Welcome to the ISLC webinar, Best of TTLC 2024. I am Dr. Kaushal Parekh. I am a thoracic medical oncologist and assistant professor of oncology at Mayo Clinic Rochester. I will be a presentation moderator today. We will start this activity with some brief housekeeping items. After the presentations have concluded, you may ask any questions by using the Q&A button feature located on your video screen. We will be addressing questions after the three speaker presentations as time permits. This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education, ACCME. The International Association for the Study of Lung Cancer, ISLC, is accredited by ACCME to provide continuing medical education for physicians. The International Association for the Study of Lung Cancer designates the live format for this educational activity for a maximum of one AMA PRA Category 1 credits. Physicians should only claim credits commensurate with the extent of their participation in this activity. All faculty, planners, and reviewers for this webinar today have disclosed their conflicts of interest. This information is provided on the following five slides. Our first speaker today is Dr. Amit Kulkarni. Dr. Kulkarni is a thoracic medical oncologist and assistant professor of oncology at the University of Minnesota. He is going to discuss management of EGFR mutant advanced or metastatic non-small cell lung cancer. I'll hand it over to you, Dr. Kulkarni. Thanks Dr. Parikh for the introduction. Let me share my screen. Thanks to everyone who's joined on a Friday morning. I am very delighted to be here and thank the organizing committee for inviting me to talk today on management of EGFR mutant advanced or metastatic non-small cell lung cancer. The brief overview, we'll start with introduction and then we'll talk about the current treatment options in the first line setting. And then after that, we'll talk about treatment consideration and disease progression, and then we'll look at emerging treatment options in the recurrent setting. So the TTLC 2024 was started by this outstanding keynote from Dr. Christine Lovely, who talked about how EGFR mutation evolved to be one of the biggest breakthroughs in lung cancer. And as everyone knows, EGFR mutation is kind of the poster boy of precision medicine, especially in lung cancer. It is common. It's found in about 15% of patients with non-squamous, non-small cell lung cancer. The incidence is a little bit higher, up to 40 to 50% in Asians. It's more common in never smokers and females. Although EGFR is ubiquitously expressed, the mutations, the activating mutations are predominantly located in EGFR exons 18 through 21, which form the tyrosine kinase domain. This specific type of EGFR mutation is important, as each EGFR mutation can have an impact in the structure of the protein and have different sensitivity to different types of TKIs. For the focus of this talk will be only classical mutations. That's exon 19 deletion and L858R located on exon 21, which comprise about 60 to 70% of all patients with EGFR mutation. Recently, our colleagues, John Hamack from MD Anderson, came up with this paper, which looked at classification of EGFR mutations based on structural impact of each of those mutations. And I think it has provided a new insight in understanding how each of those mutations impact protein function and drug binding. And in this study, they basically classified on four different subtypes, classical like T790M exon 20 loop insertions and PAC mutation. Now each of those subtypes have variable sensitivity to different generation TKIs. Over the last decade or so, the treatment landscape of EGFR mutated lung cancer has been dominated by our EGFR TKIs. We've so far had three generation TKIs. In the US, osimertinib is the most commonly used and there are other third generation TKIs commonly used and approved in other countries. All of these are characterized by increased selectivity to del 19, exon 19 deletion and L858R mutation with better CNS penetration and also activity against the EGFR T790M, which is previously an important acquired resistance mechanism to first generation TKIs. So these are all the randomized phase three studies for third generation TKIs. All of them tested against earlier generation TKIs. Very compatible results amongst all the studies. You can see similar hazard ratios anywhere from 0.44 to 0.46. Obviously, this led to the approval of osimertinib in the US and has been the standard of care for quite some time. So this is the result of the FLORA study testing osimertinib against first generation TKI median PFS of 18.9 months with the hazard ratio 0.46 led to the OFD approval in April of 2018 and has been the standard of care since then. More recently, combination strategies have been tried and there are two trials currently that have been either published or presented FLORA2 and Mariposa. FLORA2 tested combination of osimertinib and chemotherapy against osimertinib alone led to statistically significant improvement in progression-free survival 25.5 months versus 16 months with the hazard ratio of 0.62. This was just FDA approved last month. And Mariposa trial was presented at ESMO last year. This used a combination of amivantamib, which is a bispecific antibody against EGFR and MET, and lasertinib, which is a third generation TKI. This is not yet approved, but we hope that it will be approved in the coming months. This led to also improvement in PFS to 23.7 months versus 16.6 months with the hazard ratio of 0.7. So what are the rationale of combination therapies? So basically, the goal is to combine two active therapies so that we could eradicate what we call persister subclones and hope to change the natural history of disease and decrease the likelihood of TKI resistance. This hopefully leads to an improvement in PFS or improvement in overall survival, more than the sum of sequencing those two treatments. Also, there is a school of thought that giving the best therapy up front will likely lead to the best outcomes because we've seen in previous studies like FLORA that in the second line setting, about 30% of the patients drop off and could not receive any second line treatment. So this is the FLORA2 study. It's a double blind phase three study looking at patients with treatment-naive advanced non-small cell lung cancer with EGFR mutation. Patients were randomized to ozimartinib or ozimartinib with chemotherapy. It was about 500-plus patient studies. The primary endpoint was PFS. So you can see on the right side, the capital Mya curve for PFS, ozimartinib with combination chemotherapy significantly improving progression-free survival with the hazard ratio of 0.62. 