WCLC 2026 Highlights: Evolving Strategies in Early-Stage EGFR+ NSCLC

In this expert panel, faculty examine emerging World Conference on Lung Cancer 2026 data in epidermal growth factor receptor-positive non-small cell lung cancer across early-stage disease. The discussion explores the clinical implications of new evidence for treatment selection while considering study limitations and unanswered questions that may shape future clinical practice.

To hear the late-stage disease panel discussion, click here.

Transcript

Sarah Goldberg, MD—Moderator:  The way this is going to work is we have some slides, but we're going to have a lot of time for a panel discussion where I have some questions that I'm going to ask the panel and then we'll have some time for Q&A. So think of your questions as well. I'm going to give an overview of where things are in the EGFR space, and then the rest of my colleagues here will go through some of the more recent World Lung Data. 

So this is starting to think about early-stage resectable lung cancer. We have really seen a shift in how we take care of these patients in the last couple of years. This is really, again, this session is focusing on EGFR, but when we think about patients in general with lung cancer, we often don't know at first, of course, if they have an EGFR mutation. So part of the workup now is not just imaging and biopsy, it's also mutation testing for these patients. 

When we think about what is next after we do their initial workup, we're always thinking about should these patients go to upfront surgery or should they get neoadjuvant therapy? For patients with EGFR mutations, we have to think about if we should include an EGFR inhibitor in that strategy, and you're going to hear a lot more about that in a couple of minutes. And then after they get surgery, we have to then think about should they get adjuvant therapy? That used to just be chemotherapy. Now we have to consider immune therapy and EGFR inhibitors for these patients as well. 

What about for later-stage EGFR mutant lung cancer? So on the top is showing you how you could think about these patients who have locally advanced unresectable disease. So you might put this into the category of later stage, but still a potentially curable situation. So for these patients who have unresectable disease, they typically get concurrent definitive chemoradiation. And then when they have an EGFR mutation, we're giving them osimertinib until progression. That's data based on the LAURA trial and then watching them with surveillance. 

For patients with metastatic disease or those who have locally advanced disease who can't be treated definitively, that's really when we're looking at the specific EGFR mutation. We are for all of the stages, but especially in the metastatic setting, we have to look very carefully at what the mutation present is. We heard a great talk by Helena Yu just a little while ago about this. Does the patient have a tumor with a common mutation, one of these uncommon mutations or an exon 20 insertion? The strategies really differ and we're getting more and more data for all of these scenarios even over the last couple of months. 

So for the common mutations, that's where we have several options, single agent osimertinib or combination strategies, the FLAURA2 regimen or MARIPOSA. For the uncommon EGFR mutations, this is a huge basket of different mutations that have different sensitivities. So whenever I see one of these uncommon mutations, I'm really looking, is afatinib the best drug? Is osimertinib the best drug or should we be thinking about a more creative strategy? We've seen some data for amivantamab and lazertinib. And so that's also now something to think about for patients. And then Exon 20. 

So standard right now, chemo plus amivantamab, but really exciting drugs that are emerging. Here it says TKI insensitive, but actually it depends on what TKI. So there are some TKIs that are being developed that really do look promising and now actually are approved. And then what happens at progression? This is really where things get complicated. There's a lot of options and a lot of it depends on what you do first line. 

So for oligo progression, we always think about local therapy so that we can get more mileage out of that first line strategy. But for people who have multi-site progression, that's when we're thinking about a platinum-based regimen. So either platinum-based chemo with continuing osimertinib, platinum-based chemo plus amivantamab, or an antibody drug conjugate, Dato-DXd. I'm personally always thinking about a clinical trial too. There's a lot of really exciting ADCs that are being developed and are sometimes really great options for patients. 

On the bottom right, you can see the box where it says a lot of immune therapies. We could talk about that in the panel. Immune therapy is a really challenging concept for patients with EGFR mutations. I think a lot of us tend to not use them or push them to much later lines. That could be changing though with some of the emerging drugs, specifically ivonescimab. And then we're also looking at tumor expression of HER2 and MET to think if we can use those antibody-drug conjugates. 

So, it is a complicated space. I just basically summarized what Helena just talked about for 45 minutes. So there's a lot, and this is really just to set the stage for some of the newer and really exciting data that has just emerged in the last few weeks. So Jamie, I'm inviting you up here to talk about early-stage and locally advanced EGFR mutant lung cancer. Thanks. 

