Good morning, everybody. Welcome to our ISLC North American Conference in Lung Cancer Highlights. I am Luis Reyes. I am a thoracic oncologist at Memorial Cancer Institute that is part of the Memorial Healthcare System, the public healthcare system here in Broward County in Miami. It is my pleasure and honor to moderate in this seminar today. We are going to start with some housekeeping. First of all, we are going to do the presentations, a brief presentation from our three co-chairs of the meeting. And when the co-chairs finish, we're going to have time for Q&A. We really love this part because we will have a chance to ask the co-directors of the meeting about the most important findings. I also want to remind everybody that this activity has been planned and implemented in accordance with the accreditation requirements and policies of the ACCME and the International Association for Study of Lung Cancer, ISLC, is accredited by the ACME and to provide continuing medical education for physicians, probably a lot of you want to have CME credits. The International Association for Study of Lung Cancer designates the live format for this educational activity, a maximum of one AMA, PRA, category one credit. If physicians who can credit commensurate with extended order participation on the activity. As faculty planners and reviewers of the webinar today, these are our financial disclosures. Dr. Christine Vesvina, she is a researcher for AstraZeneca and BMS. She has had consulting and advisory board services for AstraZeneca, BMS, CVS, IQI-Anchio, EME, Serrano, Gilead, Mirati, NovoCure, Regeneron, Sanofi, Takeda, and Tempus. Dr. Jyoti Patel, she is a researcher for Anhar, AstraZeneca, Blueprint, BMS, IQI-Anchio, EME, Serrano, Gilead, Sanofi, Takeda, and Tempus. Dr. Mohamed Abassid, he has had advisory board and research funding from Mirati, Bayer, Siemens, and Medscape. Myself, Luis Reyes, I'm a researcher investigator for AstraZeneca, BMS, Syndex, Pfizer, Merck, Bellos, Luxor, Lillin, TJ Therapeutics, CGen, Genentech, Mirati, Garda, and Helena Thera. I do consulting for AstraZeneca, NovoCure, and BMS. Now I am going to stop sharing and give the podium to Dr. Christine Vesvina, who is going to be our first speaker. Dr. Vesvina is an assistant professor of medicine at the University of Chicago. She has a strong interest in lung cancer. That's her expertise, and she works in the thoracic oncology department. Good morning, everyone. My name is Christine Vesvina. It's so nice to see everybody this morning. It's my pleasure to kick us off by reviewing some of the highlights from our NACLC meeting. I'm going to start with our first keynote, which was Advancing Health Equity through Engagement. And then we're going to transition to some clinical trials and drug development with Zongaretanib, as well as a post-progression analysis of Mariposa. And so we started our conference off with an amazing talk by Dr. Marjorie Charleau, Anything for Us Should Include Us, Advancing Health Equity through Engagement. We know that the leading causes of death amongst both Black and white people start with heart disease but are followed by cancer, which is the second leading cause of death for both Black and white people. However, when we look from 1999 through 2020, the Black population had 1.6 million excess deaths, representing more than 80 million years of potential life lost during that period. We also know that lung cancer is the leading cause of cancer-related deaths, and that of lung cancer deaths, the highest mortality rates are among Black men compared to other racial and ethnic groups in the United States. When we look at some of the root cause of racial and ethnic health inequities, what Dr. Charleau really focused on was how do we change the narrative here, and how do we look at structural racism, its contributions to health inequities? How do we focus then on some of the social determinants of health, and those include things like access to transportation, food insecurity, access to legal support, housing insecurity? And through the framework of those social determinants of health, how can we break it down to a policy, community, institutional, interpersonal, and individual level? Dr. Charleau did an amazing job offering up solutions at each of these levels as far as how we could really change the Black community. From a policy level, we could consider things like Medicaid expansion. At a community level, we should really look critically at where people live and how that relates to access of cancer care. Traditionally, many of our cancer centers are located in areas of predominantly white neighborhoods with much higher levels of education. How do we allow for access to all communities to that level of cancer care? Then we look at the institutional level. How do we as institutions provide trustworthy care, specialty care, and how do we address certain institutions that are under-resourced, which again are often located in predominantly Black neighborhoods? Then we move to the interpersonal level, and that's really where we see the physician to patient relationship. How do we address racial bias in these encounters? How do we improve communication and racially discordant dyads between patients and physicians? How do we ensure that there's appropriate workforce diversity so that all peoples are represented? At an individual level, how do we change the narrative that we're seeing in our clinic? She ended her keynote with this adapted quote from James Baldwin or from The No Name in the Street. I'd like to share this because I thought this was an amazing adaptation. Centering the overburdened. If one really wishes to know how equity is practiced in the healthcare system, one does not question the clinicians, the administrators, the researchers, or the well-insured members of the middle class. One goes to the overburdened, those precisely who need the healthcare system the most and listens to their narrative. I'm going to switch gears now to clinical trials and drug development. First, we had an oral presentation of Zungartinib. This is an ERBB TKI. What this drug does is it's a bit different than the prior HER2 TKIs that we've seen. On the left, we