Oncology Today with Dr Neil Love: EGFR Mutation-Positive Non-Small Cell Lung Cancer Edition (Audio Program)
Oncology Today with Dr Neil Love: EGFR Mutation-Positive Non-Small Cell Lung Cancer Edition
![]() Pasi A Jänne, MD, PhD 1.25 AMA PRA Category 1 Credits™
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Design and results of the Phase III ADAURA trial evaluating adjuvant osimertinib for early-stage non-small cell lung cancer (NSCLC) with EGFR mutations DR LOVE: Welcome to Oncology Today, EGFR Mutation-Positive Non-Small Cell Lung Cancer edition, a special program focused on recently published and emerging clinical research. This is medical oncologist Dr Neil Love. For this program, I met with Dr Pasi Jänne from the Dana-Farber Cancer Institute in Boston. Besides this audio podcast, there’s also a video presentation component. To begin, I asked Dr Jänne to discuss the results of the ADAURA trial presented at the recent ASCO meeting, evaluating the use of adjuvant osimertinib for patients with EGFR mutation-positive non-small cell lung cancer. So, let’s start out talking about the ADAURA trial because that's certainly big news. DR JÄNNE: Absolutely. DR LOVE: Can you just talk a little bit about the ADAURA trial, what it showed? And the other thing I was wondering if you could clarify, which I didn’t realize initially, was this issue of IB disease. I don’t know. We did for the first time the other day, we were doing a program, it was with Lecia Sequist, and she brought up something I had not heard, which was that IB was not part of the original plan or the original design of this study. That was a supplementary thing. Are you aware of that? DR JÄNNE: Yeah. I think it's not part of the statistical endpoint. The statistical endpoint is in patients with Stage II and III disease. And I would imagine that's done because these are a high-risk group of patients and you’d be able to potentially demonstrate a benefit in that group. But it included, allowed IB patients also to go on the study. And remarkably, there’s a benefit there as well. So I think there have been prior attempts to give adjuvant EGFR inhibitors in patients with lung cancer. Now, of course, that was given or done at a time when we gave EGFR inhibitors to a broader population of individuals based on immunohistochemistry or FISH, etc, which we don’t do anymore. And there, in the adjuvant setting, although the curves were significantly different for disease-free survival, patients who got adjuvant/erlotinib, statistically they were not different and there was no improvement in overall survival. Now that was a subset analysis. ADAURA, of course, is a dedicated trial to EGFR mutant patients. I think the other difference is that taking adjuvant erlotinib for a couple of years or 2 years, which is what the RADIANT trial did, can be tough and it's tough to do that. The ADAURA trial went on for 3 years. You’re taking on a more tolerable therapy. The data was unblinded by the IDMC because of the benefit. The curves separate out significantly in early — really, in all subsets, but most significantly in the Stage II and III patients. So I think this has clear therapeutic impact for our patients. I think we had not routinely done EGFR genotyping for patients with early stage disease because, unless they’re going on a trial in case, which is on this part of the trial, but we’re going to start doing that. This is a significant impact. And when you also think about a drug like osi that can penetrate the brain which is a site of recurrence, that can be prevented, there could be more to come here. And I think this is going to be practice changing. DR LOVE: So, yeah. I guess the thing I was thinking about in terms of the IB, because some people kind of made a big deal about it or whatever. But I would guess that maybe there are not enough patients to be really precise in that subset about what the actual benefit is. I could be wrong about that. But you tell me. DR JÄNNE: And I think the other issue is that surgery alone does quite well for IB patients. And in some IB patients, we give adjuvant chemotherapy; some we don’t. But, overall, they can do well. But it looks like they can do even better if they get adjuvant osimertinib. And again, I’m finding that will impact practice here. The hazard ratio was still .5 for the Stage IB patients, which is remarkable. DR LOVE: I guess one of the things it brings up is whether or not there’s a fundamental difference in the biology of IB. And if you think about other adjuvant situations the lower risk, you need more patients to find exactly what the benefit is. So that was what I was kind of wondering maybe could that have been what was going on? DR JÄNNE: Could potentially. I mean I think one of the things that when you look at the control arms there, and these are patients that come from experienced centers, have had experienced surgeons, not all of them but a significant number of them received adjuvant chemotherapy, the recurrence is pretty high. And I think it just highlights to all of us that this is a disease where, even for early stage patients, we really need multi-modality therapy in our effective therapies to make an impact. DR LOVE: Well, also, it comes out of, sort of the perception in terms of what you’re actually doing. Clinical implications of the ADAURA trial results for the use of adjuvant osimertinib for patients with Stage IB-IIIA NSCLC with EGFR mutations DR LOVE: So, in this situation, what would you say, based on with and without chemotherapy, would be the risk of relapse for IB patients? DR JÄNNE: It's probably 20%, 25% and chemotherapy adds a few percent to that. So it's a reasonable number still. DR LOVE: I mean that's my point. That kind of recurrence rate in breast cancer will get you hormonal therapy. Granted, osimertinib is not exactly hormonal therapy but it's not chemotherapy. So a lot of general medical oncologists would look even at 50% if you believe that, and say that's a substantial benefit. DR JÄNNE: Yeah. And I think we’ll see this translate into clinical practice, even for the IB patients. DR LOVE: Yeah, I