Welcome, everyone, to the ILSRC Webinar, Best of Lower Lung Cancer Conference 2024. I am Clarissa Baldotto, I'm a medical oncologist in Brazil and the president of Brazilian Group of Thoracic Oncology, and on behalf of the Education Committee, I will be your presentation moderator today. This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continued Medical Education, ACCME. The International Association for Lower Lung Cancer is accredited by ACCME to provide continued medical education for physicians. The ILSRC designates the live format for this education activity for a maximum of 1.0 AME PRA Category 1 credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. All faculty, planners, and reviewers for the webinar today have disclosed their conflicts of interest. This information is provided on the following five slides I'm going to show you now. So, to start this webinar, I'm going to call our first presenter, Dr. Jacob Sands. He's a medical oncologist at Dana-Farber Cancer Institute and assistant professor at Harvard Medical School, Boston, U.S. Thank you, Dr. Sands. Thank you. I'm very happy to share with you three of the abstracts or the presentations from World Lung. We'll start with Harmony 2, Ivanesimab versus Pembrolizumab as first-line treatment in PD-L1 positive non-small cell lung cancer. We'll then go on to Tropion Lung-01, which was datapodimab direct-to-can versus dosetaxel, again, in non-small cell lung cancer. And then we'll move to small cell lung cancer with Adelphi 3-0-1, which was Tarlodimab in previously treated small cell lung cancer, the extended follow-up. So, first, starting with Ivanesimab. As background, of course, the anti-PD-1 and PD-L1 therapy has been a backbone at this point for quite a while in the treatment of non-small cell lung cancer. Monotherapy with Pembrolizumab in particular has been a standard in PD-L1 greater than 50%, as well as a common regimen in combination with chemotherapy in the less than 50% PD-L1. Now, Ivanesimab is a novel bispecific antibody. It's a PD-1 and VEG-S that's shown promising efficacy in the frontline trial. In patients with PD-L1 positive disease, this has been a phase 2 study. Harmony 2, which we're going to review, is a randomized double-blind phase 3 comparing Ivanesimab with Pembrolizumab as first-line treatment in patients with PD-L1 positive non-small cell lung cancer. Here's the schema. Again, a randomization of Ivanesimab versus Pembrolizumab. These are, in the first line, no prior systemic therapy and no EGFR or ALK rearrangement in the tumors of the patients enrolled. Again, PD-L1 positive to 1% or higher. The primary endpoint was progression-free survival by blind independent review at Pervitif 1.1. As far as the baseline characteristics, I'll just briefly highlight toward the bottom PD-L1. You see the greater than or equal to 50% was about 42% in each arm. So, a little less than half of the PD-1 greater than 50% and then the 1 to 49 being a little more than 50% and even between the two arms. In the fourth down from the top in smoking status, you can see around 19 to 20% of patients had never smoked in this. Now, they were EGFR and ALK negative and I also want to highlight that this trial was conducted in China. So, this is a Chinese population and we do see a bit of a difference in smoking history and the tumor across Chinese population and U.S. population. Looking at the primary endpoint, we saw a really a shockingly good separation of the curves and almost doubling of the median progression-free survival with a stratified hazard ratio of 0.51. So, very convincing progression-free survival endpoint. When looking at the subgroup, you know, with the exception of one with very low numbers, these all really lean into the Ivanesimab side of the chart. When looking at subgroups, really all subgroups appear to benefit from Ivanesimab in comparison to Pembrolizumab with convincing hazard ratios across all of them looking at PDL1 1 to 49% as well as the greater than 50% and squam and non-squam which showed meaningful improvement in progression-free survival versus Pembrolizumab. We also saw pretty convincing differences in response rates as well as disease control rates and you can see in the Ivanesimab arm was a 50% response rate and a 90% disease control rate. As far as adverse events, there was nothing particularly surprising here. We did see some of the VEGF side effects that we would expect with this drug that has a VEGF inhibition as well. You see proteinuria is on there as well as hypertension probably being the two most notable but along with some other less significant increases in toxicity relative to Pembrolizumab. The immune-related adverse events, again, nothing surprising here. If anything, there was a little bit less in the Ivanesimab arm although low in numbers. Hard to draw big conclusions from that other than the fact that this regimen seems fairly well tolerated. On the health status, the quality of life metrics appears similar. Now, in conclusion, they draw that it's very convincing median progression-free survival benefit, response rate benefit, overall survival analysis is still pending. This was a Chinese-only population and is