JS: Welcome to this exciting discussion about amivantamab sponsored by ecancer. I want to introduce my co-host, Dr Anna Minchom. Dr Minchom, give me a quick overview on the state of EGFR; we’ve been hearing a lot about this drug over the last couple of weeks. When you think about EGFR mutant lung cancer how do you break it down?
AM: For a long time we’ve been using EGFR tyrosine kinase inhibitors and we’ve been mainly focussing on the common EGFR mutations and looking at mechanisms of resistance including T790M but really we’re now moving broader than that. We are now moving towards looking at multiple different mechanisms of resistance to the EGFR TKIs, most primarily osimertinib. We’re also really looking at the rarer mutations in EGFR lung cancer and seeing if we can extend benefits to patients previous really not tested for and assessed in large randomised controlled trials, so primarily exon 20 insertion mutations and other rare EGFR mutations. Really, most of our discussion today will focus on some of the newer agents including amivantamab of which we’ve heard a lot about at ASCO with recent FDA approvals. Amivantamab is a bispecific antibody that targets EGFR and MET. It’s proposed to have three main mechanisms of action – ligand dependant, receptor degradation and also immune cell directed activity. For much of our discussion we’ll be discussing an abstract in which it has been paired with lazertinib. Lazertinib, it’s worth pointing out, is a third generation tyrosine kinase inhibitor; it has efficacy in activating EGFR mutation T790M and has CNS penetration and CNS activity.
JS: So really two separate groups that we’re talking about today – EGFR exon 20, as you mentioned, a rare mutation making up 10% of the EGFR alterations and then the EGFR activating mutations, exon 19 del and 21 making up 80-90% of EGFR mutations. We already saw the approval, the FDA approval, of amivantamab in EGFR exon 20. Dr Minchom, what do you think the next steps are for moving that drug into the front line setting?
AM: Amivantamab has been looked at in a number of different cohorts. At the moment there is a recruiting trial, a phase III trial, looking at it in combination with chemotherapy. So that will be interesting to see those results come through over the next years. Going back to the EGFR mutations, we have seen approval from the FDA and hopefully that will follow through shortly in the UK, I’m hoping, for the exon 20 insertions. We’re yet to see in the UK how that approval is structured in terms of which line of therapy it is likely to be with.
JS: Moving really to exon 19 deletion and exon 21, these are the more common mutations that we see in the clinic. What is the current landscape of treatment for patients newly diagnosed with an exon 19 deletion or exon 21 mutation?
AM: We know that of the tyrosine kinase inhibitors for EGFR that we have in use, clearly the best first line therapy is osimertinib from the FLAURA data. When our patients progress through osimertinib currently our standard of care is looking at drugs such as chemotherapy or chemotherapy-immunotherapy combinations. The challenge now is to see if we can improve on those outcomes by looking at this very heterogeneous group of patients and picking the mechanism of resistance, be it genomically or by protein expression, as in the abstract we’re going to discuss in a minute, to see if we can look at the exact resistance mechanism that is causing that patient to no longer respond to osimertinib and pick a therapy to target that resistance mechanism. That is all within the trial setting at present. It’s going to be very interesting to see how much in coming years we move towards that very targeted approach for resistance, given we know resistance is very heterogeneous, there can be multiple resistance mechanisms involved, and how much of this space is going to be left for a drug or drug combination to treat agnostic of the resistance mechanisms we identify.
JS: You make a great point, first, second generation EGFR TKI – 60% of patients had T790M resistance mutations and comes along a third generation EGFR inhibitor like osimertinib we now have lazertinib being studied in combination with amivantamab. What is the difference between the resistance mechanism landscape? You mentioned it was very heterogeneous though. Maybe talk a little about some of these resistance mechanisms and why do you think it is so different than post-treatment on a first or second generation EGFR TKI?
AM: There has been lots of work looking at the different resistance mechanisms. First of all, dealing with the resistance mechanisms to first line osimertinib, a third generation TKI, we can break it down into MET dependent, EGFR dependent, other pathways, transformation such as small cell transformation and even taking all of those resistance mechanisms into account we end up with about half the patients in which we can’t identify a resistance mechanism. But of the MET dependent resistance mechanisms it’s probably about 10-15% that have this as a mechanism of resistance to first line osimertinib and EGFR resistance mechanisms making up probably about another 10% of that.
JS: It’s really interesting here that very diverse population and maybe we’re moving backwards into non-targeted. We’re talking about combination chemo, we’re talking about other combination strategies and maybe moving away from targeted therapy. I think that’s why the amivantamab concept is so interesting. So let’s jump into this abstract here – amivantamab in combination with lazertinib for the treatment of osimertinib relapsed, chemotherapy naïve, EGFR mutant non-small cell lung cancer and the key takeaway from this abstract is potential biomarkers for response. So what were your thoughts on this abstract and how do you think this can change or move into the clinical practice down the road?