would think so. And I am curious what you, putting aside reimbursement issues, which have to get ironed out I guess, but just from a purely risk-benefit point of view, how would you think through the decision of Stage III, Stage II and Stage IB? DR JÄNNE: Well, I think in all circumstances one would certainly think about osimertinib there in the adjuvant setting. I think in Stage II and III patients, where we would still give individuals chemotherapy, I don’t think this supplants chemotherapy. I think this is in addition to chemotherapy. We know that chemotherapy has a survival benefit. We don’t know that for adjuvant osi yet. And we don’t know that you’re treating the same population with more therapy in osi. So I think for the time being the plan would be adjuvant chemotherapy, adjuvant osimertinib in those patients. One thing that isn’t completely addressed here is what do you do for somebody who needs radiation? And these are patients that were not able to receive radiation. How does that play into this? I think we’ll need more additional studies to figure that out. DR LOVE: What are you going to do in your own practice as it relates to radiation? DR JÄNNE: Well, it depends a little bit on what happened pre-op. Sometimes we end up using pre-op chemotherapy and radiation depending on what’s the extent — certainly for Stage III patients we end up using pre-op chemotherapy and radiation. I do think that given the magnitude of benefit here we’ll still administer osimertinib afterwards, especially in somebody — depending on the downstaging, even if you were downstaged from a III to a I, I think you still get adjuvant osimertinib. I think the benefits are so big here that I think it warrants treatment. DR LOVE: So, of course, we always ask people all the time in general what do you do in various situations. And one of the things that I’ve been really surprised at is when we poll general medical oncologists, not investigators, when we poll general medical oncologists and say what do you think your strategy is going to be for a patient with a Stage II or III EGFR-positive disease? The most common answer is osimertinib and not chemo. An answer that no investigators give, but it is actually the most common answer right now and maybe we need to do education. But I’m just saying, that's the way they’re answering right now. DR JÄNNE: Yeah. I think it's difficult to remove therapies that improve survival. And I think that would be my counter argument to that, that we don't know osi improves survival. We hope it improves survival. We’ll wait and see. We know chemotherapy does. Yes, it has side effects, but I think if you’re going to take every possible precaution to decrease recurrence and try to improve survival, I think that has to include chemotherapy. DR LOVE: I think what oncologists are looking at is the hazard rate and the fact that the hazard rate for chemo is not that great, particularly compared to — like I understand all the science, I’m just telling you that's kind of the way people are seeing things right now. I don’t know if it's right or wrong. DR JÄNNE: I agree. And I think when I see patients who, let’s say non-EGFR mutant patients, and we have a discussion about adjuvant chemotherapy, and we discuss what is the advantage, what do you gain from adjuvant chemotherapy, there are people who say no. They say I don’t want it. There are ones who look at the numbers and say I want to do absolutely everything to improve my outcome and there are others who’ll say, that's not that great. Why should I take the toxicity? So you definitely hear it both ways from patients. DR LOVE: And of course, I think, in the current COVID era, people are even more anti-infusional therapy, anti-chemotherapy. But again, there’s also the science that has to be considered. What about this issue about survival? Let’s just say that it turns out that there’s no survival benefit whatsoever. Now, yes, some patients are going to be treated who don’t need to be treated, but there are also going to be a bunch of people who are going to be walking around at least feeling free of disease, without brain mets, without problems. Do you think that the magnitude of the benefit here really would make a treatment an option even if there wasn’t a survival benefit? DR JÄNNE: I think so. And I think it's different than we’ve seen in the past and different than, for example, in the erlotinib era. The brain is a big one, right. Treating brain metastases, which, for people who had local therapy for early stage cancer and developed subsequent brain metastases, that can be a devastating complication. If that same paradigm that we saw in the first-line systemic trial of decrease in the cumulative incidence of brain metastases happens in patients with early stage lung cancer, that's a significant clinical benefit for individuals, even if it didn’t improve survival. Perspective on the duration of adjuvant therapy with osimertinib DR JÄNNE: The other question one can start to ask now is that the 3-year time period was picked semi-arbitrarily I would say, could one continue these therapies for longer if they’re keeping things at bay. So that's one thing to address. The second thing is that we now have technologies, the cell-free DNA technologies are getting to the point that you’re going to be able to find it from people who have undergone surgery. And so, could you potentially get to a scenario where you have an EGFR mutant cancer, you have cell-free DNA post-surgery, you are certainly at higher risk of recurrence. And if you don’t, those are people who can take osi or take it for longer periods of time, or whatever — there is some sort of risk-adapted strategy there as well. So I do think this is to come. And I think what we learn from EGFR mutant lung cancer will be an informative example for the other targetable patient populations to come. DR LOVE: You were mentioning the issue of duration of adjuvant treatment, as you said it's 3 years. I don’t know how you visualize the mechanism? Is it cytostatic? I hesitate to draw the analogy of tamoxifen, but at least clinically you have the