see the mechanism of action of ERBB TKIs. Those drugs have limited activity against HER2 exon 20 insertions, which is what we're really trying to target, while they do block wild type HER2 and wild type EGFR. This blocking of wild type EGFR is what has led to a lot of intolerance issues or problems with the GI or skin. How Zungartinib is different is that here, there's not activity at wild type EGFR, limiting some of those toxicities, while the drug is active against HER2, including exon 20 insertions. This selectivity is much better than prior drugs that we've seen, such as Poseotinib. This is the Bemian Lung O1 study. There were two different dose escalations, looking at both a BID dosing, as well as a daily dosing, to lead to the dose expansion. Here is the safety data from the phase 1a dose escalation. You'll see that, in general, the drug was generally well tolerated. There were two DLTs during this drug evaluation period, which included diarrhea and thrombocytopenia. Five total patients had DLTs during the on-treatment period, including diarrhea, edema, LFT elevation, and thrombocytopenia. And only three patients of this group had drug discontinuation due to toxicity. The maximum tolerated dose was not reached with either the BID or the daily schedule. And so the doses that were taken into optimization for the next portion included 240 milligrams and 120 milligrams daily. Here's a look at the early efficacy data. On the left, you'll see the waterfall plot. And to me, this is really impressive for a drug targeting HER2, compared to what we've seen before with other TKIs. In the overall patient population here, we saw a response rate of 49%. Among patients with non-small cell lung cancer, we saw a response rate of 58%. On the right, you'll see that the duration of drug use was really quite long for many of these patients. They were able to stay on the drug for a long period of time. The median duration of response was over a year. And at time of data cutoff, 57% of patients were still on treatment. Looking at the preliminary safety data here with this 120 and 240 daily dosing, again, looks quite well tolerated. The rates of diarrhea were 25% to 30%, with no grade 3 diarrhea events, much improved over prior HER2 TKIs. Two patients had a dose-limiting toxicity, which were febrile neutropenia and thrombocytopenia. And one patient had an additional DLT during the on-treatment period, which was LFT elevations. The antitumor activity at this phase 1b dosing looked even more promising. So here we saw a response rate of 74%, and all responders are ongoing. And so how do we put this drug into context? Early data demonstrates high response rates with durable responses, as well as a manageable AE profile. This drug also had the advantage of having oral administration. Dr. Steven Liu was our discussant and did a wonderful job posing questions about how this drug moves forward and what are the big questions that we need to answer. The first is, what is the efficacy after trastuzumab-Duroxetocin? And what will the optimal sequencing be with Zongaritinib versus trastuzumab-Duroxetocin for patients who have HER2 alterations? And the last talk that I'll summarize is a post-progression analysis from Mariposa. Mariposa was a three-arm trial for patients with newly diagnosed EGFR exon 19 or LE58R mutations. The three arms were amivantamab plus lasertinib, osimertinib, and lasertinib monotherapy. The initial data was presented at ESMO this year, and here we saw progression-free survival improve from 16.6 months with the osimertinib arm to 23.7 months with the amivantamab lasertinib arm. The new data that we saw at NACLC, however, addressed the following. The first is treatment beyond progression. We all know in the clinic that our patients who are on targeted therapies will often continue the therapy if we believe the patients are clinically benefiting, even while their scans demonstrate progression. And this trial appropriately reflected that clinical practice. About half of patients in both arms received treatment beyond progression. Time to subsequent therapy with osimertinib was 24 months, while this still hasn't been reached in the amilaser arm. And time to treatment discontinuation was somewhat similar between the two arms, 23 months with osimertinib versus 26 months with amivantamab lasertinib. Additionally, we looked at the most common first subsequent therapy is following initial trial treatment. In the burnt orange, which is the majority in both arms of the trial, patients received doublet chemotherapy. In the orange, we saw patients who got doublet chemotherapy plus either IO or VEGFI. Additionally, patients may have received a third generation TKI or TKI-COPO. The timing of onset of key adverse events was also analyzed. And here we saw that almost all patients had their adverse events noted within the first four months. And those included, for the amilas combo, rash, parenchia, dermatitis, stomatitis, and importantly, VTE. And so what we saw from this additional analysis is that of the patients with disease progression, 50% in both the amilaser and the OC arm continued treatment beyond progression. The most common first subsequent therapies were doublet chemo, doublet chemo plus IO or VEGF, and a third generation TKI in both arms. And the majority of AEs had their onset in their first four months. And with that, I'll transition to my partners. Okay. Now, it's our pleasure to introduce Dr. Mohamed Abasit. Dr. Mohamed Abasit is Associate Professor of Medicine in Northwestern University. He works in the Radiation Oncology Department, but he's also a scientist. And he's a co-leader of the Lung Cancer Program. He's going to give us a review of the selected topics that he has chosen from the North America Conference on Lung Cancer. Go ahead, please, Mohamed. Thank you. Thank you so much. Thank you so much, Luis, and thanks everybody out there who's joining in. It's a real pleasure for me to pick out selected topics from this year's conference. There are many, many abstracts and presentations that I could have selected. Unfortunately, I can't highlight all of them. The ones that I do want to highlight really span and give indications