Introduction: Genomics of EGFR (and HER2)

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome back to Year in Review, as today we’re going to talk about EGFR-mutant non-small cell lung cancer. We have a great faculty: Dr Suresh Ramalingam from the Emory University School of Medicine and the Winship Cancer Institute in Atlanta and Dr Helena Yu from the Memorial Sloan Kettering Cancer Center in New York City.

Today we’re going to talk about — it’s amazing; it’s challenging in an hour even to get through this smaller part of lung cancer — EGFR-mutant disease. We will be talking about the use of unapproved agents and regimens, so check out the prescribing information for various products for more.

As we do in all of our Year in Review programs I met with each of the faculty individually to record presentations. These are in the chat room, and when we send out this webinar it’ll also be attached. We kind of view this as a 3-part experience. In these 2 presentations our faculty go through a bunch of papers that have come out and presentations in the past year. We’re not going to go through all the details, that’s in the presentations; tonight we’re really going to focus on the clinical implications of these data and also research implications on where things are heading in the future.

Here’s where we’re heading. I want to start out with a little bit of biology discussion, and then we’ll talk about metastatic disease, first- and second-line therapy. Again, so many more options nowadays than in the past, a lot of choices to make. Then we’ll talk about localized disease, both in the neoadjuvant and adjuvant setting, as well as the locally advanced unresectable. Then we’ll talk about exon 20 insertion mutations, and we’ll finish out with some discussion about a couple of new agents.

So Suresh, I don’t know. I always — never — wonder whether it’s just me or everybody else can’t understand all this stuff, but particularly I get confused in terms of the biology of genomics of EGFR mutations and also HER2 mutations. Now that we have TKIs for HER2 TKD mutations it’s getting me even more confused because those are also in exon 20.

So when I met — when I meet with the faculty I also, in addition to doing their presentations, I just kind of brainstorm with them, and I was asking Suresh how do you explain to a first-year fellow where EGFR mutations are, what’s the difference between an exon 20 insertion EGFR and these HER2 TKD mutations, and he came up with what I’m going to call the “Michigan Avenue explanation”. I always love these kinds of simple explanations, and actually for the last 15 years we’ve been doing our ASCO Meetings on Michigan Avenue at the Hilton Hotel, which I love their ballroom. But anyhow, Suresh, can you take a step back, we’re not going to show any slides, a lot of people are just listening anyhow, and talk a little bit about the genomics of EGFR, HER2 and these various alterations?

DR RAMALINGAM: Sure. Thank you, Neil. So EGFR, as we have learned over the years, is a gene that plays an important role in lung cancer and specifically becomes important when there are mutations. And not all EGFR mutations are the same. We have exon 19, exon 21, atypical mutations, insertion 20. These are all mutations that occur in various parts of the EGFR gene.

So a simple way to understand is if you’re in Chicago, and you’re driving on Michigan Avenue, and you hear that there is a roadblock, an accident on Michigan Avenue, that information by itself is not very helpful to you if you are going to try to avoid that area. What you want is exactly where on Michigan Avenue. So if somebody said Michigan and Halsted there’s an accident, or Michigan and Ohio there’s an accident, that then tells you okay, that’s where it is, I can now pick appropriate directions to go around. And that’s where these different exons are.

These are landmarks across the part of the gene, and exon 19 is in 1 location, exon 20 is in another location, exon 21. And these have different functional implications. We know that exon 19 and 21 are the most common mutations. We treat them with standard EGFR TKIs. We’re going to talk a little later about exon 20 insertions, which occur in a different part of the gene and where the treatment options are very different for this particular.

And when you talk about HER2 mutations, that occurs in a totally different gene in a different chromosome. It’s almost a different avenue where these mutations occur, and therefore the treatments are also very different. So that’s a simple way of trying to think about the EGFR gene and where these mutations occur being significantly important to make treatment decisions.

DR LOVE: So before I ask Helena for her take on this could you just clarify one other thing that’s always confused me? I think it’s HER1 is the same as EGFR. HER1 is on Michigan Avenue for EGFR. What about HER1?

DR RAMALINGAM: That’s right. I mean, the EGFR family of receptors is HER1, HER2, HER3 and HER4, and we use the word EGFR loosely to refer to HER1. HER2 is a completely different — it’s a gene that codes for a different protein. So EGFR/HER1 are more or less — are the same basically. We refer to them differently.

DR LOVE: So Helena, anything you want to add to this? Have you heard of this Michigan Avenue analogy before?

DR YU: No. It was just explained to me. The one thing that I would say is the important part of the gene is the kinase domain, the active part of the gene, so I would say the part of Michigan Avenue that’s right in the downtown, that would be the kinase domain. So for EGFR that’s exons 18-21. So I think just to take that analogy a little bit further. That’s where we want the drugs to be active.

DR LOVE: So we’re going to move on now and talk about metastatic disease, particularly — we’ll start out with first-line therapy and see where it’s heading. But first I just want to also get your take on this. We’re going to talk later on about adjuvant osimertinib, neoadjuvant osimertinib, and Suresh, it always seems like EGFR is first.

You had the I-PASS study that — and then — which compared I think it was gefinitib or lorlatinib to chemotherapy, and then they did it in ALK, and then they stopped doing it, so EGFR always leads the band. And when I saw the ADAURA data the first thing I thought about was are people going to start using other targeted therapy, and particularly I thought about RET. And ever since ADAURA I’ve been asking investigators are you using RET inhibitors. Most people say no, I want to see the trial.

