Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to Year in Review, our first Year in Review of 2025, and today we’re going to talk about EGFR-mutant non-small cell lung cancer.

We have a great faculty today, Dr Enriqueta Felip from the Vall d’Hebron Institute of Oncology in Barcelona, Spain, and Dr Helena Yu from the Memorial Sloan Kettering Cancer Center in New York City.

Today, we can never even begin to cover lung cancer or non-small cell lung cancer in an hour, so we’ve got to pick out parts of it. There’s so much going on with EGFR-mutant disease it really clearly justifies talking about it on its own, which is what we’re going to do here today.

As is usually the case, we will be talking about the use of FDA-unapproved agents and regimens, so check out package information for each product for approved indications.

We always have the same format for the Year in Review series. I meet with the faculty individually and record a presentation with them. Both of these are now in the chat room if you want to check it out. And then once we put this together we’ll send out an email to you with both the 2 presentations, as well as this webinar here tonight, so it’s really a 3-part endeavor, as we always do.

So I met with our faculty earlier this week to record these presentations. They went through an interesting — a whole bunch of papers. We’re not going to go through all of this. Really what we’re here to do today is really pick out some of the themes that came out over this past year, but here are some of the papers that Dr Felip covered, and then here from Dr Yu further papers covered. So check out these presentations after the webinar here tonight.

We broke down the topics between the 2 presentations. We’re going to begin talking about really I think one of the most interesting and controversial questions in this field of EGFR-mutant disease, which is first-line treatment of metastatic disease, and we’ll talk a little bit about recurrent disease as well. Then we’ll get into adjuvant/neoadjuvant therapy, particularly trials that have been done with osimertinib. We’ll move out and talk about exon 20 insertions and mutations and the use of tyrosine kinase inhibitors. And of course no solid tumor program is going to be done without talking about antibody-drug conjugates, and that’s a huge story here. We’ll get into that as well.

First-Line Treatment of Metastatic Disease

DR LOVE: But let’s begin talking about first-line treatment of metastatic disease, and here are some of the papers that were discussed in the presentations, particularly by Enriqueta. But I just want to start out, and you know, clearly, Helena, the issue now is now we have combinations, and we have a lot of issues in terms of indirect comparison of data, which is always challenging in oncology in general. Can you talk a little bit? And we’ll show some of the slides that we went through in the presentation, but I really wanted to just get more of a macro view of how you see this topic. And maybe talk a little bit about how you think through you know you’re going to be seeing a patient maybe who’s presenting with metastatic disease, they’re known to be EGFR-mutant, activating mutation, how you think through first-line therapy, and what are some of the variables in the tumor and the patient that guide you in one direction versus another.

DR YU: Sure. I think that up until recently we just had the one option, right, monotherapy osimertinib for all patients. But now I think with these different combination therapies there’s really the need for the shared decision-making, where we go over different options and really understand what patients want to get out of their therapy.

So in terms of a patient I see today in clinic, I want to look at a few things, obviously kind of age and performance status. Would they be someone that would be able to tolerate escalation of therapy? Looking at disease burden. Do they have brain mets? Do they have liver mets, bone mets, or is it intrathoracic disease only? And then I think other risk factors include looking at comutations like TP53 or RB1, whether they have positive circulating tumor DNA. Did you do a liquid biopsy, where you see circulating EGFR ctDNA? And I think the more of those that you have in terms of risk factors the more I’d be inclined to escalate care.

I think we have the first chance — or the first line of therapy is the best chance of making a real difference in terms of outcome and overall survival, and so if people can tolerate it, and they’re willing to do it, for those high-risk patients I would definitely think about combination. And then maybe for an elderly, kind of frail person with more indolent disease I’d feel completely comfortable giving osimertinib monotherapy. And I think some of our questions will be answered when we see the survival data from the 2 combinations, because I think that will lead us one way or the other depending on how great the magnitude of benefit is.

DR LOVE: Enriqueta, can you put forth your approach to this? And one of the issues there is Helena referred to 2 choices in terms of combinations, how you see those 2 choices, ami/lazer versus chemo plus osimertinib, in terms of tolerability?

DR FELIP: No. I think having more possibilities in patients with EGFR mutations in first line is really good news. So it’s through that we had osimertinib alone, and now we have 2 combinations, FLAURA2 and MARIPOSA, showing an improvement in PFS when compared to osimertinib. It’s important. Overall survival was mentioned by Helena. It’s through that we have the second interim overall survival analysis from the 2 trials showing an improvement in overall survival with a hazard ratio of 0.75, not still statistically significant, but there is also the press release from the MARIPOSA telling us that there is an overall survival benefit with combination of ami plus lazer.

When I have a patient in front of me I think it’s really important, their opinion. I think it’s important to discuss of course for the patient the results and also the potential toxicities. I think also for the frail people, for patients with comorbidities, perhaps for the older population, I would agree that osimertinib may be a good treatment, and also for those patients with intrathoracic disease. But probably I would recommend combination for the patients with some high-risk features.

But I had the privilege to present … from the MARIPOSA trial at ASCO, and overall if we include the patients with brain metastases, with p53 comutation, with baseline ctDNA positivity, and with liver metastases altogether, they represent approximately 80-85% of all patients with EGFR mutations at diagnosis, so the majority of patients probably at diagnosis have some high-risk feature. So yeah, I think it could be important to have the overall survival definitive results and also to have multidisciplinary teams to manage the toxicity of the combinations that are clearly higher when compared to monotherapy.

