So good to see all my good friends here today. Thank you. Um, so I'm gonna really talk about a really interesting topic, if my slides can come up. There you go. Locally advanced mutation positive non-small cell lung cancer. We're gonna review the evidence in the emerging trial. Doctor Xavier, uh, assistant division chief of Mainland Health. Excuse me. These are my disclosures. So when I look at the data for um oncogene-driven local advanced um stage 3 non-small cell lung cancer, do practice changing data for consolidation targeted therapy in the Lara trial. We're gonna contextualize with um adjuvant neoadjuvant targeted therapy trials like Endura, Alina, and Neodura, and we've talked about some of the present uh ongoing trials and future implications. So why does this matter? So 30 to 40% of all non-smal lung cancer cases present as locally advanced stage 3. That's why the, um, mortality for lung cancer is high. That's why lung cancer is the number one cause of cancer death worldwide, right? Driving mutations like EFR and ALC are the engine for this, these cancers driving growth, including microscopic and CNS metastasis. Large molecules like immunotherapy don't cross the blood-brain barrier as excuse me, um, some evidence that activated T cells may, um, but opposed to small molecules like TKIs they do and have intracranial, um, effectiveness there. Um, so TKIs are often better for uh CNS, um, penetration, better systemic control, uh than chemotherapy, immunotherapy, um, and mut mutation positive disease. This has the potential to improve PFS. Delay res um relapse and hopefully improve OS. So we're gonna talk about the goat. I apologize, but my throat. The goat Pacific trial. Excuse me. Sorry. Sorry about that. So this has been the standard of care for the last few years, right? Patients received concurrent chemotherapy definitively with, um, chemotherapy and was randomized 1 to 1 either placebo or devalumab. Primary endpoints were PFS and OS. Significant 5 year overall survival, 50, 49.2 opposed to 33.3% in the placebo group. But we look at a subgroup, those who harbor, thank you so much, sir. I appreciate that. Thank you. Those who harbor EGFR mutations had unclear benefit or lack of benefit with the conference interval crossing one, right? And also the question about CNS relapse. So to address this topic, Laura trial was developed and conducted, and the LR trial is a phase 3 double blind study where patients receive chemotherapy and radiation, and as opposed to getting immunotherapy. Uh, we've got OCertinib, um, 2 to 1, uh, compared to placebo that was given until disease progression, looking for, um, PFS, um, and also the secondary importance of OS and, um, CNS progression free survival as well. Got a thunderous applause applause when this was presented, right? Significant, significant progression-free survival. 39 months as opposed to 5.6 months compared to um placebo with 84% reduction in progression and death. Also has significant intracranial um um protection that's at 12 months. Those who had OCMertin of 99% progressed in the brain as opposed to placebo 36 months. However, updated um OS data. It's not as robust as we'd like, given that that large PFS because it has significant crossover like 81% of the patients on this trial had, um, a crossover. So how do we interpret it? So we still think it's a significant benefit, but the data is not as clean at this point. So we talked about the um local advanced unresectable study um studies. Now we're gonna talk about Eurra, which is a phase 3 study for resectable patients, right? So patients are received um after definitive surgery they were randomized 1 to 1 to either giving OC written for 3 years or placebo and look for DFS and also for or survival benefit. Again, significant, uh, risk-free survival benefit. Also significant intracranial protection versus CNS and DFS and also, um, disease recurrence less in the Omer group. And you found that this Benefit all stage all stages 1B to 3A with or without chemotherapy and look at the subgroups that all patients benefit from um OsCurnib. So that was EGFR. Now for the AC studies, the same. Um, um, processing applies here, so patients receive definitive, um, surgery. They either receive electinib. 