Dr Chaft, MD: Okay. Thank you. All right. Hi everyone again. We're going to talk about the updated data from World Lung. All right. I thought we're starting with a different one, but we'll start with this one. I will also highlight a presentation that is not in the slide set, but this was some data on neoadjuvant chemo-immunotherapy versus EGFR TKI in EGFR-mutated non-small cell lung cancer. Retrospective data only out of China, lots of limitations, and I'm not advocating for new adjuvant chemo-immunotherapy [chemo-IO] approach in this patient population, at least not currently. But what was interesting about this data set was they did, TP53 and EGFR, that's the hot topic of the last year and a half. And they did an analysis where they found that the pathologic response rate was much lower with an EGFR TKI approach in patients with the concurrent TP53. They looked at MPR [major pathological response] with chemo IO and saw a very high response rate in the co-occurring alterations, although there has been a bit of skepticism about these type of pathologic response analyses, specifically in China. High volume centers, unclear if robust analyses are being done in the path lab for these non-prospective studies. 

So, intriguing data, not practice changing. There was a study looking at biomarker-driven neoadjuvant therapy. It was an umbrella study. And basically I think the punchline here, and we've done this in the US with NAUTIKA, but you can do it. If you look hard to find oncogene-driver alterations before neoadjuvant therapy, it is possible. There are lots of things that are important here to be studied prospectively, but the first grant I ever wrote and what discouraged me from writing grants for the rest of my career is they said that doing this was not feasible and we've now done it and they've done it. 

All right. Okay. This is the big data out of World Lung and this is the 8-year update of the ADAURA data. Did we need more data? We were already using ADAURA. So what they did was we consent patients to get an 8-year update. Why 8 years? Because 8 years is 5 years after completing therapy. And we always used to think if you haven't relapsed, if you're still well at 5 years, hopefully you're cured. We don't yet know that in this population, but the data is overall extremely reassuring. 

So what we see in this landmark update at 8 years is a persistent and very impressive separation of the survival curves for 3 years of adjuvant osimertinib after upfront resection and planned adjuvant chemotherapy versus placebo. The hazard ratio is 0.5, a very impressive improvement in overall survival, the absolute value more than 10%. So really amazing data. 

So real-world data and outcomes of adjuvant osimertinib in EGFR-altered non-small cell lung cancer. So the take home message from this project, and I had to look this author up because I wasn't familiar with them, this is out of Singapore. So what they really saw was very poor compliance to postoperative osimertinib. I think this is quite different if we were to redo this analysis in the US now, but even analyses done here previously have shown that compliance is a major problem. Not only that for patients with compliance issues, they relapse more commonly. I'm sorry, that's a different one. This one showed improvement in outcomes, but compliance issues. 

This was a project by Christian Rolfo looking at detection rates of EGFR alterations by a paired liquid and tumor biopsy approach, showing excellent concordance and amplification of detection rate by a paired approach. But the bottom line as we have seen many times is that if the liquid biopsy in the early-stage is negative, you need to follow it up with tumor testing because you're very unlikely to have a sensitive enough assay to pick up this actionable biomarker with a liquid biopsy in early-stage disease. 

So before the panel discussion, I want to bring up one more poster, which I didn't have access to until this morning that should have been included here. This was by one of our fellows who was here yesterday. I don't think I see him here right now, from University of Pennsylvania who presented a retrospective analysis looking at the added value of chemotherapy to adjuvant osimertinib. They did a very large study and looked at patients who got chemo followed by OSI versus osimertinib alone and saw an improvement both in disease-free survival and overall survival with the sequential chemo OSI versus OSI-only approach. That in no way takes away from the tremendous benefit of adjuvant osimertinib, but it provides some merit to continued prescription of stage appropriate adjuvant chemotherapy. All right, hopefully I covered that all accurately. 

Dr Goldberg: Okay, fantastic. So again, this was meant to be a quick overview of some recent data and now some time for discussion. So Jamie, I'm going to ask you first, you showed the updated data for ADAURA, which looked really impressive, as you mentioned. You didn't talk about neoadjuvant osimertinib, which I think is important to talk about in these patients because often we are finding out that they have an EGFR mutation before they go for surgery. We should be. 

So when you see a patient with EGFR mutation who's a surgical candidate and is heading to the OR, are you like, "Wait, we have to give you neoadjuvant," or, "Oh, we'll pick that up later." So how do you think about it, early-stage EGFR mutant lung cancer patients selecting neoadjuvant versus upfront OR and then adjuvant, and then any other factors, do you factor other things in like TP53 mutations? 