DR LOVE: And here’s a paper that Enriqueta reviewed, Helena. As she was mentioning, this came out of the FLAURA2 trial, and patients who had disease limited to the — I don’t know if there were enough patients to really be definitive about it, but they didn’t seem to benefit by the combination. You mentioned patients with indolent disease. What about number of metastases and this issue that it’s confining to the chest, Helena? How does that affect your approach to this?

DR YU: Yeah. I think it’s a case-by-case basis, but I think of the patients that have intrathoracic disease only, those ones are more likely to have indolent disease, where we’re not seeing distant metastatic disease, and maybe you have a few CT scans to show a pretty slow rate of progression. And then I think, as Enriqueta mentioned, in terms of the highest-risk feature, I think it’s the baseline CNS metastases.

And what I found interesting about the FLAURA2 data and CNS metastases is we know that these high-risk features are prognostic, right, they’re telling us that patients will do less well with treatment. But what I think was interesting is the hazard ratio for baseline CNS metastases with the combination, it was lower, so maybe that also there’s some predictive nature of that, too, where not only are we rescuing people that have less good outcomes, but there really is something kind of unique or additive with the combination therapy for that subgroup. So that would be one area where I really would encourage one of the combination therapies.

DR LOVE: Both of you mentioned the fact that we have a press release out there, an encouraging press release for ami/lazer, saying that there’s a survival benefit that exceeds a year. We’re waiting for the definitive survival from FLAURA2. But right now, today, Helena, how are you — you have a high-risk patient, which, as you said, represents most of these patients. If you’re going to use combination therapy which one do you use? And again, can you give — I’m not sure how much experience people in the community have with ami/lazer at this point. Can you give more of a qualitative feel for what you see with ami/lazer versus osi/chemo?

DR YU: You’re putting us on the spot, Neil. So I think that everyone knows the platinum-based chemotherapy toxicity, right? You get some fatigue. You get nausea. You can get some cytopenias. And so I think that there is a real comfort in combining osimertinib with chemotherapy because we’re familiar with both agents separately. I think with amivantamab and lazertinib it’s a more unique toxicity, and you need to get some experience with it, right? I think the things that I've seen giving these medicines a lot is the cutaneous toxicity, where really it’s the acneiform rash, but a lot of skin fissures and nail issues, which I think when you talk to your patients. A Grade 1 kind of skin fissure seems like nothing, but that’s what prevents them from doing all of their activities of daily living, so really can be dramatic in its effect in quality of life.

And then we know from other MET inhibitors that you can see MET-directed side effects, which are really on target that we can’t really explain why they happen, but it’s hypoalbuminemia and increased edema, so lower extremity edema and an anasarca picture. And so it’s not everyone that gets those toxicities, but if they do, again, there’s a larger impact on quality of life.

One thing is everyone’s going to get all of these treatments, right? Everyone will get osimertinib. Everyone at some point will get chemotherapy. And I do think amivantamab is very active, and at some point people are all going to get amivantamab.

I think generally what I've done to date is giving the chemotherapy and osimertinib and then thinking about amivantamab in second line and beyond. But I do want to see that survival data because if that blows things out of the water in terms of really showing a marked benefit with giving ami/lazer up front I could definitely be convinced to have that be my standard of care escalation therapy.

DR LOVE: Although you were pointing out to me when we recorded your presentation there that it might be a little tricky to interpret the survival data with the MARIPOSA study because I guess they didn’t get it on relapse, whereas the ami/lazer people got chemo on relapse, and osi.

DR YU: Correct, yeah. So I think that with the FLAURA2 everyone that got first-line osimertinib, of course — a large majority of patients will get chemo in the later-line setting. But I think with MARIPOSA with amivantamab not being approved at the time of the study, that people who were on the osimertinib arm did not receive — or very few received later amivantamab. And now with MARIPOSA-2 we know that we can give amivantamab with chemotherapy later, and so I think that is going to be somewhat challenging to go through the 2 different studies and try to do some cross-trial comparison to decide what to use in the first-line setting.

DR LOVE: So what about the issue of patients with leptomeningeal disease? Enriqueta, you reviewed this paper looking at osimertinib in standard and high dose, but that was in patients who’d had prior, I guess, first-generation TKIs or second generation. I don’t know. Do you ever see leptomeningeal disease at presentation as part of first-line therapy? And for practical purposes, how are you managing patients who have leptomeningeal disease, Enriqueta?

DR FELIP: Yeah. Yeah. As you mentioned, this paper published in JCO is including patients first treated with first- and second-generation EGFR/TKIs and then osimertinib at the dose of 80 mg daily. It’s an active agent in this situation, but this is in a scenario that we are not seeing today. So I think patients with leptomeningeal disease probably now I would be in favor of the combination.

It’s true that also in the paper published by Pasi Jänne in JCO from the FLAURA2 trial there is a small cohort of patients with leptomeningeal disease treated with chemotherapy plus osimertinib with very good outcomes. So yes, this is a situation that is not common, leptomeningeal disease at diagnosis, but I think in my clinical practice I would recommend the combination of chemo plus osimertinib probably in this group of patients.