being conducted now in a more broad global study. The other thing to keep in mind is that VEGF, we have previously seen some very good progression-free survival curves that ultimately did not translate to overall survival difference. Now, hazard ratio of 0.54, 0.51 for a total population is very convincing but we do need to see the overall survival data. And I think if anything, this is a very promising study where it was a highly anticipated overall survival endpoint now when we do eventually get the follow up from this as well as another study in global population. And moving on to that Apotemab drug scan versus dosotaxel in non-small cell lung cancer, this first highlighting that the initial progression-free survival was previously reported as low last year. This was a positive trial with a positive progression-free survival benefit. And you see that in the intensity population there on the left that was previously shown with a hazard ratio of 0.75. But the benefit was really noted in non-squamous. And on the right there, you see that we had previously seen an overall response rate of 31% relative to dosotaxel 13% as well as a more meaningful separation of the curves in the non-squamous population. What we saw this year at World Lung was the overall survival analysis. So first the schema, this was data DXD versus dosotaxel. It included patients with non-squamous and squamous histology as well as tumors that had actionable genomic alterations as well as those without. On the left side, you see there the key eligibility criteria and the tumors without actionable genomic alterations patients had to have received prior platinum-based therapy as well as checkpoint inhibitor either together or sequential. And those with tumors with actionable genomic alterations, they had to have received one to two prior approved targeted therapies as well as platinum-based female plus minus checkpoint inhibitor. You see they were randomized to data DXD versus dosotaxel, dual primary endpoints of progression-free survival and overall survival. And the baseline characteristics, you see there on the top right, actionable genomic alterations were present in 17% enrolled. And then on the bottom left, you see the histology 78 and 77% non-squamous histology was even across groups. But I call those out because those are really relevant to the analysis we're going to look at. And the intent to treat population, we saw a hazard ratio of 0.94, not statistically significant difference between data DXD and dosotaxel in the overall population. So much like what we saw in the initial progression-free survival, we see in the overall survival. So on the right, we see outcomes that actually favors dosotaxel over data DXD with a hazard ratio of 1.32. But on the left, we see non-squamous favoring data DXD at 14.6 months as compared to 12.3 months in the dosotaxel arm with a hazard ratio of 0.84. Now the time points on both of these approximate what we saw from the progression-free survival differences that seems to be translating into overall survival differences. That being said, the hazard ratio is 8.84 and the confidence interval does cross one. Now the trial was not powered to look at a subgroup for overall survival. Now if you see on the bottom of the slide, highlights that in the non-squamous groups in tumors that have actionable genomic alterations, we saw an overall survival difference of 15.6 months relative to 9.8 months. In those without actionable genomic alterations, we see 13.6 months as compared to 12.3 months. So a closer difference. Again, given the smaller numbers in these, in both of these, the confidence intervals cross one, even in those with actionable genomic alterations where we see a numerically wider separation of the median overall survival differences. In the forest plot, this looks similar to what we've seen before. On the bottom there is actionable genomic alterations present. You can see that leans out further in favoring data DXD. And in the squamous, that really leans toward dosotaxel. With an additional 11 months of follow-up, we did not see any change in the toxicity profile that was previously reported, and there were no increase in number of interstitial lung disease. Stomatitis continues to be the top toxicity of interest for data DXD, and we saw cytopenias in particular with dosotaxel. So the conclusion was that this study has demonstrated in the non-squamous histology an improvement in the median progression-free survival, in the response rate, the median duration of response, and an overall survival benefit that numerically favors the similar time points to what we see from the progression-free survival. But again, the confidence interval did cross one. There was, in the presidential, there was a presentation about a potential biomarker looking at TROP2 expression that still is early, but is quite promising. And so that will hopefully in the future further help us to identify patients most likely to benefit from this TROP2 antibody drug conjugate. Now moving on to small cell lung cancer, we saw the updated data for tarlatumab for previously treated small cell lung cancer. The phase two extended follow-up. Tarlatumab is a