situation where it started out being 1 year, then 2 years, then 5 years, then 10 years. Do you think that it's possible we’re going to run into that kind of model with lung cancer? DR JÄNNE: Potentially. I mean I think one thing we learned studying the adjuvant erlotinib scenarios is that if patients — let’s say you recurred after a few years after erlotinib. So you completed 2 years of erlotinib and 6 months post-erlotinib, you recurred. Those patients most of time re-responded to erlotinib. And so, what was happening is that you were suppressing the growth. It was a cytostatic effect. Once you come off drug you now have a chance for the cancer to grow. Now it's visible. You treat it and it shrinks. In contrast, if you develop recurrence during drug, then you find the resistance mechanisms that are there. So I think these two are points that we’ll need to learn from the ADAURA trial patients once they have completed therapy and if they recur, do they re-respond? I think those are pieces of data that could lead us to that same direction, as you mentioned, that we’re going to start to be questioning or asking the question about duration. And again, for tolerable drug, one can start to ask those questions that was initially harder — it was a harder thing to ask with erlotinib. DR LOVE: So another sort of conceptual question, when you look at the history of lung cancer treatment in terms of targetable treatments, we went through all the stuff related to EGFR, with the IPASS study and other studies, trying to prove it was better than chemo. We did some of that with ALK. And then after that, we just started bringing stuff into the first line when you see a response rate of 50- or 60%. Do you think that that model is going to apply in the adjuvant setting? Or do you think we’re going to have to repeat all these adjuvant studies again? DR JÄNNE: You mean take the most effective therapies and do all the adjuvant studies again? DR LOVE: No, I’m just saying — I say start treating people now. You have RET, treat them adjuvantly. DR JÄNNE: Right. Yeah, do we have to do the adjuvant trials for every single oncogene, no I don’t think so. And in fact, of course we haven’t really been — when you get to small enough patient populations, so take ROS1 for example, right, highly effective therapies. A few different agents approved. Just not enough patients to even do the front-line comparison versus chemotherapy, nor is that really a trial where you have equipoise between the 2 arms because you have such highly effective therapies. So I don’t think we need to do that all in the adjuvant setting. The other approach, of course what’s being done is in the neoadjuvant setting in this Lung Cancer Mutation Consortium, where if you find a targetable alteration in the preoperative setting, you treat individuals with a genotype directed therapy and can look at the response. So that can certainly provide data in that early stage setting. But it would be I think, impossible to do the adjuvant studies in all of the targetable patient populations. Now, maybe some places in the world would require that to be done. But I think the practicalities are impossible. Therapeutic approach for patients with locally advanced NSCLC with EGFR mutations DR LOVE: So another issue is now you have some really interesting data in the adjuvant setting. Of course, we’ve had data in the metastatic setting. But in between, you have locally advanced. And there were trials looking at using targeted therapy, you mention that. But right now there’s really not much that you can do and yet, it makes a lot of sense — downstaging people before chemoradiation. Just in some way, I mean if you’re going to use it for Stage III and II, it seems like somehow you ought to incorporate it. Do we need trials for all that? DR JÄNNE: I think one area where it would be nice to look at that is in the borderline surgically resectable patient that you couldn’t give local therapy or surgery and you have an effective strategy with an neoadjuvant targetable therapy approach that you make that individual operable. There have been trials — there was a trial that looked at neoadjuvant erlotinib versus placebo or neoadjuvant crizotinib versus placebo following chemotherapy and radiation, but closed due to accrual. Now the genotyping, we struggle with genotyping in the metastatic setting, we struggle more sometimes with genotyping in the early stage setting or the locally advanced disease setting. And so I think as we get better at doing genotyping from blood, from tumor, and faster at doing it, maybe we can reintroduce some of these concepts. Because that delay is often what’s a problem if you have locally advanced lung cancer and it's going to take you 3 weeks to genotype, then enroll in a trial and go through those trial eligibility, nobody is going to want to do that. You want to get treated. And so, you need to find that answer relatively quickly in order to implement this approach in the real world. DR LOVE: Do you think for a patient with locally advanced disease who, say, goes through chemoradiation, they go through durvalumab, is there any role for using targeted therapy after that? DR JÄNNE: Well I think it's worth asking. There is another EGFR inhibitor trial called the LAURA trial, which is a chemo/RT followed by osi for EGFR mutant patients. But I do think it's a question worth asking. We don’t cure that many people with chemotherapy and radiation. And I think if we can add additional agents to that, again one would have to then figure out what to do with the durvalumab in that scenario. Do you give it, or you do not give it? Do you worry about interactions, etc. But, we ought to be moving these concepts from the metastatic setting more into the early stage setting. And we’re starting to see those benefits in the ADAURA trial and some of these neoadjuvant trials. But I agree with you, we need to continue to do that more. And as such, lung cancer is certainly becoming a multidisciplinary disease at all levels and we need to incorporate, I think, the best tools from all disciplines. Clinical care of