Latest in EGFR positive NSCLC

Dr Antonio Passaro – European Institute of Oncology, Milan, Italy

Prof Nicolas Girard - Institut Curie, Paris, France

Prof Raffaele Califano – Manchester Hospital, Manchester, UK

Dr Anna Minchom – Royal Marsden, London, UK

AP:      Good morning to everyone. I’m Antonio Passaro, I’m a medical oncologist from the European Institute of Oncology in Milan, Italy and I’m very pleased today to have this round-table discussion around the latest in EGFR positive non-small cell lung cancer released during the European Lung Cancer Congress. I’m very pleased and happy today to share this opportunity with three friends and colleagues in the field – Professor Raffaele Califano from Manchester Hospital, Anna Minchom from London, Royal Marsden, and Nicolas Girard from Institut Curie in Paris, welcome to all of you today.

So the European Lung Cancer Congress this year was very, very interesting and full of new data, in particular for the field of EGFR in non-small cell lung cancer. Many updates and new data were presented in Paris and today we will recap all together, also sharing our feelings and perspective on this kind of new data. So I’m very happy to have the opportunity to open this panel discussion focussing on the MARIPOSA trial. So we know that at the European Lung Cancer Congress Professor James Yang from Taiwan presented the updated analysis of this major phase III trial for naïve patients with EGFR mutant non-small cell lung cancer.  So my first question and introduction, of course, is for Professor Raffaele Califano. So, Raffaele, MARIPOSA is a breakdown trial, so what’s your feeling and particularly what’s the data that we have during the European Lung Cancer Congress? Thank you.

RC:     Thank you very much and good morning everybody. So, as you said, we witnessed a practice-changing presentation at the recent European Lung Cancer Conference. Just to remind the audience, MARIPOSA is a large first-line study which randomised and treated patients with EGFR mutant non-small cell lung cancer with common EGFR mutations to receive either the combination of amivantamab, which is a dual EGFR and MET inhibitor, plus lazertinib, which is a third generation EGFR TKI, or osimertinib or lazertinib. The trial was powered to show a difference in progression free survival, which was the primary endpoint, between the amivantamab/lazertinib arm versus osimertinib. The primary endpoint was already presented and what was presented very recently, as you mentioned, was the final protocol prespecified overall survival analysis which was conducted when more than 390 deaths had occurred between the two arms.

At this presentation during the recent congress, MARIPOSA demonstrated a statistically significant and clinically meaningful improvement in overall survival favouring amivantamab/lazertinib versus osimertinib with a hazard ratio of 0.75. Very importantly, the median overall survival was not reached for the amivantamab/lazertinib arm and was around 37 months for the osimertinib arm. From a statistical point of view there is a projection of prolongation of the median overall survival in the amivantamab/lazertinib arm of at least 12 months versus the osimertinib arm which is a very relevant and clinically meaningful difference. So this is the first time that a novel generation clinical trial addressing this novel combination of a chemo-free intensification strategy has demonstrated an overall survival advantage when compared to what was considered the standard of care until recently which is first-line osimertinib.

Professor Yang also presented further endpoints. It’s important to remember that all patients who were randomised in the MARIPOSA study were screened for brain metastases at the outset. Also patients who did not have evidence of CNS metastatic disease were followed up longitudinally with brain scans, preferably MRI but also CT scans, every six months. So we do have a very solid assessment of CNS-dependent endpoints. The reason why I’m mentioning these is because in the updated analysis we also saw a longer intracranial progression free survival favouring amivantamab/lazertinib and we do know how important it is to control CNS metastatic disease in patients with EGFR mutant non-small cell lung cancer. These responses were also durable – there was, in fact, a longer intracranial duration of response for amivantamab/lazertinib when compared to osimertinib. So this confirms that amivantamab and lazertinib is a very good option as a first line treatment for patients with advanced EGFR mutant non-small cell lung cancer with common EGFR mutations. For the first time there is an overall survival benefit. Certainly we need to bear in mind that this combination has got a different adverse event profile, let’s say, compared to single agent osimertinib or chemotherapy plus osimertinib and amivantamab in this study was given as an IV treatment. With the colleagues we’ll discuss how to potentially mitigate the adverse events from this regimen. But I do feel that this was definitely a practice-changing presentation.