in terms of the diversity of topics that were discussed at this conference. The first one is the second keynote address by Dr. Pira Lita from Memorial Sloan Kettering. We're going to be talking about cutting-edge CARES-directed therapeutics. Screening was a major topic at this conference, and an interesting abstract that was discussed in the oral session was the implications for screening and the potential biases that these investigators hope to address. And the last is a really interesting and novel concept of potentially using food as medicine intervention. We'll be talking about the NutriCare study. So this is a quite extensive biochemical discussion, but I want to highlight sort of the clinical relevance of this and really give an elevated view of the importance of where we expect KRAS inhibitors to go in the next five to 10 years. So it's important to note that KRAS mutations are obviously frequently mutated in lung cancer, in adenocarcinomas, the preponderance where the preponderance of KRAS mutations occur. You have a significant proportion that is KRAS G12C, and the reason why that's important is there's obviously two FDA-approved drugs that are currently available that target this particular allele. However, it's important to note that there are other alleles, both at the G12 position and the G13 position, that aren't currently targetable, although there is an extensive ongoing efforts to target those mutations. And so we don't believe that this is going to impact just lung cancer, it's also going to impact other diseases, colon, for example, pancreas, as well as many others. So the development of KRAS G12C inhibitors has been ongoing for well over two decades with significant progress in the last decade. This has led to the development of two main compounds, two main drugs that have been clinically tested, sotiracib and adegiracib, with not insignificant potential response rates. So why is this so difficult to target? We have to remember KRAS isn't a tyrosine kinase, it's not a kinase, it's a GTPase, and so blocking it mechanistically is substantially more challenging. And the reason why the G12C transition is so important, the cysteine, is that it makes it amenable to covalent modification. So I just want to remind the group here that we see not great, but some patients with deep responses, but overall partial response rates, as indicated in this summary table. And this really suggested the question of why are these compounds, why aren't we getting more deep responses, and what are the mechanisms of acquired resistance, which is the focus of Dr. Alito's discussion. So one thing to keep in mind is that for most tyrosine kinases, we are targeting the active state of the enzyme. In the case of KRAS inhibitors, we're actually inactivating the inactive state of the GTPase. So in this scenario, GTP cycles on and off. When GTP is in its triphosphate form, when KRAS is bound to its triphosphate form, it activates KRAS, and when it is in GTP form, it's inactive, and the drug really targets the inactive form. So one mechanism identified by Dr. Alito's group is the fact that it just needs to stay in the active form, and this is how it can avert inhibition by soduracetab and adeguracetab. So this really could be the explanation of why these compounds give partial responses and not higher depth responses. And so G12C is wonderful to target, but there is active ongoing efforts to target other alleles in KRAS. As I mentioned earlier, these other alleles really constitute about a third of adenocarcinomas. And so another approach here is to use what are called GDB-bound traps. These are a new class of compounds that are being developed, and so we look forward and are excited about their development to potentially expanding the list of alleles that we can offer to patients. And lastly, to get around this adaptive mechanism, the goal is to really target the active state of KRAS. So when KRAS is active, can we find a way to block this active form? And we suspect that this is going to substantially add potency to the drugs that we're using clinically. And so this is what's called a triacomplex inhibitor, cyclophilin A, bounds a compound that binds the active state, and you can see here, at least in preclinical data, that it has substantial effects on KRAS G12C in this scenario. So G12C selective, this particular revolution medicine compound, has been tested in early phase in ongoing clinical studies, and it shows promising results in these early stages and shows tolerability as well. And so lastly, the expansion of these triacomplex inhibitors to other alleles, again targeting KRAS in its active state, is going to be crucial. And so I think Dr. Lito really gave the perspective that we've been working on TKIs for, we had worked on TKIs for over a decade before finally identifying the genetic alterations that confer an exquisite sensitivity to those compounds. We've really been only working on KRAS inhibitors for the last five years. So look at this space as potentially exploding additional alleles and potentially better response rates going forward. I want to shift gears to talk about screening. In particular, I want to highlight an oral abstract from the Mass General Hospital looking at pack-year smoking history and potential bias measures that determine lung cancer screening eligibility. I want to remind the audience that in the U.S., lung cancer screening eligibility criteria require individuals to have at least 20 pack-year smoking history, and this criteria has been historically shown to exclude many high-risk individuals, especially those from racial and ethnic minority groups. And so this data, in this particular abstract, the inclusion criteria were using a southern community cohort study of patients who had a history of smoking, both black and white. There were approximately 2,000 lung cancer cases, black women, and also used the black women and black women's health study, but a history of smoking in about 486 lung cancer cases. And the statistical analysis that was proposed was proportion of individuals who would have qualified using the 2021 USPSTF criteria. And so this is a really important slide. It shows that