patients with metastatic NSCLC with EGFR mutations who experience disease progression while receiving first-line osimertinib DR LOVE: So let’s talk about the management of metastatic EGFR disease. And we’ve talked a lot about obviously, first-line therapy in terms of osimertinib. And I guess the question is out there on the table right now about adding an anti-angiogenic. Do you think that that's something that would be reasonable to do outside a trial setting? DR JÄNNE: I don’t know that I would do it outside a trial setting yet. I’d like to see a little bit more information on that. It's certainly being tested at the moment. There’s been some data on osi and bev that has been published. It looks not that dissimilar from osi alone. Whether we will see that same sort of delta when adding an angiogenesis agent to osi that we saw with erlotinib, I think is also remains to be determined. But we know we don’t cure anyone with front-line osimertinib therapy. And I think that is the opportunity there. And I think we don’t totally know either where is the best opportunity. I think frontline is one opportunity, right. Do you develop a front-line combinatorial strategy and is that the best place to implement that? Or we do front-line osi and then develop that strategy at the time of progression? I think these are all questions that need to be answered through studies and many of them are ingoing. DR LOVE: So for practical purposes out in the community and people have disease progression on osimertinib all the time, often after they’ve had a response. Can you just walk through in your own mind what you recommend in that situation outside a trial setting, first in terms of tumor markers and rebiopsy and then in terms of treatment. DR JÄNNE: Sure. I always recommend people to get a rebiopsy or resampling of their tumor. I like doing tissue when feasible because I can get histology. I can see if there’s small cell transformation, which sometimes happens, which you don’t want miss because that leads you to a different scenario. You usually, if you can get histology, you can do sequencing and you can do a more broadly comprehensive analysis. I realize it's not always practical. And so plasma is the other alternative that is seen. So, there are a few targetable ones, that outside of a clinical trial one can target after front-line osi, and that is the secondary EGFR mutations, the C797S and others that can happen after front-line osi. Those are populations that can be sensitive to prior generation EGFR inhibitors, even erlotinib or afatinib. And finding that is important because that can lead the individual down — a treatment with those paths. The second is MET amplification and, although, there are clinical trials looking at MET inhibitors in combination with osi. We also have capmatinib and crizotinib, both of which are great MET inhibitors that are commercially available and can potentially be used in that combination setting. Once you get to some of the rarer ones, I think there you’re mostly talking about clinical trials. I think you can’t target. Find a RAS mutation you can’t target. I think there, we’re talking about chemotherapy outside of a clinical trial. So that's how I tend to look at it. I like histology. I try to find the ones that you can target, either with commercial agents or as part of a trial. And if I don’t have any of those, chemotherapy is the option. DR LOVE: What about BRAF? DR JÄNNE: BRAF. Yeah, BRAF mutations are seen, BRAF V600E mutations are seen certainly as a response — or as a resistance mechanism to osi. It gets a little complex there because you would need 2 agents to treat the BRAF and then osi, so now you’re treating with 3 drugs. I’ve personally not done that combination myself and I worry a little bit about tox of giving all 3 together. But conceptually one could simply do that. Development of resistance to EGFR inhibitors; efficacy of trastuzumab deruxtecan in patients with NSCLC and HER2 alterations DR LOVE: Can you talk a little bit about the biology of resistance? DR JÄNNE: I think one thing we’ve learned from studying resistance, it's messy. It's not a single thing. And I think that just tell us that cancers can evolve into multiple different directions. And trying to understand that direction may be helpful therapeutically. Now, HER2, or Erb2, which is where the trastuzumab deruxtecan comes into play, HER2 amplifications certainly are a resistance mechanism to EGFR inhibitors as such. EGFR mutant cancers often express low levels of HER2, but it's the amplification that's the resistance mechanism. And then HER3, the other family member, is expressed but not part of a resistance mechanism. And again, in the situation of a HER2 amplification, you could potentially target that with a HER2 targeted therapy, such as trastuzumab deruxtecan. DR LOVE: So, yeah, but you said amplification. And when I think of trastuzumab deruxtecan, I think about mutations. So you want to explain that part? DR JÄNNE: Of course. It’s approved for breast cancer and gastric cancer where it's based on amplification. But no reason to believe it wouldn’t work in lung cancer for HER2 amplified patient. That hasn’t been tested. It's in the HER2 mutants that it has been tested and has a high degree of activity. In fact, in that trial, there’s a second arm of that trial that's ongoing based on patients who express HER2 by immunohistochemistry, and the assumption would be that some of those patients would also have HER2 amplification leading to high HER2 or IHC expression. But there are many ways in which you can develop resistance. And I think it gets more challenging when you go to subsequent EGFR inhibitors. And I think the heterogeneity is such that it makes, I think, treatment challenging. And I think we need to continue to find and develop new ways of trying to prevent it or treat it. Mechanism of action, activity and tolerability of the novel HER3-directed antibody-drug conjugate patritumab deruxtecan (U3-1402) DR LOVE: So, you talked about a couple of newer therapies that sounded really interesting. One, patritumab deruxtecan, sounds