AM: I thought it was a fascinating abstract. It’s really the meat of it is not within the responses as a patient group as a whole but in delving down into biomarker data. So, to summarise, this was a study of 45 patients with osimertinib resistance who were treated with lazertinib and amivantamab. Of that group as a whole the response rate was 36% with a median duration of response of just under 10 months but patients had tissue next generation sequencing and ctDNA done though not all had tissue sequencing done at the time of trial entry. We divided the groups into those who had EGFR and MET based resistance mechanisms identified on their ctDNA or tissue and those who didn’t. Of the 17 patients who had EGFR and MET based resistance mechanisms identified the response rate was 47% with a median duration of response of 10.4 months. From this data you can see, first of all, that again it’s very heterogeneous so there were around 7 patients who had EGFR mediated mechanisms of resistance including amplification C797S and I think it was 4 who had MET based resistance mechanisms such as amplification and one rare patient with an exon 14 mutation as well. So 47% response rate so using these genomic markers we can get a better prediction of who will respond than taking the group as a whole. But that’s not the end of the story because in those who did not have an EGFR or MET based resistance mechanism identified there was still a response rate of 29% and there were responders, so numerically the same number of responders, 8 responders, although a smaller percentage response rate. I think it’s worth pointing out on that that these patients were classified as having either MET or EGFR independent resistance mechanisms or an unknown resistance mechanism. But of those unknown resistance mechanism patients 5 of those didn’t have tumour NGS done so we might just be missing the resistance mechanism on that.
JS: I found this data very fascinating and we saw this data presented by Dr Cho about a year ago now in post-third generation EGFR TKI patients, 36% response rate. What’s even more exciting moving forward is in the untreated population 100% response rate. So do you think we’re going to move away from molecularly selecting patients, maybe treating everybody post-third generation EGFR TKI? Because the response rate between the molecularly identified subset with MET amplification or C797S didn’t seem that different – 36% versus 29%. What do you take away from this clinically at the end of the day? I think interesting that you have a biomarker but clinically does this play out in the clinic here?
AM: I always tend more towards a more nuanced approach and I have a reluctance to move away from still searching for the right biomarker for these drugs. All drugs are toxic, all drugs have side effects and I still think we need to be pursuing patient selection in this cohort. There will still be a role for a non-biomarker driven drug but if we can be more clever about selecting these patients then we should continue to do so.
JS: I agree but say you find a MET amplification post-third generation EGFR TKI as a resistance mechanism, are you thinking about adding a MET TKI to osimertinib, or a third generation EGFR TKI, or are you thinking about using a more broad strategy like a drug amivantamab which is both an EGFR antibody as well as a MET antibody bispecific?
AM: We need to do the trials. We’re moving into a really exciting era where we have multiple potential drugs we can be using in this setting and this will play out as we get more data over the next months and years.
JS: So very exciting that in a subset of patients biomarker driven data here, high MET copy number, you see response. One thing that’s interesting is how do you measure MET amplification? In the plasma it’s not as straightforward as in the tissue – any colour to that story there? Because what we’re using in the clinic often is plasma ctDNA based NGS and we’re oftentimes not biopsying patients if you identify, say, MET amplification in the plasma. But how real is that?
AM: We know that plasma DNA is not perfect; we know that although we can pick it up in very many of these patients, in comparison we do not always get a total concordance with tissue. We’re not really representing the full heterogeneity or the clonal diversity of the tumour. Getting tissue in these patients can be very challenging – as we all know, who treat these patients, getting tissue can be an invasive procedure which carries its risks and it’s not always possible. But your question or your comment about the nuances of assessing MET amplification leads us on nicely to thinking about protein versus copy number. We know that the control of MET is complex with amplification, translational modifications, post-translational modifications and actually looking at protein expression, although it was what we were doing a long time ago, is maybe something we need to look at again as this abstract also demonstrated.
JS: I agree completely. So moving forward and opening up more broadly to where the EGFR space is going to be going over the next 3-5 years, how does a drug like this, amivantamab, maybe in combination with lazertinib, how does this enter the front line setting and what else is going on in the front line setting in the EGFR space? It seems like there are lots of different strategies ongoing at the same time. What’s your bet for who is going to win out?
AM: I don’t know. Amivantamab is an active drug, it produces response rates, it produces durable response rates in multiple subsets of patients. As you say, we’ve got very many trials ongoing. We’ve got combinations of small molecule MET inhibitors in combination with EGFR. We’ve got multiple other drugs which we discussed over ASCO – we’ve seen the HER3 targeting drugs that were also discussed which are really interesting. I’m not picking a winner at this stage. Too early.
JS: Too early. Yes, one interesting strategy is the MARIPOSA study, it’s amivantamab plus lazertinib versus lazertinib versus osimertinib. This is a randomised phase III study ongoing across the world at this time and that will be a very interesting study to see if this combination can move into the front line. But at the same time the front line is rapidly changing; there is a study ongoing of osimertinib plus chemotherapy versus osimertinib alone and that actually might change the landscape. So thinking in the future, does sequencing still matter? Sequencing, NGS sequencing, does that still matter or are we going to use these broad-based approaches? You mentioned that you’re still going to be targeting your patients.
AM: Yes, I think that’s interesting but also to raise a point, it is sequencing of drugs as well. This idea of do you target everything very, very early and try and prevent resistance mechanisms developing or are you saving your drug combos for progression on osimertinib? I don’t know that we really know the answer to that and that’s also really important is are you going to sequence your drugs in line or are you going to try and really, really prioritise these combinations in the front line setting?
JS: I always like to use the best drug first but you’re completely right – as toxicity of these agents change it’s important to have that discussion with your patient about what therapeutic option to use first. Using osimertinib versus a combination of chemo or other agents in the front line setting, that’s a lifestyle and a quality of life issue. So a completely important discussion to have with our patients. Dr Minchom, this has been a phenomenal discussion on the EGFR space and particularly amivantamab and lazertinib and particularly thinking about biomarkers in this setting. I want to thank you and thank the listeners and also thank ecancer for hosting us today. It’s been a real pleasure.
AM: Thank you.