Dr Chaft: I have not factored in TP [inaudible 00: 10: 55]. What should I do is that if they've had an extensive nodal evaluation and have clearly lymph node negative disease, take them to the OR, get them through the surgery, we'll give them adjuvant therapy. If they have an indication for neoadjuvant therapy such as multi-station N2 disease or even any N2 disease, a bulky hilar lymph node that we could perhaps get them through a lesser surgery, I will give them preoperative osimertinib with or without chemotherapy. But again, that doesn't take away from the survival date of adjuvant osimertinib, so all of the patients should resume therapy in the adjuvant setting. 

Dr Goldberg: Okay, so maybe I'll ask about the other coast. So Eddie, how are you thinking about selecting these patients? Let's say there is a patient who a surgeon says, "I could probably get this out, but I think it would be better if it was smaller." Are you giving these patients neoadjuvant osimertinib alone? Are you giving it with chemotherapy? I know Jamie gave all the caveats with that study looking at chemo-immune therapy patients with EGFR mutations, but is that ever a consideration? How are you thinking about what to pick in the neoadjuvant setting? You can use this microphone. I'll keep this one. 

Edward Garon, MD: Perfect. So I think that there definitely are times when we will do neoadjuvant EGFR inhibition. It has tended to be in our practice when we do it more single agent rather than a combination. And there are a variety of reasons that we do it. There are medical reasons that patients may not be a candidate for surgery today, but would be in a few months. I'm not talking about the disease, but maybe they've had some other medical event that makes delaying surgery a reasonable option. 

So it definitely is something that we do, but again, I think it is something that should be discussed at a multidisciplinary tumor board. I think there are too many times in our current era where there's sort of magical thinking about making a tumor resectable. And in those cases, even if you do shrink it to the point where now you can do the surgery, have you done the right thing by that? So I think that those cases ideally would be discussed at a multimodality tumor board where there's at least the opportunity for someone to say, "Hey, physically, maybe we could reduce this to the point that you can cut something out, but is that biologically reasonable?" 

I think I certainly would caution on the China data for the neoadjuvant. I think that the path CR rate is intriguing, but remember, even on the path CR patients, the survival is not 100%. And the idea that it's going to be exactly the same in the EGFR-mutation patients is unclear to me. We definitely have many decade-plus survivors from immunotherapy. We, at least at our institution, do not have any decade-plus survivors with EGFR mutations from immunotherapy. And we have a lot of EGFR-mutation-positive patients who got immunotherapy. It makes me really question whether the same degree of long-term benefit would be seen in the EGFR-mutation patients. 

So if you would ask, is there any situation where that data intrigues me? I would say the one situation would be in EGFR mutations that are not particularly responsive to osimertinib. So in our practice, Arjan Gower, who's a faculty member, has a grant from the National Conference of Cancer Network for a neoadjuvant study of zipalertinib. And obviously that's a situation where we would look towards that study. But the idea that we're going to take the exon 20 drugs that we have and make those into very effective adjuvant therapies to the same extent of osimertinib is very unclear. And I think that's the place that, to me, that data would be a little bit intriguing, but still not ready for clinical utility. 

Dr Goldberg: Eric, yes. 

Eric Singhi, MD: Yeah, there's one thing I wanted to highlight here going back to Jamie's nice discussion of the updated ADAURA 8-year overall survival. So our team led a real-world analysis about if patients can truly even stay on the 3 years, and I think it's a really meaningful question to ask. And what we saw for patients using the Flatiron database in the US is that although the median duration was 33 months, by year 3, there were only 33% of patients that were still on osimertinib in the adjuvant setting. And what we saw as well was that there was nearly a 2-fold or higher than that risk of recurrence or death if patients dropped off before year 3. 

And so, I think really optimizing the time that patients are on therapy, being proactive about monitoring these patients, being proactive about management strategies, [and] having more data to help patients understand the importance of staying on adjuvant therapy is going to be really important, especially as we continue to prescribe these therapies. We're finding biomarker testing actually happening more commonly, thankfully, for these patients in the early-stage rate. 