DR LOVE: So Helena, this is another paper Enriqueta reviewed, now looking at ami plus chemo in patients who have progression on osimertinib with more follow-up. But I’m just kind of curious in general what you see in the second-line setting in patients who get ami/lazer up front as opposed to let’s say either osi or osi/chemo in terms of resistance mutations. And nowadays how are you managing patients in the second-line setting? Do you try to get tissue for repeat biopsy? Do you ever use targeted therapy?

DR YU: Yeah. I think it’s a great point, Neil. I think that I do try to get a tumor tissue biopsy if at all feasible when patients progress on first-line osimertinib or combination therapy.

One thing that you don’t want to miss is histologic transformation. So we’ve seen adenocarcinomas transform to squamous cell lung cancers and small cell lung cancers, and it can happen in 15% of cases. And I think we used to think, oh, it’s only patients with fulminant progression, but if you biopsy everyone you end up seeing more of it and in kind of clinical situations which you weren’t suspicious of it.

And I’d say it’s about 15% to 20% of patients that might have something targetable on repeat molecular testing, either liquid biopsy or tumor tissue biopsy. If patients have something like a MET amplification I would try to target that. We have data from our institution that targeting something that is targetable in the second-line setting leads to improved outcomes, and whether that’s giving a MET inhibitor with osimertinib to a person with MET amplification, or whether it’s giving small cell-directed chemotherapy for someone that has small cell transformation, outcomes are better if you can personalize second-line therapy.

DR LOVE: That’s interesting. We actually have a patient in the chat room, which is pretty unusual for us, Laura, who says as a patient I don’t know if I would want 1 year extra survival if I had to go through the ami side effects. So it’s always challenging to explain to a patient what to expect, and I think you both have given some examples of that.

Another thing that’s been very exciting. We’ve seen this in a number of areas, Enriqueta, in oncology, I guess daratumumab in myeloma’s the one that really sticks in my mind in terms of really having an effect on quality of life, which is the use of subQ. And now we are seeing data with subQ amivantamab, and you discussed that. Can you talk a little bit about the difference in tolerability in terms of subQ versus IV. And also I guess there’s some maybe hint that even subQ’s going to be better. Any comments, Enriqueta?

DR FELIP: Yes. As you mentioned, so the study was presented by Natasha Leighl at ASCO and also published in JCO, the randomized trial comparing the subcutaneous versus intravenous combination with lazertinib in patients with EGFR mutations. I think the results are clear that subcutaneous amivantamab is noninferior from a PK point of view, also is less toxic, so there is a reduced rate of infusion-related reaction and VTEs.

And it was, yes, surprising that overall survival was longer for those patients treated with subcutaneous formulation when compared to intravenous. I think there is no clear explanation of what is the reason. Even in the discussion of the paper the authors mentioned that perhaps there is an impact of the subcutaneous administration on lymphatic absorption and also the immune stimulation. But I think we need to further analyze these hypotheses. But yeah, we have seen this overall survival trend favoring the subcutaneous formulation, and I think we need to evaluate further.

DR LOVE: So a question also in the chat room about the fact that “the subQ formulation is being delayed.” And you can see in the lower right-hand corner something I hadn’t heard about, a complete response letter related to the FDA. Also we saw the same thing with patritumab, I think, Helena. Can you kind of explain like what this is, this complete response letter, and the issue about manufacturing?

DR YU: So I think this is maybe something new or at least newly kind of in the spotlight. But when the FDA considers approval of a new novel agent they’re looking at efficacy and safety, so the package — the drug package that the pharmaceutical company submits to the FDA, but one thing that they have tied to approvals now is assessment of third-party manufacturing of the drug. So whoever is going to be manufacturing the drug, they do an inspection of that facility, and if there is an issue there that stops the approval of the drug.

And so exactly like Neil said, both patritumab deruxtecan, the HER3 ADC, and subcutaneous amivantamab both got complete response letters. The press releases said no issues. The FDA did not have issues with efficacy or safety of the drug, but both response letters were due to an inspection of the third-party manufacturing facility. And so this is just a kind of really unfortunate way that drug approvals get delayed because we don’t know. This can take anywhere from a few months to years in certain situations where drugs get delayed.

DR LOVE: Yeah. I think we saw that with a drug used in gastric cancer, zolbetuximab, a claudin 18.2 drug, but that seemed to get resolved pretty quickly, and it ended up getting approved.

Enriqueta, a question in the chat room from Mayer. “In a patient with EGFR-mutant disease who transforms to small cell or squamous cell, does that respond well or better to IOs?” And I’d add on to that, does it respond in general to small cell therapy? And also, I know you’ve done a lot of work on tarlatamab, the bispecific, Enriqueta, does it respond to that?

DR FELIP: I think for those patients, my experience with small cell lung cancer transformation, I have treated some patients with chemo plus immunotherapy without major good responses, so I think it’s not clear the response of immunotherapy in patients with small cell lung cancer transformation in general.

In my opinion, tarlatamab is really a promising agent. In fact, it’s so promising you have the FDA has the approval in patients with second line based on the randomized trial in second line comparing 2 doses. And I think it would be interesting to analyze these agents in patients with EGFR mutation and a small cell lung cancer transformation, although I don’t have any experience on that. So I think, yes, it’s a line of investigation. I don’t know exactly also the DLL3 expression in these patients with EGFR mutation and a small cell lung cancer transformation, but it could be interesting to analyze in this group of patients, yes.