1 to 1 basis, uh, compared compared to chemotherapy and patients receive this for two years or until disease progression and looking for DFS and also again, big important thing looking for CNS disease-free survival, OS and safety were all their endpoints. Same thing applies. Significant significant, um, the free disease free survival, uh, not reaching all stages, um, from stage 1 to 3A, the survival benefit, um, was maintained. So this is actually practice changing and has changed the paradigm of how we treat these patients. It's also proved to have significant CNS disease for free survival where patients receiving this has significant um protection from intracranial metastases. Now we're trying to turn this and see if we give these agents in the neoadjuvant setting. So giving TKI's a neoadjuvant setting, we still see the same benefit. So neodura, uh, was conducted to try to answer this. OK. So EGFR resectable stage 2 to 33 patients, um, 1 to 1 to 1. So patients either receive OC. By itself, mostly with chemotherapy and the third arm was chemotherapy. They received surgery and to determine how well patients responded in points of major pathologic response and also we looked at, um, CNS as well. Most of the patients receiving OC had significant um um zero significant response and they all had 01 resection 91% all um all patients so in each arm most of the patients were able to have um surgery at the end trial. Significant um MPR rate was um found in all the OC conducted containing regimens. We look at the chemotherapy, there was very, very little benefit, um, chemotherapy even when we added to OC. So the MPR rate was equal with, with or without chemotherapy. Without OCertinib, you didn't really have that deep response. Has significant into um downstaging as well with both OC um containing regimens 50% with mono or with chemotherapy only 21% with um those patients receiving chemotherapy only. Significant depth of pathological response in both OC containing regimens and not as much with chemotherapy. So we want to try to expand this right so we know how it works in the EGFR containing. Now we're having multiple, multiple umbrella trials to determine if this concept works in out containing, um, uh, tumors raw small. So for example we're having a nautical one trial to do answer these questions and. Significant, um, uh, for surgeries, correction for settings that have harbored these mutations and hopefully we'll start to have some of these readouts in the, uh, next few years. A lot of these are always closed to enrollment and hopefully we'll have some information, um, soon regarding, um, the benefit of adding these in a new a different setting. This is important and this, this is my little chat GPT slide, but it's important. We, I say we, we're very fortunate to live where we are because we have access to the labs and expertise in surgery, but in the community only like 40 to 50% of people get. Molecular testing either be even even in a metastatic setting, right, they don't have access to multidisciplinary tumor boards, right, so we take these things for granted. So the things we do here are not done out in the community where most of the cancer is actually treated. So it's very important. So stage 3, this, uh, you know, simple algorithm stage 3 lung cancer is is very important to have molecular profiling. If at all possible, have a multiple um multidisciplinary tumor board to determine if this is resectable or not, right? Very important. We take these things for granted. Tumor board is not offered everywhere, right? We again, we live in an area where we take these things for granted, but most. Places unfortunately don't have these opportunities. Determine its resectable or not resectable. If it's not resectable. Pacific trial right. Well, I'll type get um the value at. If it's EGFR mutated, get OC maintenance, right? If it's resectable, plus or minus, um, um, either alk or, or EGFR, either get OC maintenance or elective maintenance, very important. What do we need to find out? We need to find out the mechanism of resistance for these TKIs in stage 3, right, these new agents coming aboard, biomarkers. We talked about this, uh, somebody mentioned earlier how to use CTDNA and minimal respo and minimal, um, um, minimal disease response to see if we can tailor response for these patients, looking at trials for TKIs and radiation because we're concerned about toxicities and. In the past, but hopefully we can think about combining these things for, um, a better efficacy. We also have to start looking at EGFRs that are not the standard 21 and 19 like the 20s and see if we can include these into our um treatment algorithms as well. We have to molecularly profile all these patients. It's very important to all stages of non-small cell lung cancer, right? Specific is the, is the, is the standard for stage 3 all comers, however, limited benefit for those who have EGFR, right, adjuvant chemotherapy. Um, standard, but now we have the advent, um, TKIs in both EGFR and AC, and it dramatically improves, um, resect, um, improves outcomes and resect the disease, and we are now in the era of personalized therapy that now extends from early stage disease. It's a metastatic disease, but we have to test for the presence of these alterations. And this is just me walking through the Elysian Fields of North Broad Street. Welcome to my car. I, I, I miss my colleagues there, um, but thank you very much for your time and attention.
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