Dr Goldberg: Yeah, I totally agree. I think there are people who can stay on maybe even indefinitely in the LAURA trial, but yes, some people do struggle with staying on with toxicity and not knowing if they need it. Jamie, maybe I'll come back to you and ask you about the second question which Eric sort of touched on. What are some things that we could think about? What are the remaining gaps? I'll tell you, and maybe you can answer this or think of your own gaps. I think the uncommon mutations in the exon 20s is really where I struggle. You find one of those in the adjuvant setting, are we giving the drug that matches that mutation in the metastatic setting? Are we extrapolating or is it too soon for that, assuming you don't have a trial? So speak to that and then if you have other gaps you want to comment on. 

Dr Chaft: But of course we have a trial. 

Dr Singhi: Yes. 

Dr Chaft: I hope it's going to reopen next week after being redesigned. There's a trial of adjuvant zipalertinib after chemo. But for patients who don't qualify for the trial, which is quite common, or who've had induction chemo and it really doesn't work, it's a big question. I don't want to give them immunotherapy. I don't think it works for them, and we're not going to give them off-label other TKIs that also don't work. So that's a real challenge. And in terms of other unmet needs, I think Eric really nicely outlined it. It's really approaching the compliance issue, really encouraging compliance, and learning more, although I don't think the data's available about the implications of dose reduction to enhance compliance. 

Dr Garon: One thing I would encourage ... We've decided the microphone doesn't pass Jamie, so we've operationalized this now on our own. So one thing that I think is important in practice is to make sure your patients know to feel free to talk to you about their challenges with the drug because I have had sort of surprise recurrences and I'm like, "I'm really surprised that this would happen at this point." And then you talk to them and they quit and that's fine, except for that I remember one case where it was pretty clear that they quit for issues related to just getting a little older over that period of time rather than that these were not ... There absolutely are side effects that can be related to the osimertinib, but what they quit for had nothing to do with the osimertinib. 

And so I think that to make sure that patients know to talk to you, there are cases where we'll dose reduce, recognizing that it may be a reasonable thing to do if you're going to get someone to stay on for a longer period of time. So I think the most important thing is that the approaches are going to be individualized, but the idea that your patient should feel free to tell you, "This isn't working for me," and to talk through with you why that is, I think those are universal. 

Dr Goldberg: I agree. I often will talk to people about dose reduction and sometimes they say, "Oh yes, absolutely.” Otherwise, “I'm stopping," or, "No, I'm fine actually." But I think especially in the adjuvant setting, that's important. Did you want to make a comment? 

Dr Singhi: Yeah, no, I was just going to echo what you guys said. I think it's so important to have data for reassurance for us and for the patients that if we do a dose reduction that we're not compromising outcomes. So please, this is a plea for the sponsors to get us that data, real-world data. We really need it. And then I really like the example you gave. We always talk about how excited we get to give patients oral therapy options. They can be at home, they don't have to come to the infusion center. 

But I just had a recent example of a patient, she's in her 80s, her daughter went out of the country for 2 and a half weeks. Her daughter was the one that gave her the pill every day, and then 2 plus weeks went and she didn't take her medicine. And so these are examples of just because they don't come to the infusion center, when the infusion center, we can go into Epic, we can go into Flowsheets, we can see when they checked in, the exact time they finished their infusion. We can track that, but sometimes it's hard for patients. I mean, even when I'm prescribed antibiotics, I forget, did I take it? Did I not? 

Dr Goldberg: While you have the mic, I'll ask you this last question and we can quickly touch on it and then open the floor. So think about your questions. You saw some data on plasma testing in Stage III disease that if you find it's real. If you don't find it, that doesn't mean anything. So are you using plasma testing in early-stage patients at all, or are you just doing biopsies and testing the tissue? 

Dr Singhi: No, we are using it. So at Anderson, we are concurrently pretty much for everyone using liquid biopsy and tissue. I led a mobile phlebotomy project actually with Caris. Many of our patients come from around the nation and they get scheduled in advance before they actually make it into Houston. So we led a mobile phlebotomy project where we used the Caris Assure liquid biopsy assay to meet patients where they are. And we found that the turnaround time was within 5 days or less. And by the time patients came back to our clinic for the first visit, we already had results for them, and that was very meaningful, and that included patients even with Stage II, Stage III disease. So we were able to make treatment decisions at the time of an initial consult for a patient out of state. And so that was really exciting. 

Dr Goldberg: I will say I don't routinely test it in the early-stage setting because it's often negative and I often have tissue results back by then. But yes, if you don't have ... Maybe Stage III. 

Dr Singhi: Yeah, Stage III. 

Dr Goldberg: How can you have tissue already? If you don't, I could see that. 

Dr Singhi: Yeah. 

Dr Goldberg: Okay. Amazing.