So any thoughts about this study, Suresh, and whether you think it’s going to lead also to other types of adjuvant targeted therapy?

DR RAMALINGAM: This is a very exciting press release. We look forward to the data. Hopefully they’ll be presented at ASCO or one of the upcoming meetings. Now, we have evidence to support adjuvant targeted therapy in EGFR-mutated lung cancer and ALK-translocated lung cancer. This is now the third molecular aberration for which we will potentially use adjuvant therapy.

Now, we have a variety of other mutations and fusions for which we don’t have data, but I think the more we see these data in different genetic aberrations the more comfortable people feel about extrapolating to use in other indications when applicable.

DR LOVE: So Helena, what’s your take on this? Where do you think targeted therapy is — makes sense even before the studies? I don’t know if there are situations where you use it off label. Anything other — it sounds like RET’s going to join ALK and EGFR. I wonder about other situations, BRAF. Also, these new HER2 — or newly discovered HER2 TKD mutations and TKIs like zongertinib that seem to be well tolerated, have great — I call it the new EGFR. What about adjuvant zongertinib?

DR YU: Luckily there is an adjuvant zongertinib study that is just starting up, so I think hopefully we’ll have some data there. But I think, Neil, what —the threshold is very active drugs that are very well tolerated, right? I think if we’re going to use them for patients that are potentially cured, we want to really make sure that we’re adding something without leading to real decrements in quality of life.

So I do think that there is some degree to extrapolate, but I think it depends on the mutation, the drug and then also the clinical situation. I think the higher the risk of recurrence, so for patients with larger tumors and N1- or N2-positive disease, those would be the people that we would want to kind of potentially add something extra, such as targeted therapy, on top of a chemotherapy to help decrease that risk of recurrence.

DR LOVE: I guess I’m always anxious to see things moving forward. I remember when ADAURA was first presented I happen to be talking to Tom Lynch, who of course discovered the EGFR mutation 20 years ago, and he said well, you’ve been asking us for 15 years when are we going to start using adjuvant osimertinib, I guess it’s time, finally. It sounds like that’s happening with RET as well.

Metastatic Disease

DR LOVE: Alright. Let’s talk about metastatic disease, and we’re going to start out, of course, with the key question, which is choice of first-line therapy. And Suresh, for the last couple years we’ve had 3 major choices. You can go through that. Both of you reviewed the data in your part 1 presentation, so we don’t have to go through it all. I’ll show some of the slides, but really I just want to chat a little bit here because I know a lot of people are just listening.

So Suresh, can you talk about the 3 available commonly thought about first-line options, approved options, and in particular when you use osimertinib alone because it sounds like more and more we’re going to combinations?

DR RAMALINGAM: It is true, Neil, more and more we are going to combinations. We started initially with osimertinib as monotherapy a few years ago, and now we have 2 other more intense regimens. One is the chemo plus osimertinib, that’s the FLAURA2 regimen, which showed improved PFS and overall survival, and almost a 10, 11-month improvement in overall survival with the combination over monotherapy alone. It is now FDA approved.

We also have the combination of amivantamab and lazertinib, which is a non-chemo combination that has shown improvement in PFS and overall survival. So we have 2 intensified approaches on top of osimertinib monotherapy, so treatment decisions now become individualized to patients more so than before. I look at high-risk features. Does the patient have brain mets or not? Does the patient have exon 19 mutation along with a concomitant p53? Does the patient have disease burden that’s quite severe? Does the patient have significant symptomatic burden? The more Ss you get to these questions, the more compelled I am to use a combination approach. If the patient is very asymptomatic, straightforward exon 19, no brain mets, that might be the situation where you use osimertinib as monotherapy.

And when you think about combinations both of these combinations have different toxicity implications, different toxicity considerations, so you have to personalize that, as well, to patients. And in my practice, I tend to use chemo plus osi as my go-to regimen because of its slightly better tolerability profile.

DR LOVE: Helena, I’m curious for your take. When that overall survival data came out it was pretty striking. This is a significant survival benefit. And even though the idea of taking chemo maybe doesn’t appeal to everybody it’s kind of — I’m even wondering whether you even need a high-risk situation. I’m curious. Do you give it to everybody who wants the best outcome they can who can tolerate chemo? It’s kind of ironic. I mentioned this I-PASS study that compared a TKI to chemo. I think when we did that we were all excited about it. I didn’t hear anybody say well what about combining the 2 because we were all so excited that it beat up chemotherapy, and now here 15 years later we’re using both.

So who do you give — I mean, of course if somebody’s not a chemo candidate that’s pretty straightforward, but assuming they can tolerate chemo and they want the best outcome who do you give osi alone to, Helena?

DR YU: Yeah. I would add to Suresh that it would be really — it’s an opt-out strategy now, right, where I think the default for me for everyone is to give them the combination because I am convinced, like you are, with that survival benefit. I think 10, 11 months is very meaningful for patients, and I was really waiting for that to really change my practice and really offer this for everyone.

And the people that I offer monotherapy to are people exactly like you said, Neil, who for whatever reason might not be a platinum chemotherapy candidate, or there are some people that are just very clear that they don’t want chemotherapy, they really just want the pill. And then of course that’s shared decision-making and of course we can proceed with osimertinib alone, but really it is, I think, an opt out.