29.4 months versus 19.9 months. Remember, it was about 18.4 months in the FLORA. So very similar comparison in the control arm. And this led to about 15% absolute improvement in PFS at two years. Response rates slightly numerically higher in the combination arm. Disease control rates being very similar in the two groups. Now, these are the results of the safety. Now, we can see the PFS benefit comes at the cost of added toxicity. Now, remember, these patients who are getting in the chemotherapy also have to come in frequently for IV infusion. So we have to also consider time toxicity. We are yet to see impact on quality of life. And you can see in the combination arm, higher incidence of those interruptions and those reductions. And any grade 3 adverse events, 53% in the combination arm compared to 11%. So we are almost seeing a five-time increase. And we are also seeing on the top right, you know, the typical toxicities associated with cytotoxic chemotherapy more common in the combination arm. Next study was the first line amivantamib and lasertinib. This is a Mariposa study. It's a randomized phase 3 study. Very similar patient population. This was a 2 is to 2 is to 1 randomization in about 1,000 patients. The patients were randomized to amivantamib-lasertinib combination. I'm going to call it AMILAS going forward. And then ozimertinib and lasertinib were the other two arms. Primary endpoint was PFS. And the comparison here was made between the AMILAS arm to ozimertinib. There was no crossover allowed in the study. Now, one point about this study, which is pretty unique, was this study allowed for or had serial brain MRIs required for all patients on the study. The primary endpoint was PFS. And you can see the combination of amivantamib and lasertinib led to a statistically significant improvement in PFS, 23.7 months compared to 16.6 months in the ozimertinib arm. And if you look at the ozimertinib and lasertinib curves, they're essentially overlapped with each other, suggesting they were essentially equivalent. The benefit of PFS was seen across all the subgroups. Again, this led to about 14% in absolute improvement in PFS at two years. Now, because this study allowed for, you know, frequent CNS imaging, this is looking at extracranial PFS. And in this as well, the median PFS estimates were also improved in the combination arm if patients with CNS only first progressions were censored. OS is still immature, but trending in the right direction. 24-month OS is 74% or 69%. In this study as well, the PFS benefit came at the cost of added toxicity. Again, you see the typical toxicities of EGFR and MET. Of note, the rate of infusion-related reactions is pretty high with amivantamib, especially with the first infusion. And you can see that treatment interruptions and reductions were higher in the amivantamib-lasertinib arm. And one AE of interest was very high rates of VTE seen in the amilaz arm. You can see about 35% grade two or higher VTEs in that arm. So now it's March 2024, and let's say in a few months, we have all of three regimens available. So how do we choose between the regimens? I think patient selection is the key. I think overall thus far, if we have to balance toxicities and outcomes, I think ozimertinib monotherapy may remain standard for most patients, especially the ones with the low-risk disease. And that's one example is on the left side here. You have an older patient with oligometastatic disease, slowly growing, minimally symptomatic, you know, ctDNA negative. I think this is patient appropriate for ozimertinib alone, whereas on the extreme right side, you can see patients who are potentially high-risk patient, high symptom burden, diffused in the brain, ctDNA remains positive. I think this is a patient where one could consider escalation of treatment. I think we all agree that we need to do an individualized approach based on biomarkers for risk stratification. And we hope in the near future to use things like ctDNA clearance, looking at co-mutation status, met expression, which has, in the previous studies, have been shown to be a good predictive marker for amivantabine. So once patients experience progression, what are the treatment considerations? Now, we know that the first treatment resistance mechanisms following first-line treatment with third-generation TKI, you can have a plethora of them. You can have on-target treatment resistance mechanisms, off-target. And one thing to consider is histologic transformation. So typically, at progression, if feasible, should try to do a tissue biopsy, especially if there is a clinical suspicion of histologic transformation. We could potentially use ctDNA in patients where tissue biopsy is not feasible. And the novel therapies at disease progression have focused on addition of agents to TKIs. However, in the next few months, we'll likely see several approvals for first non-TKI EGFR targeted therapies. So now you have these three options. If you kind of stack all those three options with PFS, one next to each other, and the potential treatment options after that, you can see more or less most of them end up having at the end of second-line setting very similar kind of PFS. But I think optimal sequencing of these drug is not known. I think it needs to be determined. I don't think none of the studies actually systematically ask that question. And I think we may not have that answer. I think overall, it would depend on what first-line treatment patients got and what are the potential resistant mechanisms and patient-related factors. And we'll talk about these potential treatment options going forward. So until a few months ago, ICI or immune checkpoint inhibitors were one of the potential options at disease progression. This was based on the Phase III Empower 150 study, which had about 40 patients, subgroup patients who had EGFR mutation. Now in this study, they tested ABCP, so the quadruple combination of atezolizumab, bevacizumab, carboplatin, and paclitaxel versus BCP, the triplet regimen with carboplatin, paclitaxel, and bevacizumab. In this study, if you looked at the subgroup of patients with sensitizing EGFR mutations who had previously received TKI, you know, it led to only a numerical improvement in OS, but it was not statistically significant. But we have to remember the caveats of the study. Exploratory subgroup analysis, a very small patient population. This is another study called the ATLAS study. It's a Phase III randomized study where a similar patient population. It also included ALK mutation patients who had previously progressed on an earlier generation TKI. Patients were randomized to 2 is to 1 to ABCP versus PCARM. In this study, ABCP significantly improved PFS and objective response rate, but no improvement in overall survival. So, we are seeing a similar trend as well. So, in this, PFS was statistically