bispecific T cell engager, so it binds DLL3 on the tumor cells, and binds CD3 on the T cells, and essentially bringing those cells together, creating an immune response. Now we previously, there was a prior publication in the New England Journal on this. At that time point, the median duration of response was not yet reached, but did lead to FDA approval of tarlatumab in the second line setting and beyond. Now this trial, you'll see from the schema, enrolled those with at least two prior lines of therapy. It randomized to tarlatumab 10 milligrams or 100 milligram doses. The 10 milligram dose is the FDA approved dose, and the presentation focused particularly on that group that included a dose expansion, as well as a reduced inpatient monitoring period for an additional 34 patients. The primary endpoint was overall response rate. You see from the baseline characteristics that a third of patients had gotten at least three prior lines of therapy. Two-thirds had gotten two prior lines of therapy. DLL3 expression was very common, 95% across the cohort. Objective response rate was 40%. That was previously reported. The disease control rate of NOSA was 70%. Now stable disease, it's hard to know what to make of that in various tumors. In small cell lung cancer, generally stable disease is more likely to indicate some efficacy of the drug, given how rapidly progressing small cell lung cancer typically is. That's not the claim that every single person with stable disease benefited from the drug, but I'll show you in a moment that we do see some durability to some of those. Here is the swimmer's plot. You can see the median time to first response was 1.4 months. Essentially, the first scan, a number of patients with ongoing response to therapy. Median duration of response was 9.7 months. 43% of the patients with responses still had ongoing responses at data cutoff. Here we see some of the stable diseases I was mentioning before. In yellow, you see stable disease. You can see there are a number out beyond six months and a couple that are even out beyond a year. Clearly, those patients are benefiting from treatment, but a number of those with partial response in particular that have durability out beyond a year. 26% of the patients had sustained disease control out beyond a year. There was tumor shrinkage noted in 72% of patients and the median duration of disease control was 6.9 months. Here's a progression-free survival curve, and again, showing real stability out on the tail of the curve. The overall survival curve is here, but the next one where we see the chemotherapy-free interval from first line platinum-based therapy. Again, this is the third line, but in the patients that were enrolled to this study, those who had a chemotherapy-free interval of less than 90 days and those who had a chemotherapy-free interval greater than 90 days all benefited similarly. This sets a new paradigm in second line and beyond therapy where the chemotherapy-free interval from initial platinum-based treatment is not an indicator of what to expect from this. Now, on the one hand, you could say, well, those who had a great chemotherapy-free interval, we'd hope to see better, but on the other hand, we say, okay, those that didn't have a durable response to initial platinum-based treatment are also still seeing similar benefit from this drug to those who did. And what this highlights is that this is a different mechanism of action and therefore a new paradigm in treatment in second line and beyond. The most common toxicities were CRS being the most common, and you can see that overwhelmingly that was within the first three months of treatment. We'll dive into that a little bit more here. On the left side, you see the CRS overall incidence. The blue is grade one and yellow is grade two, so overwhelmingly grade one, two. There was one grade three event, but after the initial occurrence, to have a second episode of CRS is less common, overwhelmingly grade one. And to highlight that further a little to the right on there of the CRS chart, you can see that almost all of these happened in cycle one. There were three that happened in cycle two and beyond, and all of those were in those who had a pause between doses and a delay. ICANS was less common, but could occur a little further out into the courses of treatment. You can see that in the three to six month timeframe, there were six, and there were even two out beyond six months. In conclusion, the updated data further reinforces our lot of that as an important treatment option in small cell lung cancer with a median duration of response of 9.7 months and a median overall survival of 15.2 months. At 18 months, there was an estimated 46% also still alive. There were no new safety concerns identified. CRS is something for management, particularly in the first cycle. Thank you for your attention. Thank you, Dr. Jacobson. I'd like to start the next speaker, but before that, I'd like to introduce myself. I'm Dr. Hidehito Furinocchi from National Cancer Center Hospital Tokyo, and I'm the co-chair of this webinar. I'm very grateful for all the speakers joining, and I'm also the deputy chair of the Educational Committee of