DR LOVE: So we also talked about amivantamab. We saw the approval recently of subcutaneous amivantamab, which we really, I guess, did away with or hopefully dramatically decreased infusion reaction, but you still have issues with DVT requiring prophylactic anticoagulation, dermatologic issues as well. But another question about benefit, Suresh. Is there any kind of tail on the curve in metastatic disease here? And do we know whether or not, for example, even though maybe ami/lazer is more toxic, maybe it has a longer tail, or do neither of them have tails? What do we know about that at this point? Are we curing anybody, Suresh?

DR RAMALINGAM: Well, I don’t think there’s any proof to say we’re curing any patient with metastatic disease. In fact, I would go on to say even in early-stage disease the question is open whether we are curing or delaying the inevitable.

And the tail of the curve is something we get excited about, and it is very relevant in the immunotherapy-treated patients, where you do see long-term survival, patients living 8, 9, 10 years without continuation of therapy even, and that’s where we get excited. In this situation I don’t think there’s a whole lot to differentiate in terms of efficacy between what you see with chemo plus osimertinib or the amivantamab plus lazertinib regimens.

DR LOVE: So I want to get into a couple of other studies. Helena, you talked about these, and I really wasn’t aware of this. This is really, I think, kind of practice changing, maybe not as dramatic as choice of therapy, but a couple of interesting strategies that you talked about. Here’s the data on the subQ amivantamab. But first this COMPEL study, Helena. A lot of people have been continuing osimertinib on progression when they add in chemo or whatever, but this is a study that actually looked at that strategy of continuing osimertinib in patients switching over to platinum-based chemo for progressive disease. Can you comment on what it found and how you think it should affect practice?

DR YU: Yeah. I think this was a really practical study, where this is what people have been doing, but we really didn’t have data to support it. I think just as background we have the IMPRESS study, which was when we were giving earlier-generation EGFR TKIs like gefinitib. We had a study that told us that continuing gefitinib with chemotherapy wasn’t helpful, but we know that osimertinib is a different generation TKI. It has much better brain penetration, and we know it can be very CNS protective.

And so these results were quite different, where we really did see a clear improvement in progression-free survival and decrease — improvement in progression-free survival, both with systemic disease but also with CNS disease. And so I do think it was convincing that when you give chemotherapy you do need to add a targeted therapy partner, and so that can osimertinib, it can be amivantamab, but I do think that this was convincing that both of those strategies are better than platinum chemotherapy alone in the second-line setting.

DR LOVE: And Suresh, it also gets into what you use for second-line therapy. We talked about the 3 major choices first line and what you get first line affects second line, but I’m particularly interested, again, related to this COMPEL study, in patients not only who get osimertinib alone but particularly osimertinib with chemo. Would you continue osimertinib, for example, if you were going to use datopotamab deruxtecan?

DR RAMALINGAM: Well, there is an ongoing study that’s going to answer that question, hopefully. At this point I would say if a patient has CNS metastases at the outset, and we have had control of the disease with using osimertinib, that’s an indication to continue on with osimertinib and add whatever new therapy you bring in. And the COMPEL study, even though it’s a small study, and it showed strong trends towards improvement in overall survival, it adds to how we consider the use of TKI in this setting. So to me it’s informative and helpful.

If we already gave chemo plus osi in the front line, and the chemo-free interval has been substantially long, that makes the case for rechallenging the patient with platinum doublet at the time of progression, and there continuing osimertinib is well supported with the COMPEL results.

DR LOVE: So that was, as you were saying, Helena, something we’ve been doing, but now we know why we were doing it. But this is something else I’m not sure we have been doing, which I think is really amazing, local consolidation, not just with radiation therapy, even with surgery in patients with metastatic disease who are responding to osimertinib. This is the NorthStar study. I like the title of that. But anyhow, what did they see here, and how has it affected your practice, Helena?

DR YU: Yeah, I agree this was an important study. So we know from earlier studies from this same group that after systemic therapy, when patients are at that minimal residual disease timepoint, that doing local therapy can be helpful in improving progression-free survival and overall survival. And this study was of course focused on EGFR-mutant lung cancer and the use of osimertinib as induction therapy. I think important points were exactly like you said, Neil, that the consolidative therapy was surgery for some patients, along with radiation for others.

I think an important point is that patients that were polymetastatic or had multiple sites of disease, some of them were rendered oligometastatic or have — or to have only 5 or fewer remaining sites of disease, where local therapy was possible, and then the important point is that the benefit was really for people who had complete local consolidative therapy.

So for patients where only say 3 of the 5 sites were treated, they didn’t see a benefit. It really had to be local therapy to all remaining sites of disease. But I think if that is possible, we should absolutely be doing it, and I think there should be more tumor board discussions in this setting to really kind of decide is ablation best, is surgery best, is radiation best for a given patient, but it should definitely be considered.

DR LOVE: It kind of reminds me in a way of local treatment of oligometastatic disease, where you’re using local therapy even though you have metastatic disease. Suresh, is this something that you do in your practice? And again, what about other targeted therapies? Would you do it with an ALK patient?

DR RAMALINGAM: Yeah. I think these results are early, and I’m grounded by the fact that previous experiments with treating oligometastatic disease with extensive radiation in other settings have not resulted in improved survival and in some cases have shown more toxicity. So I would want to see more prospective multicenter validation of these results.

That being said, there are clinical situations on a patient-by-patient basis where we see you had a great response and you’re left with just 1 spot that could be or may not be symptomatic, but that’s bulky that you’re concerned could be the source of progression. So I feel a little more comfortable using SBRT to these lesions. I’m not that keen on sending patients to surgery in a metastatic disease setting, but SBRT being noninvasive and easy to administer in the outpatient setting it’s something I have resorted to in select situations.