significant, hazard ratio 0.62, you know, 8.4 median versus 5.6 median, and objective response rates were higher. Improvement was seen in all subgroup of patients, but one thing to remember is that only 10% of patients in this study got prior third generation TKI. So, you have a large majority of patients getting earlier generation TKIs. Again, you can see the overall survival not significant at all. The hazard ratio is literally 1. And again, we can see here that with the adverse events, the incidence of adverse events were obviously more common in the quadruplet arm compared to the doublet arm, a typical cytotoxic chemotherapy side effects. I think it remains to be seen, you know, what the role of ICI will be, especially in the EGFR mutant setting. I think currently, its role is entirely not clear. There might be certain subgroup of patients who might benefit, but we actually don't know who they might be. So, this is the Mariposa study, which was also presented at ESMO. This is in the recurrent setting. This is the randomized phase 3 study in patients who had previously progressed on ozymertinib. So, this is a third generation TKI. Only patients are randomized 2 is to 2 is to 1 to amylaz chemo, chemotherapy, and amy chemotherapy with the primary endpoint of PFS. Again, there was no crossover. And again, there was serial brain MRIs required for all patients. PFS was significantly better compared to chemotherapy alone in both the treatment arms. So, you can see amylaz chemotherapy hazard ratio 0.44, very similar to the hazard ratio of amy chemotherapy, about 0.48. Objective response rates were also higher in the combination arms compared to chemo alone. Again, benefits were seen across all subgroups. And if you see clearly that the amy chemo arm versus amylaz chemo arm, again, their PFS curves kind of were very close and almost overlap, especially in the first part and up to the first six months. And it appears that there might not be any additional or incremental benefit of lizardinib in this combination. Again, you see intracranial PFS is also better with the combination ambivantumab regimen in both the arms. Overall survival is still immature. So, we have to wait a while. Safety profile, again, very similar. We can see higher toxicity in the amy chemo and the amylaz chemo arm and grade three AEs, grade three or higher AEs, 92% in the amylaz chemo arm versus 72% and 48%. So, it appears to be pretty toxic regimen. Again, we see higher toxicity in the LAZ arm, especially the DVT and PE. The VTEs were more common in the first four months. And I think that recommendation might come out of doing prophylactic anticoagulation for the first few months of these patients. Now, what are the emerging treatment options for recurrent, in the recurrent setting? Now, we do have a fourth generation TKIs. At least two of them are currently under development. We have our promising ADCs. My colleague is going to touch upon that in much more detail, but pituitary myobduroxycans, dataputumyobduroxycans. You have several EGFR and met bispecific and trispecific therapies, and then novel therapies like immunomodulators looking at, you know, within the tumor microenvironment, altering some of the metabolism, and also cytokine profile within the different immune cells. This is an exciting time to be. So, in conclusion, I think ozomotin monotherapy will likely remain the standard of care for most patients and EGFR mutant lung cancer with classical mutations accounting for the benefit profile. I do think there is a role of combination treatments, third generation TKIs. It is appropriate for certain high-risk patients. We all have to agree that we need better incorporation of predictive biomarkers in clinical trials for better risk certification to truly identify those high-risk patients. Typically recommend tissue biopsy at progression to rule out histologic transformation and to look at the on and off target resistance mechanisms, and amivantamab chemotherapy combination will likely emerge as a preferred second line treatment. We have several novel TKI treatments that are in the pipeline. Thank you. Thank you very much for the excellent summary, Dr. Gulkarni. Moving on, it is my privilege to introduce Dr. Antoinette Wozniak. Dr. Wozniak is a globally renowned thoracic medical oncologist. She is an adjunct professor of oncology at the University of Pittsburgh and also the chief scientific officer at the Lung Cancer Research Foundation. She's going to discuss early-stage non-small cell lung cancer, optimal neoadjuvant, perioperative, and adjuvant therapies. Dr. Wozniak, I'll hand it over to you. Thank you, Dr. Parikh. I'm really happy to be here to discuss this exciting new area of research. Actually, not really new, but I'll tell you what's new. We'll start with immunotherapy. There's really a lot of rationale for giving immunotherapy both in the neoadjuvant and the and the adjuvant situation. First of all, preoperatively, you have the tumor in place, you have lymph nodes in place, and this triggers a broader repertoire of anti-tumor CD8 T-cells. In the postoperative situation, you have a lot of postoperative stress, inflammation, formation of prostaglandins, catecholamines, and this expands the T-cell department. There's rationale to approach both to give treatment in both of these situations. There's a lot of advantages and disadvantages to both adjuvant and neoadjuvant treatment. We've learned this over the years because both of these approaches have been taken in the past. In the adjuvant situation, there's no delay with surgery. You eradicate residual micrometastases, and you do know what the stage of the patient is. But the disadvantage is that there's sometimes low adherence to treatment when patients have to get adjuvant chemotherapy or, in this case, also immunotherapy. Well, what about neoadjuvant treatment? What are the advantages there? Well, early treatment of micrometastatic disease, you get cytoreduction, so maybe you need to do less surgery because of that. Patients tolerate it better, and you know with the tumor response, the disadvantages are that you are putting off surgery, and you may have some early progression. And so what about both? You could do both, and we'll talk about that now. So this is an overview of the reported global phase 3 immunotherapy trials. And in the middle, you do have the adjuvant trials, Empower 010 and the Keynode 091, which is also known as the PEARLS trial. In both of these trials, patients had surgery and then went on to usually get chemotherapy and then immunotherapy for a year. In the upper left area, you have the only neoadjuvant, truly neoadjuvant immunotherapy trial that we're going to discuss, and that's Checkmate 816, nivolumab, and chemotherapy for three