCO meeting we saw the questionnaires, the dermatology questionnaires. So more specific, more precise and there was a clear improvement in those questionnaires which is good because it gives a sense not only of the incidence of the events but also the duration of those events and how prophylactic management may reduce the burden of cutaneous side effects.
EF: How about to prevent and also to treat the adverse events associated with amivantamab? So it’s not only the dermatological prevention. What is your clinical practice in that?
PT: So we also know that we have to prevent the thromboembolic events with anticoagulation and we also have to prevent the infusion-related reactions with dexamethasone since we had the results of the SKIPPirr trial. So we have to do all this packaging of prophylactic interventions for the patients now we know that the quality of life of patients is better with this.
EF: How can you organise all this multidisciplinary approach to prevent and to treat adverse events associated with amivantamab? Do you have multidisciplinary discussion and also do you involve nurses in the management of these adverse events?
NG: It’s a multidisciplinary management, proactive management. There is a learning curve with amivantamab plus lazertinib. It’s very important that the oncologist has this close relationship with the patient but is not alone, nurses, dermatologists are part of the team. We are playing the role of triage dermatologist, I would say; prophylaxis is something that we can implement quite easily because these are easy measures and widely available moisturiser, doxycycline and chlorhexidine on the nails is quite easy. But once you have a toxicity maybe you can manage grade 1 with incremental dosing of doxycycline, intensification of the moisturising and so on. If it’s grade 2, grade 3, then maybe you need to refer to the dermatologist. So you have to find the limit, actually, of what you are doing as an oncologist and what needs to be referred to the dermatologist.
EF: I found it also very important two trials presented with antibody-drug conjugates in the area of patients with EGFR mutations in second line, patritumab deruxtecan but it’s not the only one. Perhaps Dr Tomasini if you want to discuss these two trials, the results.
PT: Yes, this ASCO Congress we had the results of two phase III trials with ADCs for EGFR mutant patients. The first one is the HERTHENA-02 trial with patritumab deruxtecan, a HER3 ADC, in patients who previously received osimertinib and it was compared with platinum-based chemotherapy. The primary endpoint was progression free survival; the difference in the median progression free survival is not very large but it’s a positive trial. It's also positive for all the other endpoints, response, and it doesn’t add any toxicity in comparison with platinum-based chemotherapy so this is important. The second trial was performed in Asia, it’s a trial with a TROP2 antibody, the sacituzumab tirumotecan. It was performed for patients who received osimertinib and platinum-based chemotherapy and the randomisation was between the TROP2 ADC and docetaxel. Crossover was allowed in this trial. We do not have the results of overall survival yet but it’s a positive trial regarding progression-free survival and overall response rate which was the primary endpoint. And, again, there was no more grade 3 or more treatment-related adverse events.
EF: We previously knew also the results of datopotamab deruxtecan in this scenario so it seems that ADCs may have also a place in this situation but there are some opportunities there.
NG: And probably the need to have more data, patritumab development seems to be discontinued based on this data with the disappointment in terms of magnitude of benefit. Probably it’s a shame because this is an effective drug; probably to be reserved to later lines, actually. The trial would have been against docetaxel, probably it would have been really positive and clinically meaningful. With regard to TROP2 ADCs, there are some trials that are now starting in the first-line setting, the second-line setting, in combination with osimertinib. So there is probably room for TROP2 ADCs for these patients. We have also the chemotherapy plus ivonescimab, this bispecific antiangiogenic plus immune checkpoint inhibitor. We had a press release during the ASCO meeting, I’ve not seen the data but there seems to be a significant PFS benefit, hazard ratio of 0.52, but not yet OS benefit. So more to come, probably, with this combination.
EF: So in the second line scenario MARIPOSA-2, we have seen the results of savolitinib plus osimertinib in patients with MET. We have also the ADCs and also you mentioned another study of ivonescimab that we have seen the press release during our ASCO meeting and it will be presented in the [??] meeting. And also EGFR exon 20 insertions, you are lead on the PAPILLON trial, you presented and also published in The New England Journal of Medicine. And now it seems that we have other opportunities and there was a presentation with zipalertinib in patients?