like trastuzumab deruxtecan, but I guess it's a different molecule. But what exactly is U3-1402? DR JÄNNE: So this is kind of analogous situation as the trastuzumab deruxtecan, but instead of targeting HER2, it targets HER3. And this is expressed in EGFR mutant — almost all EGFR mutant cancers have HER3 expression and it's found elsewhere as well, but predominantly in EGFR mutant lung cancers. And here the idea is that you’re using this protein that's in the tumor cells as a delivery vehicle. So the patritumab deruxtecan, the U3-1402, it's a HER3 antibody conjugated to topoisomerase compounds. And what happens is that the antibody is administered. It binds the HER3 receptor on the surface of the EGFR mutant cells. The receptor gets internalized along with the drug. It ends up in a part of the cell, like the lysosome, and it cleaves the drug. So now the drug, the topoisomerase inhibitor that was bound to the antibody is free and it can selectively be delivered to the tumor cells and even to the adjacent cells there. And as such, you have sort of targeted chemotherapy delivery into the tumor cells. And I would say antibody drug conjugates have been around in other diseases, hematologic malignancies, breast cancer, but it's a relatively new type of therapy in lung cancer. And I think we’re going to start to see more and more of that as the technology gets better. And I think it's the clinical examples support that. So the U3-1402 or the patritumab deruxtecan, there has been clinical activity in patients that have developed resistance to EGFR inhibitors and chemotherapy. Obviously, with the trastuzumab in HER2 mutant lung cancer, trastuzumab deruxtecan. So I think we’ll continue to see this as another tool or another therapy in the arsenal against lung cancer, against various subtypes of lung cancer. DR LOVE: So, again, naïve question, but I’m sure a lot of people are asking themselves, which is the issue of pneumonitis in these patients. I know it's a completely different drug, but has the same last name, so to speak. But what do we know right now about tolerability? Is there pneumonitis with this drug? DR JÄNNE: Yes, you can get pneumonitis with this drug as well. And I think one of the challenges with pneumonitis in general, not limited to this particular drug, is that it tends to be a diagnosis of exclusion. And we looked for progressive cancer, congestive heart failure, infection. If we don’t find anything, we call it pneumonitis. Sometimes our Radiology colleagues call small things that they see on CAT scans pneumonitis and now you’ve got this radiology report that says pneumonitis, and everyone is alarmed. And even though it's something small in a CAT scan only and the patient’s not symptomatic. So we certainly have a heightened awareness of pneumonitis from drugs that give pneumonitis: TKIs, PD-1/PD-L1 inhibitors and antibody drug conjugates. I would say we don’t have a perfect, uniform workup or a strategy of what to do for individuals besides stopping the drug and treating it. We know very little about should you retreat that individual? Should you retreat them with steroids? Should you cut the dose? What should you do? And I think you’re often faced with these challenges. You may have an effective therapy, tumor shrinking, but you’re develop pneumonitis, so what do you do? And I think these are things that we really need to get more clarity on moving forward. And the initial trials often don’t do that. It's subsequent studies that will give clarity to this. DR LOVE: And of course, the other consideration comes in with pneumonitis nowadays is COVID. When you said the radiologist looks at something and calls it, in thought the next thing you were going to say if they call it COVID because I hear a lot of stories about that. I don’t know if that reflects your experience as well. DR JÄNNE: Yes and no. I think the other thing that happens is that we get called, a patient is coming to clinic and their coughing, of course they have lung cancer and their coughing, but, because of COVID, they’re sent for COVID test. Or they have fevers because of fever neutropenia, and they’re sent for a COVID test. So, yes, we need to rule it out. Absolutely. But I think, especially in the thoracic patient population, there are some overlap of symptoms and one needs to certainly separate those out. Not always easy to do. DR LOVE: Yeah. Now I’ve got 3 different groups of investigators giving me input about the pulmonary toxicity, the GI people, the Lung people, and of course the Breast people. I hear some people saying, no, this is not any different than other pneumonitis, etc. I know it's early days. But do you have any sense about this? Do you think this is going to be worse than other types of pneumonitis that we see? I’m talking about trastuzumab deruxtecan now. DR JÄNNE: I don’t think so. And part of it is because we’re still fairly early on. We don't know necessarily again retreatment? Does it make it worse? Does it predict for subsequent pneumonitis with other therapy? So let’s say you develop pneumonitis with trastuzumab deruxtecan and you go on a TKI or a PD-1 inhibitor, are you more likely to get pneumonitis? There’s still pieces we don’t completely understand there. Of course it worries all of us. Pneumonitis worries all of us and we want to try avoid it and figure out strategies for it. One way to figure out strategies is understanding who’s at risk for pneumonitis. And I think we don’t completely understand that either. In the EGFR TKI space, of course there is some increase in Asian patients, particularly Japanese Asian patients. We don’t know that that same is true for an antibody drug conjugate. We don’t know that prior radiation or lung injury of other type is necessarily a risk or not. I think there’s just so many unknowns, which is partly part of the frustration I think and part of the challenge of when we try to figure out what to do for these patients if that happens. DR LOVE: Well, I’ve got to say I find it encouraging just to look at this waterfall plot of people who had progression on osimertinib, maybe it's early days, and I