So as Helena pointed out, these are tumor board conversations. When you have a patient responding really well to TKI and there’s some residual disease you can talk about it among your colleagues and see whether any of these will be helpful and in which situations and in which patient.

DR LOVE: Helena, a quick case from the chat room. Bin has a patient who got first-line osimertinib then progressed, doesn’t say how long they were on it, then got carbo/pem second line, now progressing with brain mets. What’s next?

DR YU: That would be a tough one. So if they had not been on the osimertinib during the chemotherapy I’d probably want to do a regimen where I would restart the osimertinib. There is data, as I think Suresh mentioned, combining datopotamab deruxtecan, the TROP2 ADC, with osimertinib. It is tougher, as well, but that would be a situation where coming back to the EGFR TKI when we add our next line of therapy would probably be preferred.

DR LOVE: So speaking of Dato-DXd, that’s the next thing I want to ask you about. And Suresh, maybe you can tell me where in Chicago Dato-DXd is working, but also beyond that we talk about dato all the time in breast cancer, great data in ER-positive and triple-negative disease. I was kind of surprised when it popped up in EGFR-relapsed disease, but I’m curious about your thoughts about how effective it is, why it’s so effective and also a little bit about your experience with toxicity. In breast you hear a little bit about mucositis, keratitis not so much of an issue. So Suresh, any thoughts about Dato-DXd?

DR RAMALINGAM: Sure. So first of all, it’s an antibody-drug conjugate. It targets TROP2, which has nothing to do directly with EGFR. It’s just a protein that’s present in EGFR-mutated cells, so you’re using that protein to target and get this payload into it. That’s deruxtecan. We’ve seen that this drug has about a 35-40% response rate in the setting of acquired resistance, median PFS of approximately 7 months, and therefore it has an accelerated approval from the FDA. And so when patients have already been treated with platinum-based combinations and have received — and developed acquired resistance now we have datopotamab as an option in addition to docetaxel.

The toxicities, as you pointed out, have to be managed proactively. Mucositis is one, keratitis is the other one that you have to make sure that you’re paying close attention to when you treat these patients.

My experience has been positive so far. I’ve used it in a handful of patients since it’s been approved, and when you manage the toxicities well patients — I’ve seen responders, and I’m encouraged by that.

DR LOVE: So curious about your experience, Helena, as well. The breast people, I can remember talking to Erika Hamilton, they’re so into using preemptive corticosteroid mouthwash because they say if you get mucositis it’s much harder to treat, much easier to prevent. I don’t know if you move over to lung cancer, different type of patient. What’s your experience with toxicity? And also, you were telling me something I wasn’t aware of, there’s activity with the uncommon mutations that we use afatinib for, like exon 18 and exon 20 insertion EGFR mutations?

DR YU: Yeah. So the label is actually broader than I think most people are aware of, where really the TL — the TROPION-Lung studies also looked at datopotamab exactly like you said, in uncommon EGFR mutations and exon 20, and so the accelerated approval label includes those rarer mutations. And I think it makes sense.

There’s something about EGFR-mutant lung cancer at large that (1) has more of that TROP2 protein on the cell surface and (2) we know that EGFR-mutant lung cancer has maybe a greater sensitivity to chemotherapy. So I think those things combined just make this potentially a more active drug for those different mutations.

And I’m a believer in prophylactic mouthwash as well. I think mucositis is — even at a low grade is so — effects our patients and their quality of life, right, because not only does it cause pain, it leads to anorexia, weight loss, and so anything that I can do to mitigate that, which would be that plus I don’t know how much good data there is for it, but the ice chips with infusion. So that’s something that we recommend too. If they’re sucking on ice chips maybe there’s some vasoconstriction, less of that Dato-DXd that gets to the mucosa. Maybe that helps.

DR LOVE: Yeah. I’ve heard mixed stories about the ice chips.

Any thoughts about where dato’s heading, Suresh? Here we have this ORCHARD study looking at dato and osimertinib. That sounds kind of interesting, kind of like what you were talking about, continuing osi on progression, adding in the dato. And also this TROPION-Lung15 study. Can you talk about that and where you see dato landing in the next 3-5 years?

DR RAMALINGAM: Yeah. So dato, based on the strength of results we’ve seen so far, is in Phase III testing. Here you see an acquired resistance setting where patients get randomized to either getting platinum doublet chemotherapy on 1 arm, getting dato alone in another arm, and the combination of osi and datopotamab. And this is the trial I was referring to earlier when we had a conversation about using dato in combination with osimertinib.

So I think the results from the ORCHARD are promising. This Phase III trial will have over 600 patients, and we’re looking forward to it. There’s also a front-line study with datopotamab and osimertinib that’s ongoing, also a Phase III trial. So a lot of ways by which datopotamab’s use is being studied in lung cancer.

DR LOVE: Yeah. Again, in breast cancer triple-negative we saw some positive data with dato plus IO, but I guess I don’t know if that is ever going to happen. Maybe outside of EGFR in lung cancer.

One more topic in metastatic disease. And Helena, we’ve heard a lot about MET alterations/overexpression in patients progressing on osimertinib. That’s one of the mutations we look for. Any comments on this agent savolitinib that’s being used, again in combination with osimertinib, I guess continuation of it, in patients with MET overexpression or amplification? This is not MET exon 14 mutations. This is just overexpression/amplification. What’s the rationale here and what do we know about this, Helena?