ISLC. So, another announcement is please use the Q&A feature of Zoom, and please send many questions. We will handle all the questions and answers at the last portion of this webinar. So, let's get into the second speaker. I'd like to introduce Dr. Patrick Folder. He's the co-director of the Division of Upper L-Digestive Malignancies and the director of the Swastika Oncology Research Program at the Johns Hopkins Bloomberg Kimmel Institute for Cancer and Immunotherapy, and he will cover the several important abstracts from the well in 2024, the near-post and patient-level data analysis of the CHECKMATE 770 and CHECKMATE 816, and also the pollster. So, Patrick, could you please start your spoke? Thank you. Thank you very much, Dr. Harnucci, and great to be on this webinar. As mentioned, I will review these three abstracts, starting with NEOCLOS II. So, NEOCLOS II was the first platform neoadjuvant trial in lung cancer focused on immune-based therapeutics in combination, both in the neoadjuvant and adjuvant setting, and Dr. Tina Cusconi presented this abstract in the presidential session at WCLC. The background is that the agents which will be discussed have all shown some activity, either in early or late-stage disease. Data posted by Dr. Uxtekin has recently shown an improved progression-free survival benefit over dosotaxel in the phase III tropi and lung study after a first-line chemoimmunotherapy. There have also been several neoadjuvant or perioperative trials demonstrating improved event-free survival in early-stage lung cancer and overall survival in the setting of Keynote 671. So, this was the first phase II global platform study to evaluate efficacy of novel therapies in the perioperative setting. This was the study design. So, you'll see it mirrors largely the perioperative phase III trials. Patients enrolled included stage II to IIIb disease in the 8th edition. Patients with known EGFR and ALK alterations were excluded. And the three arms of this study, which Dr. Cusconi presented, were arm 1, 2, and 4. The valrostimic arm is not yet ready for presentation. So, you'll see in two of these three arms, the alloclimab and monolizumab arms. The investigational agent was administered preoperatively with chemotherapy and drivalumab and postoperatively with drivalumab. Whereas in arm 4, the data or potumab directs to can arm was given just in the neoadjuvant setting with drivalumab and chemotherapy, but drivalumab monotherapy was administered in the adjuvant setting. Primary endpoints of the study were PCR and safety and tolerability. And this was not powered to compare the arms directly, but rather to look at pathologic complete response for an early efficacy signal. These are the characteristics you'll see, largely well balanced, about two thirds or more of the patients have PD-L1 positive tumors, as we see in most of the perioperative trials, the majority of the patients had stage three disease and between 60 and 65% of patients had adenocarcinoma. Notably, the study permitted the investigator to choose either carboplatin or cisplatin. And you'll see here the large majority of patients in all of the arms received carboplatin-based therapy. Here you'll see the treatment disposition. I think the notable thing from this is that we're, so in this study, at least a phase two study, perhaps more highly selective patients, we're seeing more patients getting to surgery than we did in most of the perioperative trials. So here, the R0, the numbers of patients, so undergoing surgery are over 90% in all arms and the R0 resection rate within that is also approaching 90%. And a relatively higher proportion of patients are also starting the adjuvant treatment. These are the pathologic response results. So going from arm one, which is with Aleklamab, with Dervalumab in chemotherapy, Aleklamab is a CD73 antibody. You'll see PCR rates of 20% and NPR rates of 45%, relatively similar to what we've seen with other agents such as Nivolumab with chemotherapy. In arm two here, you see somewhat higher rates of PCR and NPR, 26.7% and 53.3% respectively. But I think what stands out in the study so far is this arm four, which is data post-adjuvant drugs to count the trope two, ADC plus Dervalumab plus chemo. Smaller number of patients, 44, but PCR rate thus far of 34.1% and NPR rates of 65.9%. And these are quite a lot higher than we have seen from the phase three trials in lung cancer, where we've seen PCR rates of between 18 and 24%. And looking at this by PD-L1 status. And so we see here in the light blue, PD-L1 negative tumors, PCR rates between 15 and 25%. The intermediate group, we see something of an outlier in the Aleklamab group at 5.6%, but in general, relatively higher. And in the high PD-L1 group, you're reaching up to PCR rates of 41.2% in the data post-adjuvant drugs scan. What I do think though, is we're starting to see in this PD-L1 negative group that perhaps these novel agents might deliver higher rates of pathologic response. The safety profile, I'm focusing in here on the data post-adjuvant drugs scan arm because that's the one which perhaps has the highest level of efficacy in this study. And it is only four doses of treatment, which