DR LOVE: So we’ve been talking about CD3 bispecifics in lymphoma and myeloma for a couple years now, and I've been wondering when it was going to come to solid tumors. It looks like you’re going to be the group that deals with it first, but hopefully other people have that opportunity in the future.

Adjuvant and Neoadjuvant Therapy

DR LOVE: So let’s talk now a little bit more in terms of adjuvant and neoadjuvant therapy. Of course we saw the ADAURA study that really changed adjuvant therapy for these patients. We saw some follow-up data looking at ADAURA, a topic a lot of people have interest about, which is cell-free DNA measurements. But also, Helena, you talked about the issue of neoadjuvant osimertinib and the fact that at least in the initial trial that you discussed here the results maybe weren’t as exciting as we’d like. Maybe you can talk about that, and then how it’s being looked at in a Phase III setting.

DR YU: Sure. So this was surprising. This was presented at ASCO last year, where the study looked at 4 to 8 weeks of osimertinib monotherapy as neoadjuvant therapy and then patients went on to surgical resection. And the primary endpoint of this study, similar to the other neoadjuvant studies that have gone on in the last couple years, was major pathologic response, MPR rate, and that was low at 15%. As reference, we’ve seen 30% to 40% MPRs with the chemo/IO neoadjuvant studies, so this was really surprising.

I think one of the questions is was that too short of a trial with osimertinib. Is the cytoreduction kind of capabilities of chemotherapy necessary? And it really kind of is in contrast to the really marked benefits of adjuvant osimertinib. We know that after surgery 3 years of osimertinib improves DFS and OS quite significantly, so this was not expected. But the NeoADAURA study probably will definitively answer whether there’s any role for osimertinib prior to surgery because it’s looking at chemo alone, chemo plus osimertinib or osimertinib monotherapy in a randomized very large multicenter way. So we should see data from this study soon.

DR LOVE: Yeah. That’ll be interesting to see, and also because they can get it adjuvantly, as well.

I mentioned the fact we’re always interested in cell-free DNA and MRD, Enriqueta, and I guess initially this was at ASCO last year, we saw data from ADAURA looking at MRD. I’m curious whether you think we’re moving into a situation where we’re going to be looking at MRD in the adjuvant setting, and if so, how.

DR FELIP: Yeah. I think this is an important topic. We have seen this presentation at ASCO, but the reality is that I think this presentation probably will not change our standard of care, this adjuvant osimertinib for the patients with completely resected tumors. This trial show us that for those patients in the placebo arm there were low disease-free survival and also more patients with ctDNA during the follow-up. But yeah, I think we need more sensitive technology in order to — not to give adjuvant osimertinib in certain patients with completely resected tumors. So interesting trial, but I think it’s not changing our standard of care, this treating patients with adjuvant osimertinib after complete resection.

DR LOVE: Helena, any thoughts? Do you think there’s a possibility this might be considered in the future in terms of how long to give adjuvant therapy? And also, any other situations in the disease, even with the more advanced, recurrent disease, where you think it’s helpful, or maybe you see — a lot of times in other tumors, of course colon, MRD they use all the time in the adjuvant setting. We talk about it in other tumors, like breast, and people go well, we don’t have enough data, but yet people end up ordering the test, and then you have the results, and you don’t know what to do with it. Maybe oligometastatic disease. Again, what do you see in the future in any situation right now, Helena, where you think it’s helpful, even in the metastatic setting?

DR YU: Yeah. I think that it’s a tough situation because access to these assays have kind of come before the studies looking at these assays, and so I do know a lot of providers are using them. But again, we don’t have any kind of trial data to guide us. A lot of the adjuvant studies that are ongoing now are utilizing MRD. And Neil, it’s exactly as you said, it’s kind of figuring out the duration. So maybe people get adjuvant therapy, all patients get it for a set period of time, and then after a year or 2 years you’re checking for evidence of MRD and then maybe deciding whether to randomize people to observation or continued therapy.

The other place that I see liquid biopsies being used is looking at ctDNA clearance for patients with metastatic disease. And so we know that say for osimertinib monotherapy, when patients start that, and you check their ctDNA 3 to 6 weeks into treatment, 75% of people will clear their ctDNA, but 25% will have persistent positive detectable ctDNA. And we know that that is clearly associated with shorter progression-free survival on osimertinib, so a median of 10 months on osimertinib, and also shorter survival. And so I do see a lot of studies using that as not a primary endpoint but kind of an early efficacy endpoint to see whether the drug is kind of good enough to clear the ctDNA.

DR LOVE: Enriqueta, any thoughts about where we’re going to land in a few years in terms of duration of adjuvant osimertinib? And any situations in when you get to 3 years, if a patient’s really tolerating it, no problem, and you could access the drug, any situations where you’d go beyond 3 years in the adjuvant setting? Maybe you have cell-free DNA that’s positive.

DR FELIP: Again, this is an important topic, but probably the situation may be different in The States or perhaps in Europe, no, because in vast majority of cases we need to do what the clinical trials have shown. So in this case, the ADAURA is only 3 years, and I think this could be the standard of care, at least in patients in Europe.

Probably we may have the feeling that perhaps we need to escalate for those patients with certain characteristics, perhaps those patients with concomitant p53 mutations in the tumor tissue, or you mentioned patients without clearance, but this would not be based on randomized trials, so I don’t know. I think in Europe probably we would be more conservative, and in the adjuvant setting we would keep the 3-year treatment duration in patients with EGFR mutations.