cycles, followed by surgery. And in the bottom, you have three trials, AGEAN, Keynote 671, and Checkmate 77T. They all have a similar design. They got chemotherapy and immunotherapy for four cycles prior to surgery, and then went on to get IO for a year afterwards. So let's talk about a few things. Well, I'm going to briefly just talk about Empower 010, and that's because this is an older trial. It's been around for a while, and it did establish the use of immunotherapy in the adjuvant situation. And I'm just going to show this one slide. Basically, patients who had a higher PD-L1 did better. The overall survival is still immature for this trial because it is an adjuvant trial. However, there was some survival data for patients with greater than 50% PD-L1, and they seem to do pretty good. That sort of brings something to mind as to whether there is a group of patients who might do well with just immunotherapy alone. It's just food for thought. But let's get on with the neoadjuvant and perioperative trials. I have four up there, and we're comparing the patient populations on these trials. And the Checkmate 8.6, which is in the upper left-hand side, is your true neoadjuvant trials, and the other three are perioperative and similar in design. You can see that the percentage of stage 3 patients on these trials, and with the Aegean and the Keynote 671, there was a little higher percentage. There was also patients on those trials that had a little bit more positive PD-L1. So this is important to remember. So let's look at these trials, okay? What does adjuvant IO add to neoadjuvant IO? So this is sort of interesting. I'm doing an illegal cross-trial comparison here. In the upper left-hand corner is your Checkmate 8.1.6, the neoadjuvant trial. And you can see that this is three courses of chemo. The other trials all have four courses of chemo, I should say, chemo-IO. The other trials have four courses of chemo-IO surgery, then followed by adjuvant IO. And basically, we're looking at the two-year event-free survival. And if you look at the upper two trials, they're pretty similar. In fact, they're the same between the neoadjuvant trial and the perioperative trial, both using nivolumab. And if you look at the bottom two, the Aegean and the Keynote 6.71, they did a little worse. But then, you know, thinking about the patient population, maybe that's because there were more stage 3 patients and more patients who were PD-L1 positive. But they're pretty close, whether they just got neoadjuvant or got additional adjuvant treatment. So what does adjuvant IO do? Well, let's first look at the neoadjuvant trial. And let's look at how patients did if they had a complete pathologic response versus if they didn't. So if you look at the green lines, and the upper green line are the patients who got a complete pathologic response. And they did pretty well. And the likelihood of them living at being alive at three years was actually more than 95 percent, which brings up the question as to whether they do need any additional treatment. And then you have the green lines below. And you can see the difference between nevo and chemo with no path CR and the patients who just received chemo with no path CR. And they're actually pretty similar. If they didn't get a path CR, they didn't do all that well. Now let's look at a couple of the perioperative trials. You have the keynote 671 and the checkmate 717. And you can see that the patients who got a complete pathologic response also did well. The ones that didn't seem to do better than the ones on the chemotherapy alone group. But I'm not sure if that's because they got additional adjuvant IO or they just got IO, because the ones that didn't, that on the control arm, only got chemotherapy. And down below you'll see a table showing you how much adjuvant treatment these patients received on keynote 671, which is the more mature trial. Almost three-quarters of them got at least one dose of adjuvant IO, and almost 50 percent completed all of it. Just 50 percent. And the AGEAN, and you can see the other trial, was a little over 60 percent got at least one dose of adjuvant IO, and it's a little too early to see how many completed all the full course of treatment. So there was actually some suggestions on what we can do to move forward. What are potential trial designs here? Well, you could, if you were incorporating a novel IO agent in resectable non-small cell lung cancer, at the beginning you could have a control arm of just neoadjuvant chemo IO, and then the other arm would be the same with the addition of the novel IO agent. They would get surgery, and then they would get treated depending on whether you had a path CR or not. And actually, I would be in favor of just going with neoadjuvant chemo IO, taking them to surgery, and then based on the pathologic response, deciding whether to incorporate a novel agent there. But this is one of the suggestions. Another suggestion would be to do neoadjuvant treatment, surgery, and then stratify again by pathologic status, and decide whether you're going to use a novel agent or continue IO treatment, or in the case of path CR, maybe just observation. So there's a lot of different ways you could go to try to advance things. What's coming in the neoadjuvant space? Well, this is actually an interesting trial. This is the neocoast trial, and in the neocoast trial, it's a platform trial. And what they did was that at the beginning, in the neoadjuvant setting, they gave Dervalumab plus new drugs. And you can see them up in the right-hand corner. You have a CD73 monoclonal antibody, for instance. And they gave those neoadjuvantly, and then they had surgery, and then post-op treatment depending on the situation. But I think the interesting thing is it's a way of incorporating new agents. And it's also, you have the surgical specimen, so there is also the way of studying what happens as a result of incorporating these new agents. This is a platform trial, so it's going to continue, and they're going to continue to add new agents. There is a plan to try to do a trope 2 ADC also at the beginning in conjunction with IO. And I just wanted to bring this up briefly. We also need biomarkers to help direct our treatment. This is a neoadjuvant trial, a nadine 2 trial, it's a phase 2 trial, and they did incorporate ctDNA. And all I can tell you is that with the ctDNA, if it was low to start, those patients did better. And if it cleared after neoadjuvant treatment, they did better. Also, ctDNA was a better marker of a response than actually imaging. You know, this is all very interesting. I think it's too early to use ctDNA to help us make decisions, and we need better technology and more study, but certainly something that we need to incorporate in the