DR YU: So we know that the MET protein and MET signaling is a relevant pathway for resistance to osimertinib. I think what’s complicated, Neil, is figuring out what the right cutoffs are. So depending on what cutoff you use it’s up to a third, about 30-35% of EGFR-mutant lung cancer that has some degree of MET positivity after progression on osimertinib. Some of these studies, like the SAVANNAH study, used IHC, or immunohistochemistry. Some of them look at changes in copy number, which you can see by either next-generation sequencing or FISH testing.

I think that the bottom line is the higher the IHC protein expression or the higher the copy number gain the more these drugs are active. And so depending on the cutoff, the higher the cutoff then the higher the efficacy that’s seen, but it really is an active combination. And I think patients of course prefer an oral/oral regimen, so savolitinib is of course a MET oral TKI, and so I do think that this has a lot of promise but probably ultimately relevant for in that kind of 20% range after osimertinib monotherapy.

DR LOVE: So Suresh, any comments? And any comments in terms of toxicity of savolitinib?

DR RAMALINGAM: Absolutely. So you do expect to see some MET class effect-related adverse events, primarily lower extremity swelling is 1 of them. Nausea/vomiting are also additional considerations when you talk about giving savolitinib. So you do have to manage those. Thankfully, they are primarily Grade 1 or 2 in severity in the majority of the patients when it occurs, so managing toxicity along with monitoring how patient’s symptoms are improving and looking at your scans are critical.

Localized Disease

DR LOVE: So I want to move on now and talk about localized EGFR disease. We’ll start out with adjuvant therapy. Of course, we’ve seen the ADAURA trial out there, but Helena, now, of course, we see ctDNA studies all over oncology nowadays. We saw we’re about to do a Year in Review colon cancer, and that’s probably where things got started the most and at this point really helpful. But we also saw some ctDNA studies in the ADAURA trial. I’m curious about your thoughts in terms of what was seen here and in particular whether at this point you see any practical role for it.

I guess one of the questions I think that’s out there is how long to treat, and I have heard people say they think that looking at cell-free DNA maybe at 3 years might be a way to decide whether to continue therapy. I don’t know how you make that decision about whether you’re going to continue therapy at 3 years. Any thoughts about cell-free DNA in the adjuvant osimertinib situation, Helena?

DR YU: I’m excited about it, and the ongoing research personally, in my opinion, I don’t think it’s ready for prime time, so I’m not doing this routinely in patients outside of a clinical trial. But I think more and more trials are incorporating MRD status, right, in terms of whether to decide to do adjuvant therapy or, again, like you said, Neil, at what time to stop. But I think for me I’m really following the studies where I’m giving the osimertinib for 3 years and then not using the MRD testing, but I do think that it’s in our future, right? I think as the studies incorporate it and we know how to use it as a biomarker I suspect we’ll be doing it more and more.

DR LOVE: So Suresh, any comments about duration of therapy? Are there situations where you try to go beyond 3 years? How do you make that decision? Do you think cell-free DNA either now or in the future is going to affect this or any other decision in the adjuvant situation like this?

DR RAMALINGAM: On top of what Helena said, I do expect the ctDNA platform to get better and better as technology improves, and with higher sensitivity we would be able to better delineate which patient is going to recur and which patient is out of the woods and therefore not need additional therapy. So at this point I think 3 years of therapy is evidence based. Continuing it beyond that is a conversation we have to have with the patient.

My personal feeling is we’re going to need continuous therapy. Three years may not be where we end up in the long haul with regards to the duration of adjuvant TKI. The question would be if you can risk identify which patient needs that and avoid giving it to every patient we would be doing patients a big favor.

DR LOVE: So Helena, I was telling you that yesterday I had the pleasure of spending a couple hours with your colleague Dr Jamie Chaft, who presented the NeoADAURA study at ASCO. This is for a program we recorded that we’re going to put out soon, and I was asking her a lot of — she was providing me a lot of insight into that study. Can you talk a little bit about what NeoADAURA looked at, what they saw, and what you see, if any, is the current role for neoadjuvant osimertinib or osimertinib with chemo?

DR YU: Yeah. This was an important study. So we know for EGFR-mutant lung cancers that immunotherapy is less active, but understanding how important chemotherapy is and how important osimertinib is in this early-stage resectable setting is really not yet fully flushed out.

But this study looked at osimertinib monotherapy versus osimertinib plus chemotherapy versus chemotherapy alone to really try to get to the contribution of components. And so I think this was a study that we were all awaiting results. I think what was clear is that osimertinib does help, where both the osimertinib-containing arms really led to a much higher major pathologic response rate compared to chemotherapy alone. I think that the question is still now how much is the chemotherapy important.

But I would say for me with — obviously we don’t have longer-term data from this NeoADAURA study, but in patients with higher-risk disease, so larger tumors, bulky N1 or multistation N2 disease, those are people that I’m doing both in, the osimertinib and chemotherapy, and that really is — we have our best chance to address micrometastatic disease and really shrink things down prior to surgical resection. And so I am tending to use both more and then following post resection with the osimertinib adjuvant therapy.

DR LOVE: So Suresh, what’s your approach right now to neoadjuvant therapy? I was telling Dr Chaft that the 1 thing that surprised me, I was kind of expecting the path CR rate to be higher with osi/chemo based on what we’re seeing in metastatic disease, but even though both of them were higher it doesn’t look like it’s higher with chemo. She was saying maybe it’s not just the path CR there’s other variables that weren’t measured. But any thoughts about why we didn’t see higher path CR with chemo, Suresh, and what are you doing in your practice?