for those diagnosed with lung cancer, stratified by ethnicity, whites versus blacks, what's clearly evident here is that in the black category, you see a substantial lower number of pack-years leading to lung cancer. And so in relation to the first keynote address, which really, for us, bias, sort of philosophy, we really need to, this suggested that we really need to narrow in on particular subgroups and potentially alter the criteria for screening. And so this is the data that was presented from those two large studies. In the criteria that uses pack-year smoking, so 20 pack-years, about 62% of black lung cancer patients who currently smoke would have qualified. Whereas if you, and this is what the authors propose, is if you increase, if you change the criteria to 20 years of smoking duration, so not using the pack-years, but simply the duration that patients have smoked, you would capture 92%, and these are for current smokers. And a similar increase or similar in proportion increases was also observed for patients who formerly smoked. These are black patients, and you can see here that if you go from a 20 pack-year to a 20-year duration, you can capture a significant proportion of black lung cancer patients. So the conclusion from this important study was that there are limitations to the historical use of the 2021 USPS TAF guideline, and the authors suggest that potentially shifting or altering that guideline to, instead of pack-years to smoking duration, is poised to increase the number of captures, especially for ethnic minorities. And then lastly, you know, what I thought was a really, really innovative approach that addresses holistic, holistic challenges to caring for patients with lung cancer was the NutriCare study. So this was eye-opening for, certainly for me and perhaps some in the audience, but vulnerable patients with lung cancer obviously face higher rates of malnutrition, about two-thirds, half to two-thirds of the patients with lung cancer are malnourished, and 35% experience significant weight loss resulting in severe malnutrition. And so the hypothesis here is that, can you provide an intervention to mitigate this, and will this mitigation ultimately change outcomes, or at least quality of life measures? And so the patients had to be greater than 65 years or from an underrepresented minority or from a rural zip code or income level, randomized one-to-one, so NutriCare was actually the intervention group here where meals were delivered and nutrition consult was initiated, whereas NutriTool was simply given guidance and information about nutrition to maintain an ethical randomization approach. About 158 patients were consented, randomized almost equally to NutriCare versus NutriTool, and meals were actually delivered to patients in the intervention arm, as I mentioned. So the preliminary findings from the period of enrollment from 2020 to 2022, 127 patients with lung cancer were randomized, these are the patient characteristics, and again, the intervention here is approximately 12,000 meals and snacks were delivered, and 844 nutrition counseling sessions were provided. So I'm going to highlight not all of the data, but some of the data that I thought is promising in this preliminary stage, and so this is predicted in healthy eating index, so perhaps not surprising if you provide healthier meals, the likelihood of utilizing those healthy meals increases, and so the healthy eating index substantially appears to be significantly increased in the NutriCare intervention group. Overall, there were other metrics that were measured, but what seems evident even from the early data is that quality of life appears to be positively influenced by the NutriCare intervention, and so various quality of life measures here on the y-axis, so in the positive direction suggests that that is desirable, here in the negative direction that is desirable, so these are negative symptoms, if you will, and then these are positive features, and you can see here the blue being the NutriCare group, you see significant increases in at least some of these categories, and so the conclusion, although quite preliminary, is that integration of intensive nutritional intervention is feasible and can be delivered to vulnerable patients with lung cancer. There are significant improvements in diet quality, I think that was evident. Both groups appear to sustain improvements in quality of life with significant subscale improvements, and although I didn't talk about it, length of stay related to cancer treatment was trending shorter in the NutriCare group, and so the author suggests that additional nutritional studies are needed and focused on proactive nutritional support. So, with that, thank you so much for your time, I'd like to pass the baton over to my colleague, Dr. Patel. Now it's our pleasure to introduce Dr. Jyoti Patel. She probably doesn't need introduction, she's very well known, like our other co-chairs, but I want to mention briefly that she's a Professor of Medicine and Vice Chair of Clinical Research in the Department of Medicine at Northwestern University Lurie Cancer Center. She's also the Director of Thoracic Oncology Program. Thanks for joining us today, Jyoti. Luis, thank you so much for this invitation and thank you to the entire IASLC committee and staff for allowing us to highlight some of the excitement at North American Lung. So I'm going to focus primarily on early-stage non-small cell lung cancer and highlight three or two abstracts as well as one keynote, so really understanding biomarker testing in this space, understanding the implications of targeted therapy, and then I'd like to highlight Dr. Spicer's keynote address on perioperative therapy. So the first study I'll talk about was presented by Dr. Hu, who is an employee of Merck, who did a real-world cohort study about biomarker testing and adjuvant therapy in a relatively recent cohort, 2019 to 2022, and the lessons we can learn from this. So the point of this study was that certainly our world has changed dramatically in recent years, with different FDA approvals of both targeted and immune therapies in the adjuvant setting. This is a fast and furious timeline, with