know it's a different mechanism, but it's great that there’s a non-chemo thing that had some excitement, I think. Clinical experience with patritumab deruxtecan for patients with metastatic EGFR-mutated NSCLC who experience disease progression while receiving osimertinib DR LOVE: Have you had patients receive this drug? DR JÄNNE: Yes. Yes. DR LOVE: Have you seen any useful responses in patients who progressed on osimertinib? DR JÄNNE: Yes. Definitely seen responses or patients who have had prolonged, stable disease. But definitely seen responses and good responses as well. So I think it has activity and I think one of the things we would like to figure out is how to make that waterfall plot look even better. Could we do things to enhance that efficacy? Or what can we learn from this initial clinical experience to do that? And I think these are some of the things that we're trying to think about. DR LOVE: And I’m sure somebody’s thought about the idea of bringing it up front and combining it with osimertinib? DR JÄNNE: Yeah. I think any time we have an effective therapy I think you want to think about the strategy of bringing it up front. And of course, there, the balance is tox versus benefit. Median PFS is 18.9 months with osimertinib and you’d like to extend that. But you’d like to be doing it in such a way that it's tolerable. And so there, I think you have to do the test, don’t get me wrong, because if you can improve outcomes great. But you just have to figure out what the balance is. DR LOVE: What do we know right now about the tolerability issues with this agent, patritumab deruxtecan? DR JÄNNE: I think nausea in the early phases of the trial was an issue and I think that that's hopefully better now with better antinausea management. And bone marrow toxicity, still you see some thrombocytopenia and some leukopenia from there as well. So, not completely understood why it has to mean that the conjugate has to come off in order to have bone marrow toxicity or it has to somehow enter cells, megakaryocytes or whatever. Still being investigated. But those are two toxicities that have been seen. DR LOVE: We’ve been hearing about some interesting ophthalmic problems with antibody drug conjugates in other cancers, including bladder cancer. I’m guessing you don’t see that here at all? DR JÄNNE: I think it has to do with the conjugate. So one of the unique features of this conjugate is that it's a topoisomerase conjugate. In most other antibody drug conjugates are tubulin conjugates. They’re MMAE or maytansinoids, or other things, and there, you can see eye complications. It hasn’t been an issue here. So it may have to do with what you’re conjugating it with more than anything else. And I think as we learn more about this group of drugs in general, one could think about conjugating with all kinds of different things. And there’s a whole field of chemistry, of how to make these linkers and conjugating that I think is coming to light, hopefully now as more of these agents get approved and we learn how to use them clinically. DR LOVE: I can remember a time right before when the checkpoint inhibitors sort of it, there was a lot of interest in antibody drug conjugates. And then, once the checkpoint inhibitors came about, it seemed like, at least from my point of view, I wasn’t hearing as much about it. Now we’re hearing more about it. I don’t know, does that seem to be what you’re seeing? DR JÄNNE: Yeah. I think in some of the earlier ones, the toxicity was an issue. And I think it limited the development of many of those. For example, one that we’re familiar with in the thoracic field is Rova-T. DR LOVE: Right. DR JÄNNE: And that had activity but had a lot of toxicity, presumably because the conjugate came off in non-tumor tissues and you were seeing pleural effusions and all kinds of other things that happen there. And the idea is good. The targets good. It's just to figure out a way, can we now develop a strategy that wouldn’t have that same toxicity? Targeting EGFR exon 20 insertion mutations in patients with NSCLC DR LOVE: Can you talk about how you visualize how exon 20 insertions work? DR JÄNNE: So I think one thing that's a challenge with exon 20 insertions is that there’s many of them. And they alter a region of EGFR that turn it on, just the like the other mutations do. Now, one of the things that happens with L858R or exon 19 deletion, the common EGFR mutations, is that the ability to sort of inhibit the receptor compared to the wild-type receptor is much easier for the L858R and the exon 19 than wild type, meaning the drugs are much better at those than the wild type. And you don’t see that same sort of window for the exon 20 insertions. So really to inhibit an exon 20 insertion you almost have to be at a level where you inhibit wild-type EGFR and you don’t have that sort of therapeutic window. And that's why, I think one reason, at least, it's been difficult to develop drugs for, and the second is this heterogeneity. But I hope these new approaches work where there are actually specific designs of drugs against exon 20 as opposed to what we’ve done in the past, like the afatinib example of repurposing something that you know and hoping that it will work on exon 20. And sure, that gives you some degree of activity, but if you now specifically design something to go after exon 20, I’m hopeful that that approach will lead to a more effective therapy. And whether you can inhibit all the variants of exon 20 or not, or the major ones, we’ll wait and see. But the fact that there are a few entries in there and several of them moving forward, I think gives us hope that there will be an approach for that patient population. DR LOVE: So I mean is it correct to view exon 20 as another activating mutation? Same phenotype, non-smoker. Maybe doesn’t respond well to PD-1. It’s just we don’t have good agent for it? Is that the way you think about it? DR JÄNNE: Yeah, I would think about it that way. Same basic biology. Same basic phenotype. We just don’t have a drug. Our drugs just don’t happen to work for this one for so far. DR LOVE: And again, do