DR RAMALINGAM: In my practice first we need to do molecular testing even for early-stage disease. Gone are the days where you take the tumor out and then figure out what to do next. Now we have to have molecular information up front. And as Helena said, if a patient has Stage III disease, N2-positive, I tend to use chemo/osi if they have an EGFR exon 19 or 21 mutation.

I would like to see a higher path CR. This just tells us that the ability of targeted therapy is to completely eradicate tumors is still not as good as what you see with chemo and immunotherapy. And there’s also talks about the static — cytostatic effect that these regimens have compared to immunotherapy, where we do see complete eradication of tumor, higher path CR rates in the order of 25%. Here you’re seeing less than 10%. So it is disappointing that the rates are not higher, but this is the best we have, and I think for the right patient moving forward with that makes sense.

DR LOVE: So yeah, particularly when you think about Stage IIIA. And what about the issue — I was, again, talking with Dr Chaft about this, Helena, about “converting unresectable to resectable.” Is that a real potential objective?

DR YU: I think more surgeons and more DMT disease tumor sessions are looking at that. I think that I like people to — in the ideal situation we make the treatment plan up front, right? I think that kind of banking on somebody going from unresectable to resectable I think can potentially do a disservice to them because then if they end up not having a robust response to systemic therapy we’ve kind of given them the systemic therapy, and then we have to follow with sequential radiation, which isn’t ideal.

So I do think any borderline cases we like to talk about at tumor board to make that decision up front. I think that for some patients where the tumor field is quite large, and in particularly for unresectable Stage III, we definitely have done some up-front systemic therapy to potentially decrease the radiation field and then proceed with consolidative definitive radiation. So that is an area where we maybe do that systemic therapy up front.

DR LOVE: So a couple questions from the chat room, again from Bin, Suresh, about ctDNA. The question here is not so much for MRD assessment but to evaluate progressive disease before radiologic progression. We have seen that in other tumors. Do you think that — I don’t know what the lag time between MRD and clinical progression is. Any thoughts about that strategy, Suresh?

DR RAMALINGAM: Sure. So we’ve looked at this latency question both in the FLAURA study and now more recently in the ADAURA trial. In metastatic disease when you follow patient’s longitudinal MRD you only get about a 3-month heads up notice with regards to radiographic versus ctDNA detection. In the ADAURA trial it’s more about 5 months. So it’s not a big enough of a difference for you to subject patients to regular monitoring of their ctDNA.

And the second question is by picking it up early what are we doing that dramatically different and that’s altering the natural history of the disease for that patient. And those are the kind of studies that we have to do. We certainly don’t have the kind of tools if a patient is already developing resistance to osimertinib that I have something so good that I want to bring it in 3 months early, as opposed to finding out on the scans. And it’s expensive, putting patients through this. It also has psychosocial implications, anxiety, waiting for test results and all of those things, so I do not do that in my practice.

DR LOVE: Okay, Helena, 2 more from the chat room. Here’s one from Swati. This is a good one. When do you use ami/lazer first line. That’s question number 1. You answer that question first, then I’m going to give you a case.

DR YU: Sure. So now because there are some MET-directed ADCs, like teliso-V that we’re using, we do sometimes get MET IHC up front or on NGS we might see MET amplification up front. So those would be people that number 1 we know that they do worse, right, that those tumors are more aggressive and have kind of inferior outcomes to TKI. So that would be a case, I know that those are rare, but that would be a case where I’d want to go towards amivantamab and lazertinib.

And then second, we don’t have this yet, but I would love a predictive biomarker. All of these biomarkers we’re talking about are prognostic, so we know that people do less well, but I suspect that there is a predictive biomarker that we could find where some patients or some tumors would benefit from dual pathway inhibition with MET and EGFR inhibitor. And so I do — I think that that’s a challenge that’s out there to find that because right now we don’t know how to choose between the 2 regimens, we just — we kind of talk about the toxicity and then make the decision.

DR LOVE: So actually I’m going to ask Suresh this. This is an interesting case from Emily, who apparently is better read than I am about dato. 74-year-old man, metastatic non-small cell, EGFR E709T-710D, I’m not necessarily familiar with that one, but it sounds like an uncommon one, gets afatinib for a year and a half, has slow progression and now is progressing on Dato-DXd. What’s next?

DR RAMALINGAM: Yeah. So this is an uncommon mutation, as you pointed out, Neil, and if the patient has progressed on TKI and has progressed on dato the 1 question I would ask is has the patient been exposed to platinum-based chemotherapy. If the patient has not been exposed to it, then that would be an option. Beyond that, it might be helpful to get a biopsy, look for molecular results to see if there are any new targets that you can go after, not that there are a great slew of options, but certainly looking for MET IHC would be 1 possibility to see if the patient would be a candidate for teliso-V. So those are some of the things that I can think of.

DR LOVE: So speaking of getting a biopsy I meant to ask you before, and Helena, small cell transformation. I mentioned we’re doing this webinar on small cell next week. What about small cell therapy and small cell transformed EGFR, tarlatamab in particular?

DR YU: Yeah. So just to go back and say that small cell transformation occurs in 10-15% of patients after progression on osimertinib, so rare but not so rare. We gathered — a couple of different centers kind of gathered our data because we want to know are these novel therapies we’re seeing for de novo small cell are they going to be active in the transformed small cell setting.