DR LOVE: So the same question to you, Helena, but also your thoughts about the LAURA study that you discussed in your presentation. I thought it was interesting there that the hazard rate was so impressive, I think it was 0.19, and there they gave indefinite therapy. I don’t know if that’s tied into that. But again, any thoughts about whether or not you’d ever, if you could, you would extend adjuvant therapy? And any thoughts about the LAURA study in terms of clinical implications?

DR YU: It’s kind of like extrapolating from GIST tumors, right? I think they did 3 years, 4 years, 5 years, and kind of the longer the better.

I thought this was an interesting study, where of course they required or decided to treat patients with osimertinib until progression. I think that, obviously, the hazard ratio was striking and markedly positive. I think part of the issue was that this was a very high-risk population. We already know that Stage III locally advanced cancers that are unresectable have more than a 60% chance of recurrence, but this population, which was global. Only half of the patients got PET scans for staging prior to moving forward with therapy, and when they looked 10% of them had baseline brain metastases. And so they were treating patients with metastatic disease with osimertinib, so we know that works, versus placebo.

So I think it establishes absolutely that for both all locally advanced cancers treated with radiation or surgery that we should be using adjuvant osimertinib. And I do think having more access in the US, I've had a couple patients now that have surgically resected Stage III disease, they’ve hit that 3-year mark, and like you can’t pry the osimertinib out of their hands. They want to keep that going, and I think with informed consent, and if it’s accessible and not financially burdensome for patients, for a Stage III really high-risk patient I think it’s reasonable to continue. I still do 3 years routinely, but I've had some case-by-case discussions and done it for longer.

DR LOVE: Any thoughts about that IIIA situation, Enriqueta? And also, I know we’re talking about EGFR, but just kind of curious what other mutant disease will you go to targeted therapy rather than durvalumab, for example with ALK?

DR FELIP: Yeah. Yes. I think the LAURA trial is clearly positive, as mentioned, so the PFS, the hazard ratio is impressive at 0.16, powering consolidation of osimertinib after chemoradiation. It’s true that in the control arm the median PFS is really poor, so it’s showing us that probably the majority of cases had metastatic disease. And yeah, I think in this case the treatment is until disease progression, so probably this could be the approval in Europe, and we can give probably this strategy to the patients.

I have to say that I would prefer a shorter treatment because to give treatment until disease progression is probably a lot of time, and we know that you’ll have some patients with Stage III that we can cure with chemo and radiotherapy alone, and also we have seen that the ADAURA trial improved overall survival with adjuvant osimertinib, no? But this is the design of the trial. I think it’s clearly a positive trial, and I think this is practice-changing also in Europe, no?

But you have done an important reflection. So this is EGFR, but what about ALK or ROS1 or RET? We will not have the results of randomized trials in this scenario, and I think we need to work in a consensus, I don’t know, consensus probably among the experts, because I think the results would be probably the same in patients with ALK, with ROS or with RET. And this is the same in this situation, the consolidation, but also in the adjuvant setting.

EGFR Exon 20 Insertion Mutations

DR LOVE: So I want to move on now and talk about patients with exon 20 insertion mutations and particularly a new TKI, zipalertinib, that we saw a couple interesting papers on. But before we get into that, Helena, can you kind of paint a little bit of a picture of where we are today with exon 20 in terms of particularly first-line therapy and where we’ve been in terms of TKIs in the past?

DR YU: Yeah. We’re not as far along with EGFR exon 20 treatments, although further than we were — once were. And so amivantamab is a bispecific EGFR/MET antibody that has 2 approvals. It has approvals with chemotherapy as first-line treatment or for status post who've received chemotherapy first line, you can use it in the second-line and beyond setting. We previously had mobocertinib, which was an EGFR exon 20-specific TKI that had accelerated approval, but whose confirmatory study was negative when they tried to compare mobocertinib first line to chemotherapy first line. And so that approval was pulled. And so this is an unmet need where we don’t have an oral therapy for first-line treatment for EGFR exon 20.

And so there are a few investigational EGFR exon 20 oral drugs, 1 such drug being zipalertinib, but there’s also sunvozertinib, to name a few. But 1 key question that I think was answered by this abstract presented at ESMO last year is can you sequence the TKIs with the antibodies. And so we know that for TKI to TKI, if you’re trying to sequence, you tend to see cross resistance, but this study looked at whether patients — if patients got prior amivantamab could they respond to zipalertinib. And if you can see the arm there that says amivantamab alone the response rate was 50%, with subsequent zipalertinib. So it was really promising and encouraging to know that we can sequence these drugs, and there isn’t kind of overwhelming cross resistance. And so I think one of the keys is going to be which of these should we give first and kind of the ability to sequence. But I do see this as encouraging, and hopefully some of these oral exon 20 drugs will be approved soon.

DR LOVE: So Enriqueta, I’m always trying to figure out biology. I can never understand most of the diagrams that people put up about that. But when you think about exon 20 and also the uncommon “nonactivating” EGFR mutations, how do you explain to your fellows or your medical students biologically why you see such great responses to drugs like osimertinib and amivantamab, and you don’t see that level of response, particularly with the TKIs with exon 20 and these unusual mutations?