NG: So zipalertinib, a TKI dedicated to target EGFR mutations including EGFR exon 20 insertion mutations, now that we have this first-line standard of care with chemotherapy plus amivantamab, based on the PAPILLON trial, there are many questions. What are the resistance mechanisms to amivantamab in this setting? And what is the treatment sequencing? There are several TKIs that have been assessed in EGFR exon 20 insertion mutated non-small cell lung cancer – sunvozertinib, furmonertinib and now zipalertinib. Here it’s interesting because we saw data post-amivantamab plus chemotherapy. 30% response rate, PFS around 7 months, so quite interesting data showing the efficacy of zipalertinib post-amivantamab. So we are designing a sequencing of those treatments, meanwhile zipalertinib and others are developed also in the first-line setting. So what will be the best treatment sequence: TKI first and then amivantamab to cover the resistance mechanisms or amivantamab first followed by a TKI? We don’t know yet.
EF: Yes, so I think these are probably the most important studies in patients with EGFR mutations presented during ASCO but there has been also education on discussing the first-line setting and I would like to know your opinion also now we have different treatment options. What could be your recommendations for first line treatment of patients with activating EGFR mutations if everything is available. Nicolas?
NG: Yes, I’m well experienced with amivantamab plus lazertinib so I’m a believer of amivantamab plus lazertinib. It’s chemo free, there is clearly an improvement of PFS. We have also an OS benefit that is significant. So I feel that the majority of patients could benefit from this combination. Osimertinib as a single agent probably reserved to elderly patients or fragile patients. And chemotherapy plus osimertinib probably in very aggressive disease but very hard to distinguish between the populations that would most benefit from chemo up front versus a chemo-free regimen with amivantamab plus lazertinib. When starting a first line we need to think about the first line because many patients do not have access to second line. 30% in real-world data which is really high and higher than my perception in our cohort, but still this is a reality. We need to think first line which is a major contributor of overall survival in those patients but maybe we also need to think about sequencing in patients and when to position chemotherapy and the new options such as ADCs. Pascale, I don’t know what you think?
PT: Well, I think that the first question is to identify the patients whom you want to do a combination versus osimertinib alone. Then you have the choice between osimertinib plus chemotherapy or amivantamab plus lazertinib. I also have big experience of amivantamab so I’m not afraid of all the toxicities and the prevention of the toxicities but I think maybe I would want to have more data on brain metastases efficacy because for these patients maybe the combination with chemotherapy is more interesting but we don’t really know. This is something that I would have to know in order to choose for these patients. But on the other hand, yes, amivantamab plus lazertinib is a good option because we now have tips to prevent the toxicities and we know that overall survival is longer.
NG: We need probably to have another kind of multimodal assessment of the patients, not only based on the characteristics of the patients, the tumour, the biology. ctDNA – we saw during the meeting that ctDNA monitoring may be very important to stratify the patient risk. We have data from FLAURA-2 showing that when ctDNA is negative at baseline maybe the magnitude of benefit when adding chemotherapy to osimertinib is not that high. So probably we can better stratify the patients if we have the right tools and maybe ctDNA with highly sensitive methods is one of those.
EF: So very important studies presented during the ASCO meeting. Perhaps to sum up, knowing that MARIPOSA-2 there is no impact in the mechanisms of resistance, the baseline mechanisms of resistance in the activity of the combination of chemo plus amivantamab. It’s important to manage and also to prevent toxicity with amivantamab and the results of the COCOON trial show better quality of life with a dermatological proactive treatment. We have seen also very important studies with ADCs, although patritumab deruxtecan seems that it will not go for further development in this group of patients. But there are other agents, important ADCs. The study with savolitinib plus osimertinib in patients with MET amplification I think is also important in a subgroup of patients. And you mentioned sequence and for patients with EGFR exon 20 insertions there are new agents that may be active also after the combination of chemo plus amivantamab. So I would like to thank you for all your comments and thoughts and also thank you all for being with us today and to follow this conversation. And thank you to ecancer. Thank you.