probably accounts for the relatively lower toxicity profile in this study compared to the studies we've seen in advanced disease. Notably, no patient had grade three or above stomatitis, which has been a challenge for some patients with advanced lung cancer. There was one death due to idiopathic pulmonary fibrosis, which was judged locally as not related. However, it's being centrally adjudicated and that was pending. And of course, data post-adjuvant can be associated with interstitial lung disease. And in general, patients with IPF should be excluded from its treatment. So in conclusion from the NEOCOAST-2 study, promising NPR rates from novel combinations. I think this is a novel study in general and perhaps the way we should move forward in this setting of perioperative disease. Treatment had manageable safety and the surgical rates, if anything, were higher than what we've seen historically with the phase three perioperative trials. So it'll be interesting to see further arms from the study as they're reported and perhaps some of these treatments moving to phase three. Moving on to a study, which I presented at World Lung. This was a perioperative versus neoadjuvant nivolumab for resectable lung cancer. And this was an individual patient level data analysis of CHECKMATE-77D, which was a study of preoperative nivolumab with chemotherapy followed by adjuvant nivolumab versus CHECKMATE-816, which was a neoadjuvant ONI and nivolumab plus chemotherapy. So as we know, nivolumab plus chemotherapy is currently the ONI approved and guideline recommended neoadjuvant ONI immunotherapy regimen for patients with resectable lung cancer. In CHECKMATE-816, there was an event-free survival benefit versus neoadjuvant chemo alone. Building on this, CHECKMATE-77T showed a benefit for perioperative nivolumab plus chemotherapy versus placebo with a hazard ratio of 0.58. Pathologic complete response rates in both studies were quite similar. So in order to try and compare these, we want to randomize trials for many years in this setting, comparing neoadjuvant ONI versus perioperative. We conducted this individual patient level analysis of the two trials. To try and determine which patients may derive benefit from adjuvant nivolumab following neoadjuvant nivolumab plus chemotherapy. The analysis populations for the two trials from CHECKMATE-816 were those patients who received neoadjuvant therapy and underwent surgery. And from CHECKMATE-77T, those patients who got neoadjuvant nivolumab plus chemotherapy followed by surgery and received at least one dose of adjuvant nivolumab. The primary endpoint for this analysis was event-free survival landmarked from the time of surgery. So different to the traditional analysis. Two different methods of propensity score weighting were performed to try and reproduce a randomized trial by adjusting for clinically relevant baseline demographics and characteristics, and try and reduce the confounding effects of differences between the two trials. The median follow-up was similar across the two trials. These were the baseline characteristics in the unweighted population. So you'll see relatively similar apart from a higher proportion of Asian patients in CHECKMATE-816, and a relatively higher number of patients with stage three non-N2 disease in CHECKMATE-77T. However, after weighting, these characteristics were very well-balanced. And this was the primary analysis we looked at looking at landmark event-free survival from the time of definitive surgery. And this tends to favor here perioperative therapy has a ratio of 0.61 in the weighted AT analysis. Using a different method, a very similar how the ratio is 0.56, and in the unweighted analysis also trended towards favoring perioperative therapy. One question here is you're selecting the patients on what in CHECKMATE-77T as patients have to get to adjuvant therapy to be eligible for their portion of the analysis. However, when we looked at an unweighted landmark analysis from surgery among all patients who had surgery, whether they received adjuvant or not in CHECKMATE-77T, the hazard ratio trended again towards favoring perioperative therapy at 0.82. Now looking at various subgroups, these were unweighted analysis in the PCR subgroup. The hazard ratio trends towards favoring perioperative therapy, but you will notice these curves are really close together. And in general, this is a group that seems to be doing very well from neoadjuvant therapy. So it's hard to show a difference in that group. In the no PCR group, on the other hand, this is a higher risk group. They have higher rates of relapse and the hazard ratio here is 0.65, quite emerging separation of the curves favoring perioperative therapy. In PD-L1 status, again, we see in the PD-L1 high group on the right, not too much separation of the curves between perioperative versus neoadjuvant, but on the left, you'll see in the PD-L1 negative group, again, a higher risk group who likely have a higher risk of relapse with therapy. The hazard ratio is 0.51 favoring perioperative therapy over neoadjuvant only. Safety in general was similar across the two arms, including treatment-related adverse events leading to