AP:      Thank you Raffaele. I can confirm your feelings about MARIPOSA, that it’s a revolutionary trial. In this particual historical moment for patients with EGFR common alterations in the first-line setting data were impressive but we know, as you anticipated, that when we discuss new compounds, new combinations, the feelings and also the discussion around safety is very, very important. So we know from the past, from the first presentation was also true that the combination increased the rate of toxicity related to EGFR and MET pathways; this is very, very common when we use a combination treatment. But there is a very strong, robust, clinical development around amivantamab and part of this kind of new data were presented, particularly by Nicolas Girard that today is with us, related to the COCOON trial. So, Nicolas, I would like that you share with us the COCOON but also in particular the feeling around the safety of amivantamab that is changing very, very well during the last months. Thank you.

NG:     Yes, thank you Antonio. I think that we had a rapid development of amivantamab plus lazertinib from the phase I studies to the phase III trial. And actually we learned how to manage those side effects along with the development and the phase III study. So this is why parallel to MARIPOSA we have this COCOON trial which actually assessed how to prevent dermatologic side effects which are more frequent with amivantamab plus lazertinib versus third generation TKIs. So the COCOON trial aimed at, in the setting of the first-line treatment of patients with common EGFR mutations with amivantamab plus lazertinib, to compare. It was a randomised study, patients were randomised 1:1 to receive this dermatological prophylactic management with doxycycline for the first 12 weeks with chlorhexidine on the nails to prevent paronychia with moisturiser on the body and face and also topical clindamycin on the scalp. So the objective was to initiate from the beginning the dermatological management prophylaxis versus standard of care which was often restricted to reactive treatment of those side effects. The incidence of grade 2 or higher dermatologic adverse events in the first 12 weeks was the primary endpoint in the COCOON trial.

The COCOON trial actually demonstrated that we have a significant reduction, it’s a twofold reduction, in the incidence of those grade 2 or higher dermatologic adverse events with the prophylactic regimen, moving from 77% to 39%. We have also a twofold decrease in the grade 3 events. So we see that benefit is observed across all the subgroups, including patients from Asia and non-Asian patients, men and women, and we have a decrease in all the different body locations for the dermatologic adverse events – face and the rest of the body, the scalp and the paronychia. So clearly this prophylaxis has to be readily implemented in clinical practice in combination with amivantamab plus lazertinib. We have a major reduction in the incidence of those dermatologic adverse events and it has to be combined with the rest of the prophylactic measures to mitigate the side effects associated with amivantamab plus lazertinib which include infusion related reactions. We previously discussed together about the SKIPPirr trial and the prevention of those infusion-related reactions with dexamethasone given for two days before the first infusion of amivantamab.

The last point is the VTE prophylaxis with amivantamab plus lazertinib anticoagulants are recommended for the first four months of treatment. So obviously it’s a kind of intensive prophylactic regimen but, at the end, all those measures are widely available and quite easy to implement. We need to educate the patients for sure and we need also to explain to the patients that these measures prevent the side effects and the objective is to have the benefit with amivantamab plus lazertinib that is observed in the MARIPOSA trial. One year of overall survival is something that is highly meaningful for the patients and families so we need to implement those prophylactic measures to facilitate the quality and improve the quality of life of patients.

AP:      Thank you, thank you Nicolas. So I think that the discussion around the MARIPOSA today is not only focussed on the data of survival, that are impressive, as shared by Raffaele, but it is important to coordinate and discuss all together, including the COCOON regimes, that in my opinion is very practice changing, considering the clinical perspective and the daily perspective of all of our patients. Data of reduction of toxicity are very, very impressive with very easy measures and this is not enough because we know that also during the European Lung Cancer Congress there were new data around the clinical development of a subcutaneous injection of amivantamab, another step in favour of a quality of life for our patients. And my question is for Anna, that is very, very involved with the development of subcutaneous amivantamab, around the new data presented for PALOMA-3 but particularly for all the PALOMA programmes.

AM:     Yes, thank you. So, as you say, one of the issues with amivantamab given intravenously is rates of infusion reactions which occur typically in the early days of dosing and can be high grade though, as we’ve mentioned, are mitigated by pre-medications with steroids but has necessitated split dosing for the first time the drug is being given intravenously. We already have data from PALOMA-3 showing that subcutaneous administration is feasible, has equivalent pharmacokinetics and reduces the rate of administration reaction significantly.