DR FELIP: Yeah. Yeah. I think first to determine the EGFR exon 20 insertion mutation there is a need to perform NGS in the patients because the PCR based is detecting only half of the mutations, and this is also a challenge sometimes in some countries in Europe. So I think this is important to detect the EGFR exon 20 insertion in patients with lung cancer. These represent, in our experience, approximately 12% of all the patients with EGFR mutations, and yeah, we have learned that these patients are really not responding to first- or second-generation EGFR/TKIs.

And also, as Helena mentioned, first we tried to give some TKIs such as mobocertinib, and now we have this situation of the combination of chemo plus amivantamab and also the new EGFR exon 20 insertion inhibitors. I think we had the debate when the mobocertinib was compared directly to chemotherapy if this was the best strategy or it was the best strategy, the PAPILLON trial, not to give chemo plus amivantamab versus amivantamab. And I think probably this alteration is less sensitive, and I think chemotherapy is also important in the combination in the PAPILLON trial, and for this reason this study is positive.

But also we have seen these interesting results with these new generation TKIs, but I think the sequence, I don’t know what would be the best sequence because we have also first-line trials comparing these new generation TKIs versus first-line chemotherapy, no? And if positive, we will discuss again, and we need to do cross-trial comparison. So yeah, I think it’s a small group of patients with a lot of investigation, and I think this is really important.

DR LOVE: What about tolerability, Helena? For example, I don’t remember that mobocertinib had that much toxicity, but not all EGFR/TKIs are as well tolerated as osimertinib is, earlier generations, afanitib, et cetera. What about zipalertinib? How does that fit in in terms of tolerability?

DR YU: Yeah. I think that the challenge with exon 20 is to get enough drug inhibition coverage you need to have pretty high doses, and at the high doses you’re inhibiting EGFR wild type and leading to some of that wild-type tox. And so mobocertinib was really limited, actually, but GI tox and fatigue. That limited kind of going up to higher doses where maybe you would see more efficacy.

I think, I would call them the second-generation EGFR exon 20 drugs, like zipalertinib, they have designed the drugs to be more mutant specific. So you do see some rash, some diarrhea, but I would put these, having treated a lot of people with zipalertinib, kind of similar to osimertinib, where really toxicity has not been limiting in terms of getting these drugs to patients and keeping them on.

DR LOVE: So anything you want to say about these REZILIENT trials, Helena. I always love interesting trial names, and I love the name REZILIENT. But what about REZILIENT-2, zipalertinib in the CNS first line after — and also other uncommon mutations. And then I think we alluded to it before, the Phase III study that I guess is another approach to first-line therapy. I don’t know if they call it zip or not, or zipa, but zipalertinib plus chemo, Helena.

DR YU: Yeah. I think that there is, just like with osimertinib, obviously, there would be a desire to try to do a single-agent oral therapy, if possible, for exon 20. But as Enriqueta said, I think there’s a concern that they’re just less responsive to treatment, and maybe this generation of TKIs are not good. We’re not getting response rates of 80% like we do with osimertinib. And so I’m interested in obviously the chemotherapy/osimertinib, chemotherapy/zipalertinib combinations up front because I do think that that might be more — better tolerated than amivantamab/chemotherapy.

And then I think another unmet need are those uncommon mutations that you mentioned, Neil, like the exon 18 mutations like G709 or G719 or S768I. We don’t know what to do with them. I mean, the label — afatinib has a label indication, but we don’t love that medication. It has a lot of toxicity. A lot of us off label use osimertinib. But I think some of these exon 20 drugs or fourth-generation EGFR/TKIs in development, they are looking at this uncommon mutation subgroup to see if we can find a medicine that is designed specifically for those mutations that are more effective than what we’ve seen so far.

Antibody-Drug Conjugates

DR LOVE: So I want to move on, and we’re going to finish out talking about antibody-drug conjugates. And before we get into the specific papers on ADCs and some of them being looked at, I want to just get your thoughts. This is sort of an old story, and we had a couple of papers that we talked about looking at the issue of IOs in the second line in patients progressing on osimertinib. And as we know, really both nivolumab and pembrolizumab, Enriqueta, really haven’t worked out.

I’m just kind of curious. I’ll tell you why I brought this up in a second, but I’m just kind of curious, are there situations, Enriqueta, where you would like to use, or you are using an IO in patients with EGFR-mutant disease? Maybe, I don’t know, do you ever have a smoker? Anything that would get you — high PD-1 level? Anything? Not necessarily first or second line but ever?

DR FELIP: Yeah. I think these 2 trials, the KEYNOTE-789 and the CheckMate 722, are clearly negative, so in the second line after osimertinib resistance the combination of chemo plus nivo or chemo plus pembrolizumab do not improve the PFS and overall survival when compared to chemotherapy alone, so there is no indication.

But it’s true that there is new agents in this scenario, and we saw the results of the trial with ivonescimab in patients with EGFR mutations. This trial was presented at ASCO last year, and patients are osimertinib resistant were randomized to receive chemotherapy or chemotherapy plus ivonescimab, an anti-PD-1 and anti-VEGF antibody, and the trial was positive for PFS and also a trend for overall survival. And I think there is another compound from BioNTech, I think, that is also being analyzed in this scenario, no, and is also an anti-VEGF and anti-PD-1 in combination with chemotherapy in patients with EGFR mutations after osimertinib progression also with encouraging results. So I think there is — the analysis of these combinations with these bispecific antibodies are warranted in patients with EGFR mutations after osimertinib resistance.