future. So I have a whole bunch of questions here, and I'm not going to go through all of them, but some of the ones I'm going to point out are, you know, how long you treat patients. And I think this is really important, especially if you have PATH-CR patients, should they get any post-operative treatment? And if you have patients with a residual disease, do you continue IO? Do you continue a treatment that didn't result in a PATH-CR to begin with, or do you change? And there's other, there's surgical questions, there's pathology questions, so we have a lot to learn before we can actually determine what the real standard of care is. Okay, I'm going to switch to targeted therapy, and we're going to talk first about the ADORA trial. This is adjuvant osimertinib. Patients with common EGFR mutations randomized to get surgery, and then randomized to get osimertinib or placebo. Chemotherapy was allowed as per the patient and the treater's decision, and you can see the disease-free survival. It's a spectacular hazard ratio when it was first presented in 2020, and you can see a hazard ratio of 0.2. And then three years later, we have an update, and the hazard ratio went up a little bit, but it's not the hazard ratio here that's concerning. It's just that the lines come together. Patients got osimertinib, start to come together, I should say. The osimertinib was given for three years, and at the end of three years, you start to see the curves coming together. There's some concern about what would happen with overall survival on this study, but we do have overall survival data, and it does favor the osimertinib. So I think people had a little sigh of relief when they saw these data. There was also good control over the development of CNS metastases. Okay, I think one of the most interesting things about this trial is the question as to whether you need adjuvant chemotherapy. Now, this trial wasn't designed to answer that, but a lot of patients didn't get it. There were quite a few, I think close to 200, and if you look at the forest plot on the upper left, you see that the patients who got, whether they got adjuvant chemotherapy or not, did pretty well. And if you look at the survival, they also did pretty well. So do you need adjuvant chemotherapy? Let's look at the ELENA trial. This was adjuvant electinib, and the trial designed a little bit different. Patients after surgery are randomized to electinib alone or platinum-based chemotherapy. And this was presented at ESMO last year, and this is the disease-free survival which was the primary endpoint, and it is spectacular for the patients who got the electinib. And this was across all stages, so even in stage 3, 1b, I'm sorry, 1b, there was an advantage. However, there weren't that many patients who were 26, but still, there was a survival advantage across, a disease-free survival advantage across all stages. And there was also very, very good control of the development of CNS disease in this particular population. I wanted to bring up now a little bit about the neoadjuvant space in targeted therapy. This is the NEO study. This is a small 40-patient study that came out of China, and what they did was take patients with common EGFR mutations and gave them osimertinib for six weeks prior to taking them to surgery, primary endpoint was response rate. And you can see that the response rate was quite high, 71%, but very few patients, in fact, only one got a pathologic completed response, and this is a little concerning. However, it's a small group of patients, and it makes one wonder how long you should treat patients before they go to surgery, but you can't treat them too long because then you delay the surgery. And this is the neoadduvance trial. It's ongoing now, and patients with the common EGFR mutations are randomized to get chemo, or osimertinib in chemo, or osimertinib neoadjuvantally. Post-surgery, they would get adjuvant treatment depending upon the investigator's choice. All are offered additional osimertinib, and that's ongoing now. We also have another trial called ANATA-K2 that's looking at a number of oncogene-driven lung cancers in early stage, and they're getting neoadjuvant treatment. Some of the arms are already closed. This is early results with the ALK-positive patients, and there were nine patients, again, very few, but most of them did get a major pathologic response, with 30% getting a complete pathologic response, which is a little bit more encouraging, even though this is a small number of patients. This is the LC-MC4, so it's the fourth trial in the Lung Cancer Mutation Consortium, and basically, they plan to screen a thousand patients and see what kind of oncogene-driven cancers they find. Then, they then will get matched to trials for neoadjuvant treatment, and this is ongoing as we speak. So, my final slide just brings up a few questions about this particular group of patients, and I already mentioned, do you need chemotherapy? What's the optimal duration of treatment, again? Should they stay on indefinitely until they relapse or not relapse, and can you extrapolate to other oncogene types? For instance, can you do this approach with KRFs? Maybe not. They may do better with chemo-IO, followed by other treatment, depending upon how they respond, and will resistance emerge sooner? So, a lot of questions to be asked, and that's the conclusion of my talk. Thank you very much, Dr. Wozniak. That was a master class, and moving to our last speaker for this morning. Let me introduce to you Dr. Joshua Reuss. Dr. Reuss is an assistant professor, Department of Medicine, in the Division of Oncology, and he's a thoracic medical oncologist at the MedStar Georgetown University Hospital at the Georgetown Lombardi Cancer Center. Dr. Reuss, the floor is yours. Sorry, I was muted there for a second. I wanted to make sure I took care of that. Thank you, Dr. Parikh. So, I will speak on antibody drug conjugates and KRFs targeted therapies. Obviously, a large explosion in this field, and something that was discussed heavily at the targeted therapies meeting in February of this year. So, a brief review on an antibody drug conjugate. Now, this may be familiar to many of you, but there are three key components. First is the antibody, and by nature, the target. So, the target should be overexpressed or exclusively expressed on tumor in order to prevent on-target, off-tumor toxicity. The antibody obviously targets the target, and it's typically a humanized immunoglobulin of the IgG1 class. Now, the linker obviously links the antibody to the payload, but more than that, it's important to maintain stability in circulation to prevent premature uncoupling. And in addition, the nature of the linker can affect the efficacy profile of the compound as well by