Chapters Transcript Video Adjuvant and Neoadjuvant in Early-Stage Lung Cancer with Actionable Genomic Alterations Back to Symposium Thanks Haas and thanks to the organizers for inviting me to speak on adjuvant and neoadjuvant uh with actionable genomic alterations. So the impact of targeted therapies for those with advanced non small cell lung cancer has obviously been quite vast. Both when we talk about the first generation of targeted therapies compared to chemotherapy and then the subsequent generation of targeted therapies, you know, with improved cns penetration, overcoming resistance mechanisms and improved tolerability. So I think we're getting used to being able to drive these trucks through the curves, right? My, my two year old is also really obsessed with trucks. So it's a good analogy. But we contrast that with the adjuvant setting, right, where at least with the earlier generation of targeted agents, we really weren't seeing that impact. And so I think the big question as we saw the next generation of targeted therapies under the metastatic space was can later, later generation targeted agents with improved efficacy, CN ss penetration and ability to overcome resistance mechanisms. Could that lead to durable clinical benefit in the perioperative setting? So the first, the first study to really show that and this is probably old hat for a lot of you in the room now was the phase three adora trial. So this study took patients with resected stage one B to three, a non small cell lung cancer with EGFRX on 19 deletion or L A 58 R mutation uh by AJ CC seven staging criteria, randomized 1 to 1 to 3 years of Omer River placebo and a few key points on this study was that chemotherapy was not required. So some patients received chemo, some did not. Uh and then also again, three years of targeted therapy or placebo with primary end point of disease free survival and those with stage two and three A disease. So, what did we see? Well, the the key primary end point here was overwhelmingly positive. You could see disease free survival in the stage two and three A and then the intention to treat population with hazard ratios. I know they're kind of small. I believe that says 0.23 and 0.27. Um And again, I think this passes that truck uh uh criteria uh to see benefit with disease free survival. But moving beyond disease free survival and even overall survival, there are other important elements uh for clinical benefit. And I think one is CNS disease free survival. We know patients with driver alterations really have a high tropism for the CNS. And we saw that this adjuvant targeted therapy with osimertinib led to improved uh CNS disease free survival. Uh in these patients, in terms of toxicity. Again, by and large, these are side effects. We've come to expect that these agents uh fairly low grade diarrhea, skin toxicities, but low grade does not mean that it's not clinically impactful, right, low grade diarrhea can be up to six times above uh baseline. And so, and I do think that these side effects overall are somewhat magnified in those in the adjuvant setting because they're not seeing symptoms of their cancer alleviated. They're just seeing toxicities without necessarily feeling better from the therapy. Another important thing I think that we were all worried about was that what happens when you stop the targeted therapy? Are we going to see recurrences happen? Are we going to see a waning effect? And I think to a degree, we did see that, right. So we see the three year time point of the targeted therapy and we see that patients in the Osa Merton of arm, uh we see that when that therapy is stopped, you see the recurrences start to pick up, you see the slope of that uh recurrence free survival uh start to, to really uh pick up. Um And then shown another way here. Similarly, again, the probability of both cns and systemic recurrence really going up after that three years. So I think a lot of us really had this concern. Well, given that will we see an overall survival benefit? Thankfully, we did. Uh So this was uh presented at as o last year showing how Saer nib improves overall survival. Again in the primary efficacy population here, hazard ratio of 0.49 favoring uh osimertinib. And then looking across stages, you could see here that really that benefit probably most pronounced uh in the stage three A population. At least when you look at that five year landmark, uh almost 20% magnitude of benefit, 85% versus 67%. Moving on to the newer kid on the block lectin. So this is the phase three Elena study, some similarities but also prominent differences to the adora trial. So similarities stage one B to three A population uh resected disease randomized 1 to 1 but key difference here. Two years of Ecton, I want number one and number two randomized against chemotherapy. So patients in the elect nib arm did not receive prior chemotherapy as part of this study. And again, primary endpoint was disease free survival. So we did see a very prominent disease free survival benefit both in the stage 2 to 3 a population and the intention to treat population. You see here, a very impressive hazard ratio of 0.24 again, passing the the truck test. Um and then when you look at the breakdown, you could see benefit across disease stages. And again, I think the magnitude of benefit perhaps greatest in that stage three a population, right? Even at that two year landmark, we're seeing almost a 30% absolute improvement in that landmark two year uh disease free survival and again, CNS, disease free survival benefit, right. So, uh the tropism for the CNS elect, it definitely helps to safeguard and you could see help to limit the risk uh for recurrence of disease in the CNS. Again, briefly on toxicity. Again, I'd like to, to reiterate that I do think these toxicities are somewhat more magnified in the adjuvant setting but overall uh well tolerated. So this is just a summary slide uh for your reference, highlighting some of the differences between the two studies. You could see actually a lot of uh uh surprising kind of similarities in terms of the disease free survival and the CNS, disease free survival between these studies. Obviously, we don't have overall survival with Ecton. But I think there's also an important distinction here in terms of the FDA label. So the FDA label for OSA me, it actually does not specify disease stage. It just has resected uh Exxon 19 deletion or L 858 R mutation. But for ac actually the label is for tumors