discontinuation and surgery-related adverse events. So in summary, we won't have a randomized controlled trial addressing this question for many years. So this was an attempt in an exploratory fashion to compare perioperative versus neoadjuvant. In this analysis, perioperative seemed to deliver up to a 40% reduction in the risk of disease recurrence or death after surgery. Benefits were seen regardless of stage with perhaps a higher magnitude of benefit in those patients with PD-L1 negative tumors and those patients who don't have a PCR at the time of surgery. So moving on to the last abstract, this was a phase three trial from China entitled amilartinib after chemoradiation in unresectable stage three non-small cell lung cancer. The POSTAR study focused on patients with EGFR mutations, very similar population to what we saw in the LORA study presented at Asperger's here. So several subgroup analysis from the Pacific trial have suggested that patients with EGFR mutations may not derive benefits from consolidation or value map. We have, of course, the LORA data showing a significant benefit for osimertinib in terms of progression-free survival and that has now been approved in the United States. Amilartinib is a very similar third-generation TKI which has received regulatory approval in advanced disease in China. And the POSTAR study aimed to address this question of use of amilartinib after chemoradiation. This was the study design. So you'll see the randomization here is versus placebo similar to LORA stratified by a specific EGFR mutation stage and whether sequential or concurrent chemoradiation was delivered. A quite ambitious statistical design here, you'll see a very high bar for the study to be positive at the interim analysis. So where the goal has a ratio of 0.42. And this was the disposition of the patients in the study. So you'll see in both arms, and not quite as large as the LARA study, which was just over 200 in this study, 147 patients were enrolled across China with a two is to one randomization. So you'll see here a guess as to the results and many more patients ongoing in the amilartinib arm. So far, these are the baseline characteristics of the patients. You'll see relatively high number of patients with L858R, which historically is a higher risk mutation. And here you'll see the curve, which might've been expected based on the LORA results. And a median follow-up is short here, 16.36 months, but has a ratio strongly favoring amilartinib 0.2, a significant at this first interim analysis with at the 12 month period, 69% of patients progression-free in the amilartinib arm versus 21% in the control arm. And the benefit appears to be across all subgroups in the study, including the different EGFR mutations and whether the patient received sequential or concurrent chemoradiation. Some interesting data here on relapse. So you'll see a reductions in particular in those patients with intrathoracic relapse, brain relapse, and overall a major reduction in relapse from 58% in the amilartinib arm down to 20.7%, or sorry, in the amilartinib arm. Safety in general is what you might expect with the third generation EGFR TKI. CPK seems to be elevated for some patients with this agent, radiation pneumonitis in close to half the patients in the amilartinib arm, but these were generally grade one or two events. So in summary, in POSTAR, amilartinib exhibited a statistically significant improvement in PFS in patients with unrespectable stage three EGFR mutant lung cancer as a ratio 0.2. I think these results reinforce the results of the lower trial and suggest to me that EGFR TKIs at third generation are now the standard of care for these patients post-chemoradiation for stage three lung cancer. So thank you very much, and I'll stop sharing and pass on to my colleague. Thank you, Dr. Ford, for the great presentation. And now I'm gonna invite Dr. Xinyun Li. Thank you. She's a thoracic oncologist at the Department of Thoracic and Head and Neck Cancer at the MD Anderson Cancer Center, University of Texas. She will cover data for targeted therapy on advanced disease, the studies SOHO-1, BMI-LUNG-1, and further trial. Thank you, Dr. Li. Yeah, thank you for having me. So let me get the screen going. Yeah, so it's an honor to share some of our updates from WCLC this year. I will be talking about two trials focusing on HER2 mutation lung cancer and one on EGFR. Let's start with HER2. There are two major abstract presented this year at WCLC. So HER2 mutation in lung cancer occurs in around 2 to 4%. So it's not a large population, but given the size of lung cancer itself is still a significant patient population, probably at 50,000 new diagnosis yearly. The most common subtype is HER2 kinase domain insertion. And among them, YVMA HER2-772 is the most common. Currently chemotherapy and antibody drug conjugates are the standard of care options for patients worldwide. And there is a great unmet need to develop oral medication. So this year at WCLC, we heard about two HER2-TKIs having a very interesting efficacy. So those two HER2-TKIs, one is Bayer88. The other is Zungertinib developed by Bringer Ingerheim. So on these slides, I quickly summarize