nature of one being a cleavable or a non-cleavable linker. Non-cleavable linkers require trafficking to mature lysosomes for degradation, and by nature of that biochemistry, frequently can't traverse cell membranes. And on the flip side, cleavable linkers, which utilize cell physiology to uncouple oftentimes can traverse cell memories and we'll talk about why that's important in a little bit. And then the payload of current generation ADCs is typically a highly potent cytotoxic, basically chemotherapeutic, and the ratio to which a payload to antibody is on a specific ADC is called the drug to antibody ratio or DAR. Typically ranges from 2 to 8 and that may influence efficacy as well. So these mechanism of action, these introductions were presented by Dr. Levy at TTLC and in the middle of this slide you can see kind of the most intuitive mechanism of action here which is internalization of the compound release of cytotoxic payload. But it's also theorized that at least on the left side of the slide you can see here antibody dependent cell cytotoxicity and if an ADC targets an oncogenic driver for example blockade of signaling may play a role as well. And then on the right as I alluded to earlier the the bystander effect is incredibly important. This is the effect of cytotoxic compounds ability to diffuse across cell membranes and affect neighboring cells. This is particularly important in tumors with heterogeneous target expression as well as in tumors that are dense and we've seen how this can be important efficacy in several of these ADCs as I will discuss in a moment. So probably the most famous of the ADCs for lung cancer, the only one that's currently approved, carries an accelerated FDA approval in the subsequent line setting is tristuzumab durextican or TDXD. This was discussed in detail by Dr. Scott at the targeted therapies meeting. The first study to show the efficacy of this, the first prominent study in HER2 mutated lung cancer was the Destiny Lung-01 study. You could see promising response rates and efficacy outcomes that have been published in the New England Journal. Really this is the first compound that has shown an acceptable safety profile and efficacy in HER2 mutated lung cancer, though you could see in this first study an ILD rate of 26%. Now importantly the approval was based not on the Destiny Lung-01 study but the Destiny Lung-02 study which randomized patients to doses of 5.6 or 4.6 mg per kg of TDXD and while efficacy was comparable at both doses, importantly toxicity was much improved with the lower dose with an ILD rate probably around half that was seen at the higher dose and at the rate that was seen in Destiny Lung-01. So there are many promising ADCs in development. Probably the next closest to quote-unquote prime time are the TROP2 ADCs. Two most prominent ones are datapodumab durextican, a TROP2 targeted ADC with datapodumab as the antibody conjugated to a DXD payload and on the right sasituzumab govatican, another topoisomerase inhibitor payload conjugated to a TROP2 antibody. TROP2 itself is overexpressed in non-small cell lung cancer. Some data suggests it may be associated with poor prognosis, so a really good biomarker to utilize for exploration of ADCs. Now the largest data we have, this is the TROPY on Lung-01 study. This was presented initially at ESMO in 23 and discussed by Dr. Sands at Targeted Therapies. This is a phase 3 randomized subsequent line study of DADO-DXD versus docetaxel co-primary endpoints of PFS and OS. So the big question, as has been the question with a lot of recent conferences, is can we beat docetaxel? And the answer is probably. You know the PFS here, you can see met the primary endpoint hazard ratio 0.75, though when you talk about clinically meaningful PFS of 4.4 versus 3.7 months. Now the signal looked strongest in non-squamous adenocarcinoma, where that hazard ratio was a little bit better, 0.63. Also really a clearer difference in response and duration of response. And in addition there's data that DADO-DXD has efficacy in driver populations as well. That's from the TROPY on Lung-05 study. So I think there is promise here, but the degree of benefit I think remains to be seen. And then from an efficacy standpoint, or sorry, from a safety standpoint, you know this isn't like our targeted TKI agents, right? There's still toxicity that we have to manage, some similar to chemo and some other unique adverse events. For the TROP2 ADCs we see an increased frequency of stomatitis. We can see ocular events. And then for the DXD payload ADCs, of which there are many in development, we can see a prominent significant incidence of ILD, which is something that can be very challenging to manage and something that we need to watch closely. Now what about the frontline setting? So there is emerging data for both Sassatuzumab, Dovatecan, and DADO-DXD that perhaps we can utilize TROP2 directed ADCs in the frontline setting. So promise here, but I think it remains to be seen how this improves upon either IO alone or IO with chemo. And is there an improvement either in safety profile or an efficacy here? So still a lot to discover with the TROP2 ADCs. This was again a summary slide by Dr. Sands at Targeted Therapies. What's interesting here too is that while DADO-DXD met its primary endpoint in the subsequent line setting, we have top-line press release that Sassatuzumab, Dovatecan did not meet its primary endpoint in the subsequent line setting. So why is this? Is it a slightly different target? Is the payload different? Is there a different ability for these payloads to traverse across neighboring cells? It'll be interesting to see how this layers out. So another promising ADC is Petritumab, Dovatecan, or HER3-DXD. Now this in particularly is showing a lot of promise in EGFR-mutated lung cancer. HER3 is upregulated in EGFR-mutated lung cancer. And importantly in the top-line data that we have and in the published data, this is from the HER3-Lung O2 study. And this was discussed by Dr. Timothy Burns at Targeted Therapies. And you could see progression-free survival of five and a half months, median survival of 12 months. But this was a heavily pre-treated population. And importantly, the efficacy was seen across mechanisms of resistance, suggesting this could be, you know, an important compound to consider in really across the spectrum of resistance mechanisms for patients with EGFR-mutated lung cancer. However, despite successes, there have also been several prominent failures. These are summary slides from Dr. Walker and Dr. Velez that were discussed at Targeted Therapies. On the left, the CKAM5 Targeted ADC-2 Submit-to-MAB-RAFT Hansen. Unfortunately, it had development halted due to not meeting its primary endpoint in a Phase 3 trial. And