Uh, good morning, everyone. Thanks Doctor Borgai. All right, so we're gonna talk about moving these therapies in the earlier stage setting. So talking about adjuvant and neoadjuvant EGFRTKI and EGFR mutated lung cancer. Uh, these are my disclosures. So the objectives that we'll cover in the next 10 minutes, I want to introduce some concepts. The neoadjuvant, adjuvant means preoperative, postoperative, respectively. I want to talk about the role in EGFR mutated lung cancer specifically, and then also this concept of minimal residual disease since this is the first sort of operative talk that you're having. Then we'll move to the data that's supporting adjuvant osimertinib for resected EGFR mutated lung cancer, and what are the ongoing clinical questions there. And finally, we'll touch on neoadjuvant EGFRTKI approaches that are emerging, uh, in this disease. So first, what is the purpose of neoadjuvant adjuvant therapy? The purpose is to increase the rate of cure. So we know that a proportion of patients are cured with surgery alone, uh, but then there are those patients who are going to relapse. So how do we decrease the risk of those specific patients? There are, of course, risks to this approach, because all of our systemic therapies, despite all the progress we've made, do have Toxicities. And then for these trials, when we move it to the earlier stage space, the primary endpoint of overall survival can take some time. So then we're looking at sort of intermediate time, time points such as disease-free survival or event-free survival, and also pathologic complete response, especially after neoadjuvant therapy to see if you have no viable tumor cells, uh, at pathology at time of resection. So why consider neoadjuvant or adjuvant TKI therapy in sort of earlier stage 1 through 3A EGFR mutated lung cancer disease? So we heard from our colleagues here that EGFRTKIs, especially, uh, data with osamernib and, uh, uh, laser AMI, do demonstrate efficacy in the metastatic setting. Uh, there's also a suggestion in the literature that there are high rates of systemic relapse, specifically for people with earlier stage EGFR mutated lung cancer. And then we have this problem with predilection of recurrence with CNS metastasis, which obviously can be quite comorbid. And now I want to introduce this concept of minimal residual disease. I mean, we've seen a lot of data and applicability in the colorectal cancer space, but we're starting to also look at this in lung cancer. Many of these are tumor informed assays. So they look at the genomic landscape of the tumor. They Design a circulating tumor DNA assay to match that patient's tumor, and then say after a landmark time point, such as after surgery, is there presence or absence of circulating tumor DNA or positive or negative minimal residual disease or MRD. So I'll, I'll come back to that. So first, there have been many adjuvant EGFRTKI studies conducted in EGFR mutated lung cancer. Uh, many of these studies were done with first-generation EGFRTKIs, and none really showed an overall survival benefit except one with Eloib. So really, we're going to focus on Adora, which has changed the landscape, uh, and I'll show you the study design here. Uh, so this is the, uh, phase 3 design. It's important to note that, uh, this was using version 7 of the staging system. Uh, this is stage 1B through 3A lung cancer. Again, talking about the specificity of EGFR, uh, mutations. This only includes Exon 19 deletion and Exxon 21LA58R mutation, and all these patients underwent a complete resection. Now, they were randomized either to osamertinib versus placebo, and the duration was pre-specified at 3 years. That's kind of the magical number that was chosen for this trial. And the primary endpoint was disease-free survival, with a key secondary endpoint, of course, of overall survival. So these are the disease-free survival and overall survival curves from Adora. You can see DFS was a hazard ratio of 0.27. Pretty remarkable separation in those curves. What's interesting, if you look at the 3 year mark or the 36 month mark when the patients stop ossuertinib, those curves are kind of coming to Together, suggesting one of the clinical questions, do we have to keep these patients on longer therapy, or at least the subset that we think have a higher risk of recurrence. And then the overall survival also, uh, is quite reduced by 50%, that results in an absolute 5 year overall survival benefit of 10%. Uh, so we have great data there. Now, the one caveat of the study, and this was a big criticism of the study, of half of the patients on placebo arm who went on to subsequent therapy, only 43% received subsequent osertinib, which really is the standard of care. So not everyone received osertinib in the placebo arm at the time of relapse, which is a problem. So we talked a lot about CNS metastases. Uh, this drug, I think also very importantly in the setting, uh, improves the CNS disease-free survival. So you have less patients who are relapsing in their brain, uh, because of being on adjuvant osamertinib with a hazard ratio of 0.24. Now, let's look at subgroups for overall survival. Similar to other adjuvant studies, uh, higher risk disease, so higher stage disease does derive the most benefit of this approach. And then we see the same pattern that Exxon 19 deletion tends to do better than Exxon 21L858R mutation, as we've seen also in the metastatic setting. So this is safety, right? We're talking about adding additional therapy after surgery. Uh, there was a higher rate of AEs in the Osomernib arm leading to treatment discontinuation, 13% versus 3%. Higher rate of grade 3 AE is 11% versus 2%. Uh, but luckily, uh, no AE is relating to death. Now, if you look at completion rates, right, this is, uh, a patient who's gone through surgery, uh, and now you're telling them they have to receive 3 additional years of therapy. So about 66% of patients in the Osmernaarm actually completed all three years. I think that's useful to know. So these are the pending clinical questions. I think, um, one thing to note in this