osimertinib approved in 2020, seeing overall survival results from osimertinib at ASCO this year, to two adjuvant therapies, immunotherapies approved, atezolizumab for patients with resected PDL-positive non-small cell lung cancer, and pembrolizumab as adjuvant therapy for all non-small cell lung cancer. So based upon these approvals, current standard of care for resectable early-stage non-small cell lung cancer does include testing for EGFR alterations in PDL-1 expression. So this was really to understand how we in the U.S. are practicing and how this has evolved with these new therapies in this timeframe. So what they did essentially was to describe the rates of testing over time and to get the results and to really dive down into our use of adjuvant therapies. The group from Merck partnered with Flatiron Health, which brought together de-identified data from 280 U.S. cancer clinics and looked at patients with stage 2 to 3b non-small cell lung cancer from January 2018. Patients could not have received prior therapy, and they had to have a tumor resection before January of 2023. So this is the data they found. They had over 1,000 patients using the Flatiron early non-small cell cohort, sort of teased out the number of patients with stage 2 and underwent tumor resection. I think this is representative of the patients that we see. 57% of patients had stage 2 disease, half of the patients were women, 8% of the patients were Black, most patients were former smokers or current smokers, predominantly non-squamous histology. It was a nice mix of about a quarter academic sites and some community clinics. There were some sites that were both, or patients got treatment at both centers. So if you look at the breakdown, you can see that there is certainly some testing gaps here. So about 50% of patients underwent EGFR testing. Of those, 13% of patients had EGFR mutations. 55% of patients underwent PDL testing. And corresponding to data that we think is reasonable, about a third of patients either had no PDL, had low PDL, or had high PDL. And you can see the breakdown by stage. If we look by year, there was certainly uptake. And so this is exciting because we see progress based upon results, but certainly even in 2022, after I think osimertinib as adjuvant therapy was standard of care and has been widely adopted, we see that only 68% of patients had EGFR testing. At that juncture, 75% of patients had PDL1 testing. And so again, that is often done reflexively for PDL1 testing. Whereas I think for EGFR testing, there are still questions about what that ordering looks like for certain patients. But really remarkable that we're doubling of testing over this short period of time. If we look at the therapies that were assigned based on this, we can also see that patients, the majority, but not all patients received adjuvant therapy. So looking at platinum-based chemotherapy, so 65% of patients received initial adjuvant therapy. And then of those, another two-thirds of patients received PDL1 treatment. And you can see that again, over time, these numbers increase. I would say that these are primarily healthy patients who had undergone resection and even in a predominantly a stage two and a stage three population where we have strong evidence suggesting that all patients should get platinum therapy to reduce the chance of recurrence and to lead to an improvement in overall survival. But still a large number of patients were not receiving adjuvant therapy. So certainly some space to make up there. The authors concluded that certainly we saw an improvement in testing rates for EGFR and PDL1. However, even as recently as last year, a quarter of patients were still not tested. Only two-thirds of patients receive appropriate adjuvant therapy after resection of stage two and up to three B non-small cell lung cancer. Most patients still get platinum therapy. Often we'll see this introduction of PDL1 treatment. So 15% in 2019 to only about half of patients in 2022. And again, that sort of also reflects the initial approval of atezolizumab in a PDL1 population compared to all patients with pembrolizumab. The next study was certainly important. Dr. Barlessi from France presented electinib versus chemotherapy in resected non-small cell lung cancer. This was in the non-Asian cohort. Remember that the primary results were presented recently at ESMO. And so as background, a four to 5% of patients have ALK rearrangements. Usually these are younger patients, never smokers. We know there's a predilection to developing brain metastasis. So preventing that is certainly of importance. Based on three phase, three trials, electinib improves outcomes compared to crozotinib. It's highly CNS active and the side effects are well characterized. So this, the ALENA trial that was presented is the first and only positive phase three trial in the ALK positive space. So these are the results from the ESMO presentation from Dr. Solomon for all patients. So as a reminder, ALENA was a randomized phase three trial of patients with stage 1B to 3A non-small cell lung cancer with ALK rearrangement. Patients were randomized to electinib 600BID or platinum chemotherapy. So this is dissimilar from Medora where all patients got platinum chemotherapy. And I think many of us have some concerns about it. Patients were followed until recurrence. Electinib was only for two years. The primary endpoint was disease-free survival. So certainly this was highly positive. We can see sort of the significant improvement compared to chemotherapy that electinib brings in disease-free survival. Importantly, we see a corresponding improvement in CNS disease-free survival. This was certainly felt to be a very positive study. So in the non-Asian subgroup of patients, so sort of looking again at the global population, the non-Asian parents or patients were a little bit younger. They were more likely to be female. Only surprisingly, about 50% of patients in the Asian subgroup and 57% of patients in the non-Asian subgroup were never smokers. Most patients had stage 3 disease and predominantly non-squamous as one would suspect. So in the non-Asian subgroup, you can see an improvement in disease-free