on the right, you could see several promising early studies, but also several no longer in development. And I think what this speaks toward is the biomarker identification for ADCs is absolutely critical. And what's interesting is that for the TROP2-directed ADCs, such as Datapodumab, top left, the expression level does not appear to correlate with efficacy. The same for HER3 with the Petrichumab-Diruxtecam. On the contrary, though, at least early data from an antibody drug conjugate, Telisotuzumab Vedotin, or TelisoV, has shown a prominent efficacy, promising efficacy in patients with high MET expression. And that's what carries an FDA breakthrough designation in this category. So I think that will be important. Biomarker is really important to see who can really derive durable benefit from these compounds. And then I think what's really exciting is that this is a construct for future drug development. So bispecific ADCs, dual payloads, future payloads, such as immune stimulating and radionucleotides, I think those are really the next generation of therapies that can help patients. So the summary of ADCs, Trisuzumab-Diruxtecam, currently only FDA-approved ADC in lung cancer. I think the TROP2 and HER3-targeted ADCs have really promising supportive data. They're probably closest to prime time. But the big question is, are these therapies going to provide incremental benefit or will they actually enhance, synergize, provide durable long-term disease control? And can we synergize with other agents to optimize that? But I think the discontinuation of some promising agents also shows that biomarker identification is critical. But I think the construct here is really, really important in really optimizing and developing therapies of the future. So with the remaining time that I have, I want to switch gears and talk about another complex topic, which is KRAS-mutated lung cancer. Now, KRAS-mutated lung cancer is an incredibly complex and heterogeneous disease. You can see here just the pathways. They really have very different, diverse pathways that feed into each other in terms of the pathway of oncogenesis. So how can we effectively blockade this pathway that is so frequently mutated in lung cancer, maybe 30 to 35% of our patients? So we obviously have therapies for KRAS-G12C. So one interesting question is, can we combine the KRAS-G12C targeted therapy, sotoracib, adagracib, in the frontline setting with immunotherapy? We know that other targeted agents have really not been able to combine with IO due to issues with toxicity, but what about the KRAS targeted agents? So Dr. Gaynor discussed this. It's very interesting. The data from Codebreak, which is the sotoracib combination study, did show signs that, you know, perhaps that combination is still going to be met with toxicity. Now, lead-in doses of sotoracib looked a little better, but I think suggests that there's caution to be had with this approach. But when we look at the CRYSTAL-7 study, which looked at adagracib with IO, that safety signal appeared less prominent. Now, I think we need more data. In my opinion, we really need to kind of hone in on who should warrant this combination up front. I don't think we're ready for prime time, but we definitely need more data to see, is this safe? And in who should we deploy this? And Dr. Awad had a really awesome summary slide on this at Targeted Therapies, because we know that a lot of patients with KRAS-mutated lung cancer do respond well to IO. So who is it that we need to deploy the inhibitors up front? Is it with certain PD-L1 and TMB levels? Is it the SDK11, KEEP1, SMARTK4 mutations that we believe are associated with immunotherapy resistance, where we've seen perhaps upfront CTLA-4 maybe of benefit? But we need to identify these patients. Moving on, and to really speak towards something very fascinating, is that there's a novel KRAS-targeted agents in development. Our existing inhibitors target RAS in the off state, and there are several inhibitors that are being developed that target RAS in the on state, which may enhance efficacy, and I think are very exciting. So first, just to comment, there are several RAS-off inhibitors for KRAS-G12C that are under development, for which we have emerging data. This was presented by Dr. Pata at TTLC. But my big question here is, are these agents have any added benefit over what's already approved? You know, these aren't really developed as subsequent line inhibitors to overcome resistance, or I should say, subsequent generation. So what will these add beyond what the agents that are currently approved, I think, remains to be seen? And then there's the exciting class of KRAS-on inhibitors. So this is data, emerging data for RMC Revolution Medicine 6291, KRAS-G12C-on inhibitor, and a small sample size. But as you can see here, very promising efficacy, particularly that several of these patients did receive prior KRAS-G12C-off inhibitors. Same for the RMC-6236. So this is a KRAS-G12X drug, and you could see here promising efficacy of 35% among patients, including G12D, V, and A mutations. So really promising here that we can hopefully drug previously undruggable targets. To that end, there are several studies to look at KRAS-G12D. We know that the biology of these KRAS subtypes are very different. KRAS-G12D, a more immune cold phenotype that perhaps doesn't respond as well to IO. So these studies are incredibly important to see about emerging treatments in this space. And then we have a combination strategy. So there are several combination strategies that are being investigated. SOS-1, SHIP inhibition. So SHIP inhibition in combination with KRAS inhibitors was discussed in great detail by Dr. Marone at Targeted Therapies. Now SHIP-2 is encoded by PTPN11 gene, and it is required for RTK evoked RAS activation. So it's an important supplemental activation pathway with RAS-RAF-MEK inhibition. And there are several ongoing combination studies. And just to highlight the summary slide from Dr. Marone's talk, these early studies have been somewhat complicated by toxicity. So as is the theme in my discussion today, biomarkers to really identify the subsets who are most likely to benefit from this combination inhibition, I think is incredibly important. So in summary, the concluding remarks for KRAS. I think the number one point is many patients with KRAS-mutated lung cancer do have deep and durable responses to immunotherapy. So we really need to identify those where a frontline targeted combination or targeted alone strategy may be beneficial or preferable. Is it certain commutational profile, some aspect of the tumor microenvironment where we don't think IO is going to be beneficial? I think that's important to determine. There are many promising agents