So what we saw at ELCC this time was some data from PALOMA-2. PALOMA-2 is interesting because it’s looking at patients who have been already receiving intravenous amivantamab two-weekly, either as standard of care or as part of expanded access programmes, and switching them over to the subcutaneous version. Which I think is interesting because it gives us the opportunity to ask patients what they feel about these ways of administering drugs because they will have experienced both. So there were relatively small numbers of in-patients included, about 25 patients, and they were switched over from the intravenous to the subcutaneous administration. There were no surprises particularly in terms of the adverse event profile with the side effects that we’re familiar with in terms of MET inhibition with some oedema and some rash and paronychia. But to focus on the infusion reactions, no adverse events from infusion reactions were reported. A PK analysis was done which showed, again there were no surprises here, the PK was very satisfactory. Importantly, when patients were asked, 83% of them found the subcutaneous administration more convenient with only 8% preferring IV to subcutaneous. So that’s a vote of confidence from the patients there, which I think is very important with this drug as we move forward.

AP:      Thank you. Thank you Anna. So globally we can confirm that the first-line setting is changing very, very fast. So today we are discussing the update for the MARIPOSA but we know, of course, that the FLAURA2 was another trial positing that osimertinib alone is still the standard of care worldwide in waiting for the implementation of this new combination. But together with the development in first-line setting we know that there are many, many trials ongoing showing very interesting results in the resistant setting where the only phase III trial at the present time with positive data is the MARIPOSA-2 of the combination of chemo plus amivantamab. But during the ELCC this year were presented very interesting data from my side. So one of the first in the oral session was the update of the SAVANNAH trial. The SAVANNAH trial was a trial that evaluated the combination of savolitinib plus osimertinib in patients with a MET overexpression or amplification progressing to osimertinib. So, Raffaele, what’s your feeling about this phase II? Of course we’re waiting for the phase III, SAFFRON, but very, very interesting to consider the clinical implication.

RC:     Thank you very much. This is a very relevant trial, in particular for patients who have been treated with first-line osimertinib, because we know that one of the dominant mechanisms of progression is the presence, or development I should say, of MET amplifications.  So the SAVANNAH study had this rationale in mind, so patients who had progressed on osimertinib, whose disease progressed after osimertinib and they were found to have a tumour with MET overexpression amplification, as you said, were treated with savolitinib, which is a MET inhibitor, plus osimertinib. The rationale was to continue to address the TKI-sensitive clone with osimertinib and then to try and address the MET, amplification of the MET-expressing clones. This was a study which we need to bear in mind had a primary endpoint of response rate and then there were, of course, PFS and other secondary endpoints.

With the expanded cohort what we saw was that there is indeed activity when you combine a MET inhibition plus osimertinib in the post-osimertinib setting in the MET overexpressing amplified. The response rate was pretty high, it was more than 55%, which was confirmed to be very similar also at blinded investigator review. This is very important because we know that at present the standard of care for these patients will be, of course, the MARIPOSA-2 regimen but if you want to think about infrastructures or healthcare programmes where you don’t have the MARIPOSA-2 regimen and you treat your patients just with platinum/pemetrexed, the response rate is going to be 25% at best with a progression free survival of four months only. So I think this has a strong rationale and the SAVANNAH study reinforces the potential benefit of combining a MET inhibitor with osimertinib in the MET positive disease at progression from osimertinib.

Now, of course, as we have discussed, the first-line paradigm is changing and what we have seen is that for patients who are treated with the amivantamab/lazertinib combination upfront the biology at progression changes compared to what we have seen from the osimertinib progression. Because addressing at the outset MET, with the dual MET and EGFR inhibition from amivantamab, what we have seen from plasma data in the MARIPOSA study is that there is a considerable reduction for patients treated with amivantamab/lazertinib of the MET amplification as a mechanism of resistance and also reduction of the EGFR dependent mechanism. There is a switch towards other bypass drugs. So I think we need to bear in mind that of course for patients who are treated with osimertinib the SAVANNAH strategy would be relevant but as we hopefully move towards a different intensification strategy the biology of progression will change and that will determine how we need to address the second-line setting and beyond.