that are at least four centimeters in size or node positive. So I I'm not entirely sure why there were differences with the FDA labeling and and how that indication uh was brought forward. But just important to note those differences in these studies and approvals. So with the remaining time that I have, I want to speak on some important questions in this space. And I think one of the key questions here is, is chemotherapy still necessary in the adjuvant setting. We saw the differences in the designs of these studies. And I think it's an important question and, and I think the adora study can give us a little bit of insight there. You could see that on the left hand slide, you see overall survival curves for chemotherapy versus no chemotherapy uh in the stage uh in the, in the stage one B to three A population and and on the right, in the, in the 2 to 3 A population, and you could see that in the overall population, not a lot of differences. But when you look at the stage 2 to 3 A, uh you know, the population that's primarily getting the chemo, perhaps you see numerically some trends toward the chemo arm having a longer landmark survivals. So I think it's a tricky question, you know, I still tend to give the chemotherapy in stage two and particularly stage three disease. But definitely, I think it's the targeted agent that's driving uh the significant benefit a little bit of pun intended there. So another big question here is can CT DNA monitoring be used to guide treatment decision making in this setting? At as O this year, we saw some very interesting data from the adora study looking at MRD analysis, uh a tumor informed MRD assessment. Uh and what was interesting is that for those that were MRD positive, so they detectable, minimal residual disease and blood after surgery. These patients by and large did not do well. You could see particularly for the placebo arm really quick recurrences. But even those who got Osimertinib ha had recurrences as well. Importantly, the MRD detection preceded recurrence by about 4.5 months. And then I think lastly, and this is probably the most important thing for those who had the MRD and DFS event on osimertinib. The majority of these happened after osimertinib was stopped. So this perhaps could give some insight into the appropriate duration of osimertinib in this setting. Other questions, what's the appropriate duration? How can we expand the stages? These are a few studies that are looking at that the phase two target study is saying, well, if three years of oser is good, maybe five is better. So it's looking at that um on the right, the phase three, adora two trial looking at particularly that stage one, a two and one, a three population. Another important question is can neoadjuvant and peri operative strategies be applied to those with driver mutations? Uh This is uh data from the phase A phase two multi center study of neoadjuvant Oumar nib. And you could see that while there are responses, when you look at pathologic responses, M pr so less than or equal to 10% viable tumor cells that was only seen in 14.8% there were no PC RS observed and while overall response rates were high. Oops, sorry, I just saw my, my slides uh move around a little bit. Uh while overall response rates were high, um and median uh disease free survival was also quite high as well. Um You know what we uh sorry, there's a lot of movement on my slide. So I'm just gonna look over here. Uh The, and the majority of patients got surgery. This is a very stark difference compared to what we see with our immunotherapy based strategies, right? Where we're seeing an M pr rate, 37% PC R rates almost one in four and so, and I don't say this to, to indicate that I'm in any way advocating for immunotherapy for those with target or uh driver alterations. I absolutely am not. We know that that is not an effective strategy for those with EGFR and AC, but I think it highlights the difference in mechanisms of these therapies. Uh And you know, suggests that perhaps we should have different expectations for the neoadjuvant and perioperative approach for targeted therapy. Um as opposed to with immunotherapy strategies. This is just a summary slide of uh other studies in the perioperative space. Uh not all inclusive, but you could see uh particularly the phase three Neo AORA is an ongoing study that we hope to get results from as well as all these other studies too. So in conclusion, uh adjuvant osimertinib improves disease free and overall survival uh in resected. Uh Egfr mutated non small cell lung cancer and is approved irrespective of stage uh uh lectin. On the other hand, uh only has uh uh um so far uh survival, a disease free survival benefit observed. And it's specifically approved for those with at least four centimeter tumors or lymph node positive. Um What is the role for chemotherapy? I think this is an open question, but we really need to make sure that patients can get the targeted therapy. That's the more important piece. And I think that's something to keep in mind when you're evaluating a patient in the adjuvant setting. Uh Other important questions here, can we use CT DNA and MRD assessment? Something I didn't have time to discuss. But what about the other drivers? What about rat ross? One? Can we extrapolate this data and you know, it's careful, it's a data free zone. But I think the key variables here are tolerable therapy, CNS penetration. Um And, and really something that we can expect patients to tolerate for a long period of time. Uh In addition, what would be the role for neoadjuvant and peri operative? My take on this is, I don't know if we're going to see that EFS and OS benefit over current strategies and if that's the case would ability to, to lead to response and, and reduction in size. And, and ultimately, perhaps if safer, more effective uh uh easier tolerated surgery could that lead to use? I think time will tell. Importantly, immunotherapy is unlikely to be beneficial in the majority of these patients. Um, and to that line, I didn't touch on this, but we won't have this discussion. If we don't do sequencing, you have to do sequencing before you're deciding on the appropriate neoadjuvant therapy for this patient. It's absolutely critical. So with that, I want to thank you for your attention. Created by Related Presenters Joshua Reuss, MD Assistant Professor, Department of Medicine, Georgetown University Medical Center,Thoracic Medical Oncologist, MedStar Georgetown University Hospital