in development, including the novel RAS on targeted agents. So stay tuned. I think these look very promising. And then lastly, just remember that disease biology here is incredibly complex. Many patients are former smokers where there's lots of neoantigens and DNA damage, where there's lots of competing activated pathways. So I think multifaceted RAS inhibition is really going to be the key to promoting durable disease control, limit toxicity. So with that, I want to thank you all for your attention. And I think with the remaining time, we're going to address questions. Dr. Royce, thank you so much. That was a total force. With the next last few minutes left, if possible, I'd like to ask some questions. My first question is these are to all the panelists. Let's dive into the role of chemo plus osomatinib and flora to what the patients where you would recommend an addition of chemo to osomatinib. I understand that we don't have overall survival data, at least it's not mature yet. And who are the patients who would offer locally ablative therapies to such as SRS or just radiating the oligometastatic disease versus doing chemo or osomatinib? Any comments, Dr. Gokhani? Yeah, so that's, that's a good question. I think I did have a slide on it. I think in the end, it's a good patient selection. I think at progression, you have to look at how the patient is doing, what's the degree of progression, it's a multifocal progression. It's an oligo progression. Again, the definitions of oligo progression, one site, two site, they all can be debated. But I think there is good evidence to suggest that if there is, if the progression is, is limited to one or two organs, I think a consolidative type of definitive therapy like using radiation, SBRT is a reasonable approach, and we could continue the targeted therapy. I think the other question is the first line question. And I think, as you as you pointed out, I think we have to still wait for overall survival in some of the biomarker data. But I think it, it makes sense, especially in high risk patients. Now in in the subgroup analysis, there was some suggestion saying that patients with brain metastases or patients with L858R, that we know, do relatively poor compared to exon 90 deletion. I think those are maybe the couple patient population where you would consider upfront chemo combination with those. Dr. Wozniak, fantastic, fantastic presentation. I think it was extremely educational to all of us listening here. You did, you did mention that patients who have PCR, we don't know if they will actually benefit with the addition of adjuvant immunotherapy. Any speculation on who are the patients who would benefit those with an NPR, those with 50% residual tumor, those with those with 80% residual viable tumor on the specimens? That's a really tough question. I think that it's very difficult to tell right now. I think patients with path pathologic complete response, in terms of whether you continued treatment or not, I think it's a discussion with the patient. Okay, I'm not convinced that a year of adjuvant treatment in those particular patients really help. And then you have to think of the cost and the side effects, you know, especially when you don't know if it's helping. Okay. Now, in terms of somebody who's had a major pathologic response, again, it's difficult to tell. My feeling is, probably you need a different type of treatment. And these are patients that are ripe for a trial, because you did not have elimination of the tumor. So I think that idea of stratifying patients in a trial based on what kind of what kind of response they had is really good idea, and maybe adding a new agent, maybe in combination with IO in those particular patients. So I think, you know, just identifying those patients on trials, stratifying them on the basis of their response is really important. Anyone else, any comments on this topic? If I move on to the next question? So, Dr. Royce, again, that was a lot to cover in 15 minutes. We spoke of KRAS, you know, KRAS inhibitors. And one thing that we did notice with the SOTAR-ASF trial was, you know, negative study compared to docetaxel. We recently heard about adegrassive yesterday that it met its PFS endpoint, at least against docetaxel. My belief is that these targeted agents and antibody drug conjugates are probably best suited for first line when the actual target or the driver is driving the cancer. What's limiting us in identifying the upfront, best upfront strategies of these ADCs and KRAS inhibitors? No, that's a very good question. I mean, I think for the targeted agents, toxicity is obviously the name of the game there in terms of a limiting factor. And I think it scares a lot of us, knowing what we've seen in the EGFR space, the ALK space, and knowing that patients with KRAS mutated non-small cell lung cancer can respond very well to IO. I mean, some of my longest, most durable responses are patients who have KRAS mutations. So I think on the KRAS space, I think it's I think that that is just an open question to find who is most likely to benefit, because that combination strategy I think is a little scary and something that we need to really slowly work on finding the sweet spot there. For the ADCs, I think it's also interesting because, you know, I think we got to see what compounds are likely to best synergize. You know, for some of these ADCs, it's interesting, for example, Trastuzumab, Duruxtecan, there's data out of Bob Lee's lab to show that actually HER2-TKI can actually lead to enhanced uptake in receptor cycling. For HER3-DXD, Osimertinib pretreatment can enhance HER3 surface expression and uptake of the HER3-DXD. So I think that's the kind of studies that we need to see kind of what combination strategies can really make the ADCs work better. So we're not just, you know, subbing them in and out for other chemo agents, because my worry is that right now, what we're seeing are incremental benefits, kind of like the pre-IO era of VEGF inhibitors and maybe more novel chemo agents. So I think we got to find out how we can actually synergize and create combinations where we see that durable enhanced benefit. Any other questions from the panelists and the speakers to us? To discover more educational activities being offered by IASLC, please visit the website at IASLC.org. IASLC 360 is also a wonderful resource for all educational activities conducted by the IASLC. With that, I would like to thank you all for joining us today for this very informative webinar. And until next time, please have a good summer.

KRAS-targeted therapies

immunotherapy

frontline setting

lung cancer

patient selection

biomarker identification

RAS inhibition

novel KRAS-on inhibitors

antibody drug conjugates

combination strategies