DR LOVE: So Helena, of course no program on lung cancer’s complete unless we mention ivonescimab, the bispecific that hits both PD-1 and VEGF that was reported, I guess, in EGFR, as you mentioned, at ASCO and then at World Lung. In general it looked positive, and I guess it hasn’t really been tested outside of Asia. Are we seeing trials now that are becoming available with this fascinating agent? And we’ve already had hints that maybe recurrent EGFR might be sensitive to bev or other antiangiogenic strategies. Any thought about whether ivonescimab is going to be more effective?

DR YU: Yeah. I mean, I think that there was a lot of excitement after World Lung because chemotherapy/pembrolizumab or pembrolizumab alone has been king and kind of standard of care for quite some time now. So I think the data really looked provocative. The confirmatory global studies that might lead to global approvals are ongoing, both in squamous cell and non-small cell adenocarcinoma, so we’ll see that.

And I think we — knowing how beneficial immunotherapy is to other subgroups of lung cancer there’s a real interest to figure out how to make some of these drive mutation-positive lung cancers respond to immunotherapy. So I think we’ll have to see with this ivonescimab, but I think there’s also interest in cellular therapies, T-cell therapies, figuring out is there any way for us to kind of make these EGFR-mutant lung cancers that are immune cold responsive to immunotherapy. So hopefully more to come there.

DR LOVE: So one of the reasons I brought that up is a prelude to talking about these ADCs. We’re going to talk about datopotamab deruxtecan, patritumab deruxtecan, and I call it sac-TMT because I can’t pronounce it too well, but all being looked at in EGFR-mutant disease and others being looked at in this scenario. And one of the things I was reflecting on, before we get into these specific papers, and I asked you, Helena, about this, is the larger study on dato-deruxtecan that showed a benefit, but it was mainly in adenocarcinoma. And now I see all these trials with ADCs, including dato, in the not just EGFR-mutant but other mutant, RET, ALK, et cetera, and kind of — the fact that you have part of lung cancer that seems different, to me, and I’m a simple person, doesn’t respond to IOs, the other part does, and I wonder, like this centralization movement towards ADCs in the targetable mutation, is that a reflection of — and what they saw with benefit greater in adenocarcinoma, do you think that’s because adenocarcinoma’s inherently different, Helena, or because you have a whole bunch of activating mutations and nonsmokers in there?

DR YU: Yeah. I do think that a lot of us think that the adenocarcinoma benefit with datopotamab in the larger TROPION-Lung studies was probably from this AGA, we call it AGA, or actionable gene or genomic alteration-positive subgroup. And I do think it’s very interesting, where these ADCs are being tried broadly, we’re looking for biomarkers.

The kind of lowest hanging fruit is protein expression of the antibodies’ target, like TROP2 or HER3, and we’re hitting negative there, right, where those don’t seem to be a great biomarker. And so now we’re looking at AGA, right? Like we know that there’s an enrichment of activity in these AGAs, and so that seems to be kind of the biomarker strategy of a lot of these drug companies, to focus EGFR or ALK, RET, the other AGAs, as a place where they can get a higher efficacy and maybe an approval.

DR LOVE: And Enriqueta, I curious about your thoughts in terms of ADCs, and for example dato, in patients with targetable mutations outside of EGFR. When we talked you brought it up in terms of RET, ALK, et cetera. And do you view all these AGA cases similarly, or do you look at like BRAF and KRAS, where you see a lot of smokers differently?

DR FELIP: Yeah. What we have seen in the randomized trial in the TROPION-Lung01 is that for those patients with actionable genomic alterations in general the hazard ratio favoring dato-DXd was very good, was 0.38, when compared to docetaxel. So in my experience I have treated a number of patients with dato-DXd, not only with EGFR but also with ALK, with RET, and I have a very good feeling of this treatment in patients with actionable genomic alterations, not only EGFR, but also other alterations.

I think it would be important also in the future to analyze the use of these agents in patients for KRAS G12C that is mainly seen in smokers. I think at this moment currently we have not a lot of data of the activity of ADCs in patients with KRAS G12C. But when we think in the biomarkers for ADCs we have the approval of trastuzumab deruxtecan also in patients with HER2 mutations, so an alteration that is also a mutation. We have the results of dato-DXd in patients with actionable genomic alterations, and we have also patritumab deruxtecan that is active in patients with EGFR mutations.

So it seems that these agents are really active in those patients with actionable genomic alterations in general, not only patritumab deruxtecan, but also dato-DXd and probably trastuzumab deruxtecan that is active in patients with HER2 mutations, but we have seen also some results in patients previously treated with EGFR/TKIs, no? So yeah, we need to learn more, but at this stage I think the agents in general are really active in patients with actionable genomic alterations.

DR LOVE: So Helena, anything you want to say about the TROPION-Lung05 study that we’ve just been alluding to in terms of again, not just — if you look in the upper right-hand corner you can see, even though EGFR was the most common, you see other actionable mutations that were seen in this study. Anything you want to say about what was seen efficacy-wise? Also the CNS benefit?

DR YU: Yeah. That would be what I’d want to mention. I think before we looked at ADCs in lung cancer there was a thought that these are big, bulky molecules, that they wouldn’t cross the blood-brain barrier, and we’d see systemic responses, but we might see the CNS being a sanctuary site without responses. But I think with the data from datopotamab, patritumab we are seeing kind of clear CNS efficacy. I think that really matches the systemic efficacy. So I think we can feel confident, especially in these AGA-positive lung cancers that have a very high incidence of brain metastases, that these agents can affect and treat disease both systemically and in the CNS, which is, I think, reassuring.