AP:      Thank you Raffaele. Of course the identification of MET after resistance to osimertinib is a key factor, it’s very, very important. But do we know the limitations around MET and the rate of patients with high MET? During the meeting there was another very interesting presentation also looking for the future. This focussed in particular for biomarker agnostic procedures, in particular the results of the cohort of the ORCHARD trial that evaluated a combination of osimertinib plus datopotamab deruxtecan in patients progressing after osimertinib. So, Nicolas, can you summarise this data and try also to consider in the field of this great evolution?

NG:     Yes, post-osimertinib here this is a strategy that is not biomarker driven, or at least in the ORCHARD trial there were some biomarker-driven strategies. Here, for patients without a clear mechanism of acquired resistance to osimertinib, patients received datopotamab deruxtecan, which is a TROP2 directed antibody-drug conjugate, with the continuation of osimertinib post-osimertinib. We had some data from the landmark trial with datopotamab deruxtecan in the second-line setting versus docetaxel, some hints that in EGFR mutant non-small cell lung cancer we had some efficacy of Dato. Here with this combination osimertinib plus Dato, especially in the 6mg/kg every three weeks cohort, we see a quite impressive efficacy with a median PFS of nearly 12 months with osimertinib plus Dato. So obviously it’s a phase II multi-cohort trial so selected patients, but there is a signal that adding Dato to osimertinib at the time of resistance may be an effective strategy, at least it has to be evaluated in a randomised study.  And these studies are actually now starting in multiple centres.

So it’s clear that we will have several strategies post-osimertinib, the ones that are driven by biomarker, such as we discussed with SAVANNAH, and also some will not be driven by a biomarker. We have now MARIPOSA-2 already, maybe datopotamab deruxtecan, at ASCO we will see patritumab deruxtecan, which is a HER3 directed antibody-drug conjugate, data lung trial. So multiple proposals, which is also a drug of interest in this setting.

AP:      Thank you Nicolas. So you confirmed that today we have many options as biomarker agnostic treatments in the clinical setting. In this field I think that during the meeting there was a very interesting presentation. So, Anna, can you recap for us the results of the ETOP AMAZE-lung trial that confirmed the way of biomarker agnostic after osimertinib?

AM:     Yes, absolutely. So there has been quite a long history of targeting angiogenic pathways for drug resistance in EGFR-mutant non-small cell lung cancer and this builds on that. This is a trial from ETOP, a phase II trial, of amivantamab in combination with lazertinib and bevacizumab, the antiangiogenic drug, in patients who have already progressed on osimertinib. So this phase II study included 61 patients, its primary endpoint was overall response rate. After the first 60 patients there was a response rate of 39%. So bear in mind these are patients who were already progressing on osimertinib and you’re essentially adding in the amivantamab and the bevacizumab. Quite reasonable durations of response – a median duration of response was 13.9 months.

What I think is important about this combination is that in contrast, perhaps, to some of the other agents, including antibody-drug conjugates as a group, this was well-tolerated with the amivantamab bringing its expected adverse events in terms of rash and paronychia but potentially the bevacizumab adding little in terms of toxicity. There were some thromboembolic events but these were low grade.

So I think this is an interesting trial. Of course, it’s difficult to unpick how much the angiogenic drug is actually adding because we are adding amivantamab also, but it clearly has potential in terms of tolerability. It’s perhaps challenging to see how this will fit in with our evolving standard of care, given we may be using amivantamab first line. But this was postulated as a chemo-sparing regime which is certainly of great interest as we move forward in this field, pushing chemotherapy potentially further down the line.

AP:      Thank you very much Anna. So I would like to thank all my colleagues today – Raffaele, Anna, Nicolas – because thanks to you today we understood very well the great developments, the last data, in the field of EGFR non-small cell lung cancer. So many, many data transforming the clinical perspective for our patients – the first line with the MARIPOSA, the second line with very novel multiple options, biomarker oriented, some are also biomarker agnostic. And in particular from my side the great advance in the management and the safety, so the COCOON and the PALOMA programme, I think, are very, very important considering our clinical implication and the view of our patients, in particular the improvement of quality of life, considering the long-term overall survival we discussed before with Raffaele. So I would like to thank all of you again, so thank you to ecancer for this webinar, for hosting us today. Thank you very much.