And we really didn’t find that to be the case. I think there were 13 patients treated with tarlatamab with transformed small cell, and only 1 had kind of a modest response to tarlatamab, which is quite strikingly different than what we’re seeing with tarlatamab for de novo small cell. So I think we can’t assume that the same treatments will be active, and so studies really need to be done in this specific population to see what might be active.

DR LOVE: So continuing on the theme of localized disease let’s talk about surgically unresectable localized — locally advanced disease, the durvalumab territory from the PACIFIC trial but now the targeted therapy because of the LAURA trial and more. We saw follow-up data now. Here the osimertinib is used indefinitely, which I think is interesting, compared to the ADAURA study. But we have seen now survival benefit, again, in this setting. Suresh, I’m curious what your thoughts were when this was seen, but also in terms of, again, some more data with MRD. Can you talk about what they saw there and again whether you see any potential role in this setting for MRD assessment?

DR RAMALINGAM: Sure, Neil. In the LAURA study, as you mentioned, we have seen statistically significant improvement in PFS. We’re seeing a favorable survival trend in this updated data that you just showed. We’re waiting to see the full mature survival results, hopefully in the next 12 to 18 months.

These MRD results are important for a couple of reasons. One, of course, is both in patients who are MRD-positive and MRD-negative giving osimertinib was better than getting placebo on this study. The second is nearly 100% of the patients, after they had completed chemo/RT, had either actual residual disease or MRD-positive disease in this EGFR-mutated non-small cell lung cancer patient population. This tells us that while chemo/RT plays an important role, we’re not curing these patients with chemo/RT because micrometastases happens, and that’s the rationale for giving targeted therapy even for an extended length of time, as we did in the LAURA trial.

DR LOVE: So any comments on using targeted therapy, Helena, in this locally advanced unresectable setting, particularly osimertinib, what your experience is, any kind of tolerability that have come up? And also your thoughts, we were talking about neoadjuvant osimertinib before, but neoadjuvant or up-front treatment in this situation before chemoradiation with targeted therapy with osimertinib.

Suresh was telling me about this trial called NEOLA that’s I guess just getting started that’s going to look at osimertinib, chemoradiation and then back to osimertinib. Any thoughts about that strategy? Do you ever do that? That always made a lot of sense to me, shrink down the tumor, maybe smaller radiation fields. I think they tried to do that in the past and couldn’t accrue or something. Any thoughts about that? Do you ever do that right now outside a trial setting?

DR YU: I think it makes sense because of what Suresh pointed out, where these patients are almost universally micrometastatic, right? So I think we treat them with these aggressive concurrent chemoradiation regimens, but really an overwhelming amount of them do have micrometastatic disease. And so I think that doing the most effective systemic therapy up front, which we know for EGFR-mutant lung cancers is osimertinib, and then shrinking down the disease to its smallest burden possible and then trying to do some consolidative local therapy definitely just makes sense, right, where you’re trying to consolidate a smaller tumor and would likely have greater success. And you’re also treating micrometastatic disease beforehand, which of course is helpful too.

EGFR Exon 20 Insertion Mutations

DR LOVE: Alright. Let’s talk a little bit about exon 20 insertion mutations, and of course we’ve had amivantamab and chemotherapy, the PAPILLON trial, that has been out there. Can you talk a little bit about what we know about this regimen, Suresh, in exon 20 insertion, what your experience is, and also what your experience is with amivantamab in terms of toxicity? We mentioned the fact that now there’s a subQ formulation that I think just mainly improves infusion reactions, maybe not so much the dermatologic and other issues. What have you seen in terms also of responses to this combination, Suresh?

DR RAMALINGAM: Yeah. This is an approved regimen now, chemotherapy and amivantamab for first-line therapy for patients with insertion 20 mutation. And the topline results of the PAPILLON trial showed that the PFS was improved from 6.7 months with chemo alone to about 11.5 months with the chemo/amivantamab. Now, this was done when amivantamab was given IV. Of course now we have the subQ ami option, which at the minimum reduces the risk of infusion-related reactions.

What you also see on the lower part of this slide is the patient-reported outcomes data that were reported in Lung Cancer journal last year, where despite the toxicities associated with amivantamab with appropriate management we are seeing that overall patient physical function/global health status were maintained in both the chemo arm and the chemo plus amivantamab arm. So these patient-reported outcomes add to the clinical benefit that we see to support the use of amivantamab in this particular patient population.

So curious about your experience also, Helena. I know a lot of times we see significant toxicity in the trials that get drugs approved, and then after a couple years we come up with a more effective amelioration of symptoms or prevention of them. Right now, in your hands, how well tolerated is amivantamab/chemotherapy, and what have you seen in terms of the quality of responses?

DR YU: I think that this is even in the best of hands a regimen that does have moderate toxicity. I think that Janssen has done a really good job of putting forth a lot of different proactive prophylactic regimens, and so 1 includes the COCOON study regimen, which really is combinations of lotions, antibiotics, topical creams to really try to mitigate in particular the scalp rash, which I think can be quite problematic for some patients. I think that we have a little bit longer ways to go with the paronychia, which can be very challenging for patients.

But I think this is what we have, and this is the best of what we have, so I think of course we are doing it and trying to get those best outcomes for our patients. But I think in this EGFR exon 20 space we are all very excited about some of the oral therapies which are coming down the pipeline because I think being able to give something that’s equally efficacious but better tolerated is really, of course, the goal.