survival. Again, even a higher, more deep hazard ratio than in the global population, corresponding improvement in disease-free survival in the CNS state. And so the author's conclusions were that this DFS hazard ratio, 0.16, was highly significant. It is. There's an improvement in CNS disease. In this non-Asian population, we're seeing again the deep benefits for our patients. So certainly adjuvant electinib is an important new treatment strategy for all patients with resected 1B to 3A non-small cell lung cancer. I think many of us would think that these patients should still undergo chemotherapy, but certainly electinib improves outcomes. And so this again posits the testing that we should be doing for our resected patients. We should find out whether or not they would benefit from such an impactful therapy. The next talk I'd like to highlight, it was a really great keynote by Dr. Jonathan Spicer. Dr. Spicer is a thoracic oncologist from McGill University in Montreal. He has been involved in many of the neoadjuvant and perioperative trials. And so he started with, I think, a very provocative slide to really think about how we've been assessing preoperative versus postoperative or adjuvant therapy and went back to the NACH study by Dr. Philippe, which was published over a decade ago. And really thinking about how preoperative therapy, although associated with a slight benefit, has really never been, I think, widely embraced with just chemotherapy. Remember, though there was a benefit, this was not statistically significant by any means, and adjuvant therapy improves outcome after surgery slightly. So we've been used to delivering systemic therapies that are marginally helpful, but do lead to overall survival benefits in the three to five range for many years. So he made us sort of provocatively think about, okay, now in the age of neoadjuvant and adjuvant immunotherapy, how should we be thinking about lung cancer? The problem is that most patients will end up recurring. And the problem is that our imaging and current assessment of patients doesn't really help us distinguish those patients that have micrometastatic disease at the time of diagnosis who are destined to recur despite our best efforts, our best efforts at PET scans, MRIs, and EVAS. Says that this sort of artificial conundrum we've created for patients with a resectable disease, thinking about upfront surgery, followed by adjuvant, chemo, immuno, treating patients only with neoadjuvant therapy, thinking about perioperative therapy, all of these three strategies, the goal is the same to improve overall survival, but maybe this isn't the best way to think about how we assess treatment. He really pushed us to think about, okay, how are we curing some patients? And one of the things that he highlighted was how well the pathologic CR, complete response rate correlates with improved outcomes. So data that we're seeing from the combination of chemotherapy and nivolumab for patients. So you can see again, this significant improvement in event-free survival and really an amazing overall survival for patients with stage 1B to 3A disease who achieved a pathologic CR. So those patients that receive a pathologic CR after initial therapy have an overall survival of 95%. So this is certainly much more impressive than what we do even with stage 1 disease. And really thinking about, okay, is this an end point that we can hang our hats on? He highlighted a paper that was published several years ago by Matt Hellman and his colleagues at Memorial when he was there, really thinking about how we accelerate drug approval and adoption of practice based on path CR data. And you can see that if we're looking for overall survival from enrollment to the publication of data can take a decade. Whereas using path CR as a surrogate for OS, certainly in the breast cancer space has improved delivery of optimal therapy significantly. And now we're seeing that same thing in lung cancer. And then this sort of area at the bottom, if we think about hazard ratio for death, it is likely that we can be more granular about the amount of treatment effect. And that correlates pretty significantly with the hazard ratio of death. So minimal response in the tumor with over 70% residual volume has a five, almost a five-fold increase in your risk from death versus having a path CR. So certainly provocative data. So if he thinks about the association between path response and survival after neoadjuvant chemotherapy and lung cancer, what we can conclude is that patients with path CR after neoadjuvant IO are probably as close to cured as we know how to achieve. That patients with residual disease like greater than 80% inevitably progress within those two years. And then that sort of middling, it's a coin toss. So it's really this group of patients in whom we should be intensifying our efforts, really thinking about research for these patients and how to best improve their outcomes. So this sort of area, if we just kind of wait until OS, I think it will take a long time to figure out. And so this is the case for perioperative therapy or neoadjuvant therapy. We can focus on those patients and again, try to make inroads. So certainly this is some of the data for perioperative pembrolizumab. Again, evidence that patients who have a complete response do really well. But what's really interesting, I think, is that patients who don't have a pathologic complete response continue to benefit from adjuvant pembrolizumab. So this is one data set, not a huge number of patients, but clearly you see a difference with giving more immunotherapy post-path CR or without attainment of path CR than placebo alone. So what do we do in the meantime? We have a number of studies, right? So we have 816, which is just induction therapy and then a number of perioperative studies. We can see they're remarkably consistent. Most patients get to surgery, but almost 20% of patients don't. And that's a real problem for us. We still need to make sure that we don't cripple patients with our therapies and make sure that they get the local therapy that's impressive. 