you delay using PD-1 agents for that reason? DR JÄNNE: I typically do. Typically, in somebody who has an exon 20 insertion, I would give chemotherapy alone and not a PD-1 necessarily because of that. And I don’t think that the EGFR mutant patients in general, respond very well, regardless of what EGFR mutation you have to PD-1 or PD-L1 inhibitors. Even in the situation where you have very high PD-L1, you can see responses, but that durability tends to be less than what you see in other genotypes. Biologic rationale for and available data with mobocertinib (TAK-788) or amivantamab (JNJ-6372) for the treatment of metastatic NSCLC with EGFR exon 20 insertion mutations DR LOVE: So let’s talk about a couple of these agents. They look really exciting. Amivantamab. Can you talk a little bit — it's a very interesting looking compound. Can you explain what it is and what we know about it? DR JÄNNE: Yeah. So it's sort of a 2-armed compound, 1 arm binds EGFR and 1 arm binds MET, which is a resistance mechanism. And you would sort of think, well, why would this compound work in an exon 20 insertions to begin with? But in the clinical development, in early clinical development of when this agent was tested, they treated a few exon 20 insertion patients because it was a trial for patients that had failed prior EGFR TKIs and saw some responses. And subsequently, did an additional cohort and has activity and now breakthrough designation by the FDA. And what happens here is that unlike a small molecule, is that you’re binding the outside portion of EGFR, whether or not has exon 20, and MET, and once it binds the antibody sort of internalizes the receptors from the surface. And it's that internalization that takes the receptor from being an active receptor and making it essentially inactive receptor, brining it inside the cell. And since these cancers are so dependent on EGFR, if you take away the engine for this cancer, then you can see shrinkage, which we’re seeing in these situations. So, it's an interesting approach. And I think perhaps not something that one would have predicted preclinically, but clinically there was a signal and certainly continues to be a signal there. And again, the trials moving forward with the breakthrough designation from the FDA. DR LOVE: Again, just trying to understand how these things work, we hear about different bispecific antibodies in leukemia, blinatumomab is an example. Is this a similar technology where we’re trying to juxtapose 2 things? DR JÄNNE: Yeah. Or it’ s not really juxtaposing because they’re present on the same cell. It's just that the antibody should work better in a cancer cell that has both EGFR and MET expression because binds both at the same time versus something that just has EGFR or just has MET. So that was the idea I think behind the development of that. And it's clearly active. It's got activity in the osi resistant patient population as well because of that. And is being developed in that patient population as well. DR LOVE: So the other agent you talked about, which is equally fascinating, was mobocertinib, TAK 788. What’s that? It's a TKI I guess? DR JÄNNE: It is a TKI. And this was one that was essentially based a little bit on osimertinib. And subsequently developed with the idea or knowledge of exon 20 insertions to make it more selective for an exon 20 mutation compared to the other mutations. So this is, I think, an example of what I mentioned earlier, we’re getting into the situation where we’re not just repurposing drugs for exon 20 insertions, we’re actually proactively developing one and this fits into that category. So, based on osimertinib, but with changes to allow it to do that. And here, too, activity in the patients that have progressed on prior therapies. And this is now in a Phase III trial as first-line therapy for our patients with exon 20 insertions compared to chemotherapy in a Phase III trial. So, an exciting development there too. Also has FDA breakthrough designation. Hopefully one or both of these will make it and it will be wonderful to have 2 options for patients. And one can start to ask questions, well why not give the antibody and the TKI together? And I think these are things that we can continue to study in the future. And there are many others in earlier phases, still in Phase I clinical development. But nice to see that for this patient population. DR LOVE: What about tolerability issues with both of these drugs, mobocertinib as well as the prior one that we were just talking about? DR JÄNNE: A little bit of a different side effect profile. We think of EGFR inhibitor toxicities, we usually think about two toxicities. We think of skin toxicity and gut toxicity. With the mobocertinib, it's more balanced towards are more skewed towards gut toxicity, so diarrhea, loose stools, more of an issue there than skin toxicity. With the amivantamab, it's more of a skin toxicity as opposed to diarrhea. There, you also have some infusion reactions because it's an infusional agent. So, just a slightly different balance in toxicities. DR LOVE: I know the initial drugs we heard about were not very well tolerated. Is this sort of in the same camp or maybe better tolerated? DR JÄNNE: Initials drugs? DR LOVE: To target exon 20. DR JÄNNE: Some of the earlier drugs, for example, poziotinib, which was tested, which is kind of an afatinib analog, that had a lot of skin toxicity. I don’t think we see that degree of skin toxicity on the amivantamab. But any time you have an antibody that binds the outside portion of EGFR, that's going to be the same whether you have a mutation or not in the kinase domain. And so, you are at risk of getting wild-type EGFR toxicity and skin toxicity. It's different you can more selectively bind the internal part where the mutation is with a drug compared to wild type. There, you can potentially develop that therapeutic window. But it's harder to do for the antibody. DR LOVE: How do you figure out whether something theoretically would be, for example, sensitive to something like a trastuzumab deruxtecan? Any alteration that you would see