DR LOVE: So Enriqueta, it seems like this progression on osimertinib space is getting more and more crowded and likely to be extremely crowded, maybe, over the next year with these ADCs, and we’re going to have to do indirect comparisons, and also indirect comparisons in terms of tolerability. I’m curious what your thoughts are in terms of dato. We bring this up in breast cancer, too, where dato has some interesting data, but there we’re seeing some reports of mucositis, which is something we didn’t see with T-DXd in the same payload, ocular effects, as well as the potential, it seems like it’s lower, but of ILD. What’s your take in terms of tolerability with dato? What are the clinical issues you have to deal with, and how can you prevent and manage them?

DR FELIP: Yeah. Yeah. It’s true that with dato-DXd, for example, yeah, we have seen more toxicity probably than expected, and also now we are working to manage mucositis, as you mentioned, ocular toxicity and also nausea for the patients. But yeah, I think, as you mentioned, this is really a scenario that we have a lot of possibilities after osimertinib now. We have discussed previously the possibility to give targeted treatment for those patients with ALK or BRAF V600 or RET as a mechanism of acquired resistance. We have the ADCs, and we have dato-DXd but also patritumab deruxtecan that we have a press release that is positive. We have the MARIPOSA-2 trial with chemo plus amivantamab. So there is a lot of options in this scenario. And again, the opinion and the involvement of the patient in the decision is key.

DR LOVE: I want to hear a little bit about your thoughts about patritumab, but just to finish out on dato, Helena, what about some of these trials? We mentioned down here in the lower left-hand corner a couple of really interesting studies that are being done.

DR YU: Yeah. I think one thing that when you asked Enriqueta about tolerability, I think one question is can these be combined with TKIs, right? I think both datopotamab and patritumab are being looked at with osimertinib, which I think might allow these drugs to move to the first-line setting or might lead to added efficacy, and so I think toxicity profile, if they’re overlapping, like mucositis, I think that that’s going to be something to watch out for.

And really all of these ADCs are looking at moving up, right? So I think can they be combined with osimertinib in the first-line setting, which is that first study, TROPION-Lung14, and then if not there, after osimertinib progression, can they be used before platinum-based chemotherapy? And this is a very similar strategy to what we’re seeing with patritumab deruxtecan, too. So I think understanding toxicity and efficacy and how to distinguish between these ADCs, which hopefully will all be options, is going to be kind of the next step in trying to manage treatment for these patients.

DR LOVE: We talked about the efficacy that’s been seen with patritumab, again, in this recurrent EGFR setting. I’ll just add, too, I just noticed in the chat room, I mentioned Laura, the patient who’s in the chat room, and she just put in a little interesting thing, that she’s been on osimertinib for 8 years. I thought that was kind of interesting.

DR YU: Amazing.

DR LOVE: She’s concerned about progression, concerned about what’s next, but 8 years is pretty encouraging.

Enriqueta, any comments about patritumab in terms of, again, indirect comparison to some of the other ADCs, including dato, and also tolerability? How much of an issue with both dato and patritumab is ILD? Do you have to screen aggressively?

DR FELIP: No. I think the results of patritumab are also really interesting. Probably the toxicity profile is slightly different. The percentage of patients with ILD is not easy to compare to different trials, but ILD probably is slightly lower when compared to Dato-DXd. And yeah, I think we have this press release that we have a positive trial after osimertinib, and it would be important to see the results. So yeah, I think we have to say also that it’s active in the presence of brain metastases, and again, this is important. And I think the activity is irrespective of the molecular mechanisms of acquired resistance.

I don’t know which is better, patritumab deruxtecan or dato-DXd in this scenario. This is the reality. But yeah, as you mentioned, toxicity, discussion of the different toxicities may be important. And also we need to see the results of the randomized trial, the registrational Phase III trial, the pivotal trial that we know from the press release that is positive.

DR LOVE: So a final comment on this other antibody-drug conjugate, sac-TMT. Also, I stand corrected. Actually, Laura was on erlotinib for 4 years and now — and then osi for 4 years. So wow, what a case.

Anyhow, what about so-called sac-TMT, or maybe you can take a shot, Helena, at pronouncing tirumotecan. I don’t know. I just can’t do it. What is it, and where is it heading? I know — yeah.

DR YU: Yeah. So sacituzumab tirumotecan is another TROP2 ADC. It similarly has, I think, a TOPO1 chemotherapy payload and shows efficacy, again, in this AGA population, and they are also focused on EGFR-mutant lung cancer. I think they got breakthrough designation for looking at this in EGFR-mutant lung cancer.

And so maybe to end I would say that we’re going to need to learn about mechanisms of resistance to these ADCs, because can we sequence them? I think that’s going to be just like we talked about antibodies and TKIs. It’ll be really interesting to see whether someone that gets patritumab can later get datopotamab, and so we need to understand resistance and cross resistance.

DR LOVE: So I want to thank the faculty for working with us today and also recording their presentations earlier this week; thank the audience for attending as well. Be safe, stay well, and have a great night. Thanks so much, Enriqueta. Thanks, Helena. Have a good one.

DR FELIP: Thank you.