trial, only 60% of patients received adjuvant chemotherapy. So a lot of patients just went straight directly to osumertinib. So is there a role for chemotherapy in this treatment paradigm? What optimal duration. We see those curves start to come together after 3 years. And is there a strategy to tailor use of adjuvant osomertinib with MRD assays? And what do we do for patients who relapse on or shortly after osumertinib? We really don't know those resistance patterns yet. So this is the analysis looking at overall survival with adjunct chemotherapy on the left without on the right. And we can see that the hazard ratio is very similar. But if you look at the absolute 5 year overall survival, it's 97% if they've received adjunct chemotherapy with osamertinib, while it's 80% if they have not. So there is, there is some suggestion that potential, there is still benefit there. If we talk about duration, there was an interesting study that was presented at ASCO this year looking at a first generation drug, just 6 months of vicontiib versus 12 months. Interestingly, with a shorter duration, there did not seem to be any real difference in DFS or OS, but that's quite different than the 3 years of osamertinib that patients are receiving. So there's a target study that's going on, which is looking at 5 years of adjuvant osmertinib. And then there's also another trial that's trying to bring osamertinib into resected stage 1A disease, again, because of the likely higher systemic relapse rates, even in earlier stage disease for EGFR mutated lung cancer. So minimal residual disease, this is data from a subset of patients from Adora, uh, baseline MRD status was after surgery and after, uh, adjuvant chemotherapy. The positivity rate was only 8%, and all of these were patients with stage 2 and stage 3 disease. Really, none of the patients with positive MRD had stage 1B disease. If we look at post-treatment MRD, like after a patient has completed 3 years of osamertinib. Uh, what's the relapse rate in terms of disease-free survival or MRD? It's about 17%, with the majority of those occurring in the first year. So after Osamertinib completion, if they're going to recur, they're generally going to recur in that first year. And then if we look at the disease-free survival and MRD event-free rate after Ososomerini discontinuation, you can see that it does sort of fall off 12 months and 24 months. Uh, so there is, I think, a real question here if we need to do longer duration of therapy, at least for a subset of patients. So now let's briefly move on to neoadjuvant EGFR TKI studies. There have actually been many done. Uh, these are mostly with 1st and 2nd generation EGFRTKIs and for a relatively short time interval, like 6 weeks to 8 weeks, these were mostly phase two studies. And as we move into the neoadjuvant space, we start to talk about pathologic complete response, meaning no viability of tumor cells at the time of surgery or major pathologic response where you're talking about. Uh, 10%, uh, tumor viability. And so what did these studies, uh, report, at least with earlier generation EGFRTKIs, really not much in the way of pathologic complete response and major pathologic response ranging somewhere from 9% to 24%. So we're not seeing that PCR rate that we see with neoadjuvant immunotherapy approaches that are around 20%. So there have been some studies looking at, uh, neoadjuvant osamertinib as a monotherapy. Uh, this was just given for 1 to 2 months. It did not meet its end point. The NPR rate was only 15%. There were no pathologic responses. There was another study, NEOS, uh, which had an NPR rate of 10.7%. Again, not great. Uh, then there was a NOA trial looking at perioperative, uh, osamernib, where the NPR rate was 24%. So, again, the take-home message with neoadjuvant, even 3rd-generation EGFRTKIs, you really don't see much in the way of pathologic complete response, and your MPR rate is OK. So there's also this other, uh, third generation EGFRTKI o alertnib. Uh, this was an interesting trial because this was an unresectable stage 3 lung cancer, uh, population. They received a longer duration of therapy, 16 weeks, and they noted that they were able To convert 45% of these patients to surgery and all of those were indeed are zero resections. They also did some fancy RNA sequencing and, uh, basically, it transitioned the TME to a little, uh, better, more friendly environment. So this data was presented at ASCO. This is a neo Adora study. This is a phase 3 study looking at neoadjuvant osamertinib plus or minus chemotherapy. So those are the top 2 arms, and there was also a placebo-controlled chemotherapy arm. The primary endpoint was major pathological response. Now, we could debate whether that's a good primary endpoint given what we've seen. Uh, with earlier studies, uh, but they did, uh, meet their primary endpoint for NPR, uh, 26% for OC chemo, 25% for OC monotherapy, and limited PCRs ranging from 4 to 9%. Uh, this was a tolerable regimen. Most patients were able to complete, um, the 3 cycles of chemo plus or minus osamertinib, and it doesn't appear that surgical resection was impacted, and the R0 resection and N2 down staging was potentially slightly higher with the osamertinib containing arms. Um, just to mention as well, they did this with an earlier generation TKI in a phase two study, and it really didn't go well. NPR rate was only 7%. So in summary, adjuvant oscierib is the standard of care and resected EGFR mutated lung cancer with the caveats noted, uh, below in terms of EGFR mutation restriction. I think there is a potential role of minimal residual disease to avoid overtreatment of patients who are already cured by surgery, especially if you're telling them to take 3 additional years of, uh, treatment. Uh, based on the data that we have so far, I'm really unclear how neoadjuvant, uh, Osamernib or other EGFR targeted strategies will add to the current landscape, especially since pathologic complete responses are uncommon to rare with this approach. Thank you for your time.
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