theoretically, or it has to be something specific? DR JÄNNE: I think one can of course, model some of these things in preclinical models. But I think the trastuzumab deruxtecan one is an interesting example because many of these agents work well in cancers that express HER2, for example, of higher levels. And HER2 mutant lung cancers are not one of them. They typically don’t have the 3+ HER2s. They may be the 1+ or 2+. And it may be that when the antibody binds and again it internalizes it, since it's such a critical component to the growth of the cancer that that is what leads to the higher efficacy, or maybe these mutant HER2s just internalize faster and you’re bringing the drug in faster. There may be something biologically there that's a common feature to having a mutation versus not compared to the specific mutation. I don’t know that we completely understand why the efficacy is what it is the HER2 mutant population. We’re happy about it because we don’t have effective targeted therapies for that patient population. But I’m not sure we completely understand the mechanisms. And from the trial that was presented at ASCO, we’re missing a lot of correlative science information to understand to figure out are there subpopulations there that respond better than others? And what are those determinants? And, hopefully, that will come with additional data.
Novel agents and approaches under investigation for patients with NSCLC and EGFR mutations; ongoing ALCHEMIST trials evaluating available and investigational drugs for early-stage NSCLC with EGFR and ALK mutations
DR LOVE: Any other agents or strategies, particularly as it relates to EGFR, but targeted therapy in general in lung cancer that you’re excited about? DR JÄNNE: Well, I think for EGFR, for example, I think continuing to think about ways to target EGFR that are not susceptible to the same mutational mechanisms or resistance mechanisms, are things like osimertinib. So on the preclinical side, there are what are called allosteric EGFR inhibitors that bind to a different part of EGFR where osimertinib doesn’t bind and can be effective in osimertinib resistant models. People are developing next-generation EGFR TKIs that can overcome or be used in these triple resistant mutations. So I think that there continues to be activity there. Finding different types of EGFR inhibitors or degraders of EGFR. There’s a whole field of chemistry of degrading the target by linking, in this case, EGFR to a degrader molecule and you can degrade EGFR. And maybe that's an alternative strategy. So I think there still are approaches to go after validated clinical targets with novel therapies. And I do think that that's one approach. I do think the other approach is to ask how can you make a good drug work better, right? How do you make a drug that gives a high PFS, how do you make it work better? What do you add to that to increase the initial efficacy? Or, how do you selectively treat that residual disease that happens? I think these are areas where we still have opportunities to not only understand the biology, but understand how to turn those into therapies. And so, that may involve adding a second EGFR inhibitor. It may involve something completely different. And I think the biology will tell us that. DR LOVE: Any updates from the ALCHEMIST trial? DR JÄNNE: It's ongoing. Of course, the treatment arms have not completed enrollment yet, which are the adjuvant erlotinib and the adjuvant crizotinib. And I think this is a little bit of a reflection of — maybe a good reflection of what happens in the field of lung cancer in that things move so fast, which is a good thing for patients, that the ALCHEMIST trials, those agents that are being test are, perhaps, not the ones that we would use today if someone was diagnosed with advanced disease and so why are we testing them in the adjuvant setting? And it just takes time for these types of studies to be conducted. And hopefully, we’ll provide the proof of principle of what to do. I will say the ALCHEMIST trials are adding additional arms. There is a chemo/pembrolizumab arm being added in the adjuvant setting as well. And I think for us to ask the question now, what can we learn from adding adjuvant chemo/PD-1 inhibition. Does that have the same potential benefit as in the metastatic setting? So we’ll continue to add arms to that to ask questions. DR LOVE: What’s the likelihood in terms of seeing some results from this study, particularly as it relates to — I’m not sure, I’m guessing there are other trials looking at adding chemo and checkpoint in the adjuvant setting? DR JÄNNE: Maybe, I’m not a hundred percent sure. There was a single-agent nivolumab adjuvant arm which completed enrollment. This one will be chemo/pembro. I think that one of the challenges is the time here. How long will it take to find the results? And I think you saw that with adjuvant chemo/bevacizumab trial. I think by the time that information became available in the adjuvant setting, we had moved away largely from chemo/bevacizumab in the metastatic setting. So, I think this is one of the challenges in the adjuvant era, and how do we develop better approaches? I think what’s been done in breast cancer by using neoadjuvant as a way to stratify potentially effective therapies that you use in the metastatic or adjuvant setting is something where we need to move to as well or develop risk stratified approaches in the adjuvant setting. Like I was saying, someone who gets surgery and has a positive cfDNA or something you can detect in the blood post-surgery versus not, that's a high risk population and maybe with a smaller sample size, in a higher risk population, you can more rapidly identify or prioritize what therapies work in the adjuvant setting. So, I think those are approaches that we need to move to moving forward so we don’t delay what we give in the adjuvant setting compared to what we give in the metastatic setting. I think the ADAURA trial is a perfect example of that. The impact in the adjuvant setting is huge. We need to do more of this and move more of our agents into that space. |