DR LOVE: So speaking of oral therapies and TKIs, curious about your thoughts about sunvozertinib. I remember there used to be I think it was called mobocertinib. I think there may have been another TKI that kind of went away. I never exactly understood that. But anyhow, there’s another TKI with the WU-KONG18 trial, and now, as we’ll say, there’s apparently a Phase III trial, a positive press release, on this agent. I don’t know whether that’s going to be presented at ASCO.

But Suresh, can you talk a little bit about sunvozertinib, and there’s another one, zipalertinib, how they compare to the previous therapies in terms of efficacy, tolerability? And any comments on this Phase III trial that’s about to be presented?

DR RAMALINGAM: Sure. So sunvozertinib is an orally administered small molecule inhibitor. It is approved by the FDA for second-line treatment of patients with EGFR exon 20 insertion. The drug is active. The response rate is approximately 35%.

And you see here on this slide in this particularly experience the response rate was 46%, and it depends on whether or not patients had prior amivantamab. You can see patients who had received prior amivantamab had lower response rates. Patients with baseline brain mets the response rate is quite respectable as well.

The side effects here are diarrhea mainly, anemia and CPK in the blood that needs to be monitored.

So overall this is active. It’s available. What’s even more exciting is this press release, which just came out a couple of weeks ago, which noted that in a Phase III clinical trial comparing sunvozertinib directly to chemotherapy showed improvement in outcomes with sunvozertinib. And you mentioned mobocertinib. This was exactly the setting where mobocertinib failed to demonstrate improvement. So the fact that sunvozertinib has shown benefit is very exciting. Of course, we wait to see these results. And this could potentially open the door, as Helena said, for first-line use of a TKI in EGFR exon 20 insertion-positive patients.

Zipalertinib is another exciting TKI that’s being studied, the results show positive response rates in the second-line setting. Once again, keep an eye out for this drug as well. It seems to be a relatively well tolerated, active drug with a respectable response rate; median PFS of about 6, 7 months in this patient population in the second line.

DR LOVE: So Helena, I’m curious about your experience with both of these agents. And also, I just noticed here in the press — this always happens in oncology, that you start a randomized trial and then by the time you report it the control arm is outdated. So I don’t know. It looks like this is comparing it to just chemo and not chemo plus ami, so I’m not sure what we’re going to do with this, but any thoughts about this or these 2 TKIs?

DR YU: Yeah, no. I think that the TKIs I am really excited about, again because these would be the first oral approved TKIs that are currently available. I also am pleased that both the zipalertinib and sunvozertinib studies looked at kind of efficacy post amivantamab, because either direction you want to go, whether it’s zipalertinib, sunvozertinib first followed by amivantamab or vice versa, having these different options with different mechanisms of action will only benefit our patients.

And you’re right. I think that studies happen sequentially so things change, but I do think that if there could be a chemo-free first-line regimen that looks to be superior that would be, I think, what most patients would prefer as long as the trial — cross-trial comparison is similar. So again, we’ll hopefully see that data later this year.

New Agents

DR LOVE: So a couple other agents I’d like to get your thoughts on, new agents, ivonescimab in the HARMONi Phase III trial. So this is ivonescimab/chemotherapy. We started hearing about this I think at the World Lung meeting a couple years ago, a bispecific targeting VEGF and PD-1 that I think comes out of China. Any comments on this agent in terms of EGFR disease and lung cancer in general, Suresh?

DR RAMALINGAM: Neil, there’s a lot of excitement around the PD-1/VEGF bispecific antibody. Ivonescimab is the first in the line of a number of drugs that are being studied. We’ve seen the results of the HARMONi-3 trial, which was primarily done in China first, and then they added a cohort of patients from the rest of the world, and this trial showed improvement in PFS, but the overall survival results, while there was a favorable trend, did not meet statistical significance. The combination was tolerated well, and you saw what you would expect: PD-1 kind of toxicities and VEGF blockade-related toxicities. This is in front of the FDA, as I understand, and we’ll wait to see what the decision is.

Some of the parts of the study that are a little harder to interpret is the fact that the follow-up time for patients from China in this trial are much longer, whereas for patients enrolled from North America and Europe it’s much shorter, so it’s hard to know how the drug works in the rest of the world, whether it’s the same as what it is in the Chinese patient population.

DR LOVE: So a lot of people, including your colleague Dr Heymach from MD Anderson, wondered would bev plus IO kind of be the same, which of course we don’t really know, but bispecifics are always interesting.

So final question. We talked before about Dato-DXd targeting TROP2, Helena, and we’ve heard about sac-TMT with — in breast cancer. It kind of seems like similar efficacy to dato and sacituzumab govitecan. What about sac-TMT in EGFR? We know dato works. What about sac-TMT, Helena?

DR YU: I think this OptiTROP study really was quite convincing. I think it compared the TROP2 ADC versus platinum-based chemotherapy in EGFR-mutant lung cancer, showed improvements in PFS and early improvements in overall survival. I think it just, I think, reinforces that these TROP2 ADCs are active in EGFR-mutant lung cancer, and I think, again, having multiple options in this space is only a good thing.

DR LOVE: So Helena and Suresh, thank you so much for working with us today. Audience, thanks for attending. Be safe, stay well and have a great night. Thanks so much, Helena. Thanks a lot, Suresh. Have a great night.

DR RAMALINGAM: Thank you.

DR YU: Thanks, guys.

DR LOVE: Take care.