the preclinical data from both of the agents. In the preclinical model, each of the drug have demonstrated excellent preclinical efficacy for key subgroup mutations, as well as having very good EGFR and HER2 wild type selectivity. With those preclinical data, so both of the drugs has entered a clinical evaluation. So let's start with SOHO-1. SOHO-1 evaluate Bayer88 in different cohorts of patients focusing on HER2 mutation patients. This time we presented HER2 activating mutation non-small cell lung cancer patients who have received the prior treatment systemic therapy, but no prior anti-HER2 treatment. The primary endpoint is a safety and response rate by investigator evaluation. In this cohort, a total of 44 patients were enrolled and the demographics are very consistent with what we know about this patient population. They are female dominance, a lot of patients who are never smokers and around 20% of the patient has baseline brain metastasis. In term of efficacy, Bayer88 in this 43 patient evaluable cohort demonstrated a response rate of 72.1%, with one patient achieved a complete response. Overall disease control rate is 84%, so excellent numbers. The duration of response is 8.7 months and then progression-free survival is 7.5 months. We also reported the subgroup analysis of this most common genomic alteration of 772-5VMA. In this 30 patient cohort, the response rate is as high as 90% and the progression-free survival is 9.9 months. So in this subgroup is highly promising, Bayer88 have a good efficacy. We don't have a lot of mature brain metastasis data, but the patients who had the baseline brain metastasis derived a similar level of benefit by Bayer88. The move on to abemian lung 01. So this one is evaluating Zangertinib in a multi-cohort phase one, phase two study as well. So in this time, Dr. Reuter reported also similarly pretreated patients with a HER2 TKD mutation. In this group, there are two dose levels evaluated at 120 milligrams or 240 milligrams. As you can see, there are more patients were enrolled into the 120 milligrams as this gonna be the dose for phase three randomized study. The tumor response with Zangertinib is also excellent. The response rate by central reveal is 67% and then there are a lot of patients are still receiving ongoing treatment. The PFS and duration of response are not mature yet as a lot of patients are still receiving treatment at the data cutoff. But from the waterfall plot showing here, you can see a really nice tumor reduction in majority of the patients. In the Zangertinib trial, they were able to report around 50 patients who had the brain metastasis and also the tumor is amenable for renal evaluation. So here, Dr. Reuter reported a response rate with this medication around 30 to 40%. Again, demonstrating this is a drug with good CNS efficacy. With those two medication, we have to look at their toxicity profile. With Bayer88, the diarrhea is to represent a challenge where 86% of the patient having any grade diarrhea and the grade three is 25%. In comparison, Zangertinib has much better diarrhea profile only in the 120 milligrams, only half of the patients having diarrhea and rarely have grade three. So the toxicity management ongoing forward will be very important. With those two drug reporting out very encouraging at least initial response rate, we're hoping that those TKIs will help us to change the standard of care going forward. As currently we have only chemotherapy and one ADC approved in this space, we're hoping that some of the oral medication can start to be added into physician options and start to benefit our patients. Currently, both Bayer88 and Zongertnib are entering phase three randomized study. Both of the studies are designed very similarly with randomization to chemoimmunotherapy. Both of the trials, basically even the sample size are very similar. Two of them are global study. So we're hoping to see the results hoping to see the quick enrollment to both of the studies in the near future. Moving on to EGFR, this year, we reported out of a new prospective trial in EGFR-PAK mutation population. EGFR mutation can be classified many different ways, including classified by exon. But two years ago, our group proposed a function structure-based classification that we can start to group some of the uncommon mutations together. By this approach, PAK mutation group is a isolated group, share a lot of structural similarity, therefore can be amenable for the same TKI to treat. This is a sizable patient population, around the 12.5% of all EGFR kinase domain mutations. Further trial enrolled PAK mutation patient to cohort four. In this trial, a newer EGFR TKI formalinertinib was evaluated at two doses for PAK patient population. The primary endpoint is response rate and the duration of response and other clinical parameters are the key secondary endpoints. Showing here is the efficacy reported at WCLC. At a higher dose of 240 milligrams daily, the response at the confirmed response rate is 63.6%, and then the best response rate is 82%. In this particular cohort of 22 patient, disease control rate was 100%. Showing on the right is a waterfall plot for both doses. Both doses