90-day mortality, this is pretty exciting too. Look at how, look at the improvements in our surgical outcomes for our patients. So patients are doing well, despite some studies even having pneumonectomies. The R0 rate is certainly reflective, I think, of differences in clinical trials. So patients who could not be on with pneumonectomies, but again, pretty high R0 rates and then event-free survival that is much better, again, than one would have thought years ago. And we're waiting for some of this OS data. So we have some mature data, but I mean, this is certainly impressive to think about the older slide from Natch. So if this is a paper that Dr. Spicer has submitted, it's not yet published, but you can see that compared to chemotherapy, if we look at sort of the hazard ratios, perioperative therapies and induction therapies improve outcome. I think the data with perioperative pembrolizumab certainly sticks out a little bit. Many of these other trials such as Neostar, such as Nadeem potentially give further evidence that this is the way we should go. So we think about what's the optimal perioperative therapy for early stage non-small cell. We want to improve survival efficacy certainly, but we want to make sure that toxicity is minimized. That AE profile on both short and long-term, so there's 20% of patients that don't get to surgery, patients that may require a year of immunotherapy and the toxicities that come from there. We want to decrease functional loss and how do we really think about maintaining quality of life. This idea about, is there a way to sort of personalize, follow up. So for patients who are destined to be cured because of APAXE-R, is there a way to change surveillance and to decrease sort of the cognitive effects of anxiety? How do we think about patients in terms of maximizing therapy to improve, to decrease toxicities and improve quality of life, I think remains sort of North Star for the next years. And we have to do this in a way in which we can provide the best therapy for a range of patients. So how do we do this at a lower cost? How do we use better diagnostics and surveillance to find therapy that's both affordable and equitably distributable? So this piece, he actually started with this slide and I'd like to end with this slide to really think about how we bring patients with early stage to us. It is not easy and it is a team effort. And again, this is why I think this conference is so wonderful. It brings people from all sorts of disciplines to us. But if a patient is felt to have early stage disease, they undergo a number of diagnostic tests, pathologic diagnosis. How do we think about the best approach for patients? Should they get neoadjuvant therapy or perioperative therapy at this tumor board? How do we think about getting adequate testing? Do we do it in-house? Do we send it to third parties for testing? How would we integrate clinical trials? It's not so easy to get to that single slide. So again, this idea about truly multidisciplinary care is paramount. So in summary, I think these are the takeaway points from early stage disease. We need to get appropriate biomarker testing. Certainly we know electinib improves outcomes and perioperative therapy improves outcomes. There is room for refinement, but we'll continue to study the outcomes of these patients. And then to harken back to what Dr. Bustovina told us about, we need to find more early stage lung cancer if we're going to cure more patients and to really share some of these benefits. So with that, I will stop. Thank you. No, thank you very much to all of our presenters. We are going to ask some questions briefly, please short answers. The first one is we're very glad that we are discussing social determinants of health because we are scientists. We can give you the best immunotherapy of the world, but if we don't contemplate the social determinant issues, the patients are not going to get the benefit that we expect. In that regard, the SLC is not only a worldwide association for over 90 countries with all the races, but we also have our own committee for DEI. You will know more about this as more events are coming in the near future. Christine, you presented mariposa. You know, amivantamapraslacertinib. Maybe it's better than oxymertinib. Now our community oncologists are asking very often, oxymertinib is our standard of care for EFR. In World Long, they said oxymertinib plus chemo, maybe it's better. Now we have the data from amivantamapraslacertinib that maybe it's better. How are you going to pick and choose if all of these regimens are FDA approved or EMA approved? Yeah, it's an amazing position to be in to have so many options and to be debating what the best path forward is. For me in my clinic today, I'm still using oxymertinib monotherapy for the large majority of patients. I am considering oxymertinib plus chemotherapy for patients who have CNS metastasis based off of the FLORA2 data. We're still waiting for overall survival from both FLORA2 and also the amivantamapraslacertinib trial. And so if we see a positive overall survival, I think we may have to reconsider that treatment paradigm. But for right now, I'm sticking primarily to oxymertinib monotherapy. Excellent, excellent. And then Mohamed, there was so much in the conference, I guess we didn't have a chance to discuss the radiation part, but we are always looking for the opportunity to incorporate IO with radiation therapy, especially for locally advanced. So what is your opinion? Because recently we had this news that the Pacific 2 study was negative combining immunotherapy with radiation. Do we still have a chance maybe with other studies that are pending to combine immunotherapy with radiation? Maybe one get rid of the chemo one day? Right, that's a great question, Luis. I think it's important to caveat the discussion about Pacific 2 with the fact that we don't have all the data. And so I'd love to sort of look at the data before coming to a final conclusion. But what is evident to the top line here is that when given together radiation and immunotherapy, it appears, and we'll know more from ECOG and other studies that are pending, but it appears that it is less effective than when given separately. And so it turns out that perhaps retrospectively we got it right in Pacific 1, which is chemo and radiation work better together and chemo and immunotherapy work better separately. There's a lot of active research going on to try to unlock this mystery of radiation, potentially radiation suppressive effects on immune environment. And potentially that it's an area of further investigation. For the time being, both in lung cancer as well as head and neck cancer and cervical cancer, most studies that have done immunotherapy with radiation given large field, small doses incrementally given over six weeks of radiation, those have generally done poorly. With SBRT, there seems to be a different type of phenomenon. So we had the EyeSaber study, which I didn't have a chance to highlight today, but in that study immunotherapy is given concurrently and adjuvantly after SBRT. And those patients did substantially better. It's a small study, it's a two arm phase two, but there were better local, nodal and distant control rates. And so I think a lot more to investigate in this space, but certainly the trend line here is that for large field radiation, probably not great to combine them. Yeah, also a quick question. There is somebody in the audience that wants to know what is the definition of health and nutrition is unique, the one that you did in the presentation? Yeah, I'm happy to answer that. I don't think the definition of health and nutrition per se is unique. I think what is unique is using nutrition as thinking about it to deliver care. I'm thinking about it as a critical component of the oncological care process. And so we give really, really expensive and sophisticated drugs, but perhaps we're missing the obvious intervention here, which is given somebody just simply a nutritious and good meal. Great, great. Also, there is another question, more is like a comment, you know, that how we went to practice lung cancer treatment in time of war. As a scientist, you know, the world is not going to help us. Maybe that one is... I want to let you know that in the Journal of Clinical Oncology Practice, 20 ISLC scientists of us wrote a paper about Ukraine, how the Ukraine war only in the first six months can decrease markedly the mortality and the population in the four most important cancers. So you're welcome to review the paper, it's for Dr. Christian Kaglievic, that it goes exactly what you are asking. Jyoti, you just said about Alina, but you know, first question is, should we testing now early stage patient? You have a patient with stage two and three, should everybody gets now NGS? Because we have data for EFR, we have data for ALK. So should we do NGS in everybody? Only PCR for EFR and ALK and wait for the others? So that's a really provocative question. My feeling is that patients at the time of diagnosis, so on E-Best specimen should undergo appropriate molecular testing. And so that means that we have EGFR and ALK to incorporate into our perioperative therapies. So those patients need to be excluded from neoadjuvant chemoimmuno. So I think we need that upfront. If patients, once patients are resected, then I think it's absolutely appropriate to do NGS. There are a number of phase two studies that are ongoing at this juncture, looking at different consolidative therapies. So for RET, for example, or for KRAS, there are a couple of induction strategies as well, but that I think really is on a protocol. You know, the question that I get often in clinic and from friends and colleagues is, okay, so I've excluded EGFR and ALK. Oh no, this patient now has a ROS1 translocation or this patient has a RET or a met exon 14. Should I give neoadjuvant chemoimmuno? And I think this is an area in which we don't have a lot of data. I kind of use the same barometer to think about, would this patient off of, in the metastatic setting, benefit from immunotherapy? And if the answer to me is no, so perhaps for ROS1, I'd probably treat that patient only with chemotherapy or resection followed by chemotherapy. Perfect, perfect. There is a quick question about for stage 1A, what we can do. For stage 1A, our standard of care is only observation, but there is a gene signature, if you guys are familiar, that you can do, but it's not validated. Not all of us do the gene signature. I don't want to advertise the company, but the gene signature can classify the tumor in high risk and low risk. So giving you the idea that the tumor is high risk, you can give chemo, low risk, no chemo, and also we have a pending EFR study with Osimertinib for stage 1A, so keep tuned, but we don't have a standard of care yet. Christine, sorry to interrupt your question, but that's why they ask, if you have a patient post-surgery with another genetic aberration than EFR or ALK, RET, KRAS, you will give the patient adjuvant therapy extrapolating the data of the other two studies or no yet? So I will give chemotherapy. I think chemotherapy absolutely still plays a role here. And then as far as the other targeted alterations, to me, it depends on how high risk the patient is, the efficacy of the oral drug, and the toxicity of the oral drug. These are patients who are going to be on these drugs for two to three years if we're extrapolating from Molina and Adora. And so I want to make sure that we're not impairing their quality of life too much, given the fact that these patients may already have been cured. Yeah, that's a very controversial topic. Thanks for the short answer. You know, we're running out of time, unfortunately, and for the people that wants to have, thank you very much again for our panelists. I was telling you at the beginning, really appreciate your help on behalf of the SLC because you guys worked months to put the conference together, and now the conference is over, and we're still asking you to do more, so thank you. We really appreciate that. Thanks for that. So thank you very much on behalf of the SLC. It was a pleasure to share this with you. This will be recorded if somebody wants to review it. Have a great day.

ISLC North American Conference

lung cancer

health equity

disparities

structural racism

social determinants of health

biomarker testing

targeted therapies

nutrition intervention