are active, but the 240 clearly have better tumor reduction and better disease control for PAK patient population. In this small cohort, we start to see initial CS benefit from formalinertinib to PAK mutation patients. In the cohort of around 16 patient or so, we see a CS confirmed response from 40 to 55%. Showing on the right is a patient who received the formalinertinib, but never received the CS radiation. As you can see, the medication were able to shrink the tumor by 80% and give clinical benefit. This data is consistent with what we know about the formalinertinib. In fact, formalinertinib have demonstrated good CS efficacy in other study populations before, so this is consistent with our knowledge. The side effect of formalinertinib is also consistent with what we know before. Diarrhea still remain a challenge for this patient population, although high-grade diarrhea is relatively low, so it's quite manageable, and physicians need to pay attention to liver enzyme elevation, but usually this is a numeric change rather than need to dose discontinuation. In fact, in this patient cohort, cohort D, in the PAK mutation, there's no discontinuation needed because of the toxicity, and there's no grade four or five TRAE observed. I just want to put this trial in the perspective in that we start to classify EGFR mutation by classical T790M PAK and exon 20. Going forward, the approval pathway can be quite different. This is the first trial, further trial is the first prospective trial to evaluate EGFR TKI in the PAK mutation patient population. We start to see very, very promising initial response, and we look forward to see the PFS as well as duration of response. Thank you. Thank you. Thank you for your excellent overview of the very important abstract. So now we are at time for the discussion. So since there seems to be no questions so far, the moderator can monopolize the privilege of asking questions to three wonderful speakers. So Clarissa, do we have any questions? Yeah, I have plenty of questions, but please go ahead. Well, I'll start with Dr. Sands. I think it's very interesting data presented. It was presented before in ESMO meeting last year. Do you consider adequate to include patients with PD-L1 intermediate 1 to 49 in this first line trial? What's your thoughts about, what are your thoughts about that, please? The harmony. Sorry, you mean in, I have an SNAP study. Well, you know, we did, so I think you're probably highlighting that because Pembrolizumab monotherapy is not a commonly used standard in this population. It is approved. It is approved for anyone with tumors with PD-L1 expression, but the data for Pembrolizumab monotherapy is not as good, and more commonly we use chemo plus Pembrolizumab in that population. Now, that being said, whether to include them, there are patients that we do choose to treat with Pembrolizumab monotherapy. I think more commonly is the reverse where patients with PD-L1 of greater than 50%, I'll sometimes use chemo plus Pembrolizumab in that population, just further highlighting the complexity of whether or not to choose chemo with Pembrolizumab alone. But Pembrolizumab monotherapy is an approved option. And I think for a patient that you'd consider treating on Pembrolizumab monotherapy, it makes a lot of sense to allow for that. The other thing is that PD-L1 expression can be variable and it can be heterogeneous. So sometimes when there's central testing required, we'll get PD-L1 at one site and then another site, the PD-L1 testing can be different. And so this 50% cutoff, I'd also just say, is not such a hard line cutoff where we can see variability within that expression as well. So it may be more representative of the patients involved and not just PD-L1. Of course, PD-L1 of 90% using Pembrolizumab monotherapy is more common than the PD-L1 of 1%. So if we're going to extreme, there is a nuance to this, of course, which is why you're asking the question. So I guess that's kind of a long-winded answer of saying that I think it's reasonable to include that while acknowledging that not everybody with a low PD-L1 expression would I choose Pembrolizumab monotherapy for. And so that comparison needs to be, you know, analyzed with that in mind. Thank you. So I have another question for Patrick. So I would like to ask about the CheckMate 770 and the A1CX combination as a direct comparison using the propensity score matching. So based on this result, can we conclude that we should choose a perioperative ICI? And in other words, is it necessary to conduct another randomized trial directly comparing the management and perioperative strategies? Yeah, I think it's still a kind of an ongoing question. I think the idea of the analysis was to try and add some kind of base information to the question. I think the key element to my mind would be the phrase eligible patients. So the perioperative trials, when you start out, and then probably only about 70% of patients in the perioperative trials will start the adjuvant therapy. So I think what the analysis suggests to me is that those patients who get to that point who have their preoperative chemoimmunotherapy have a full resection and they've recovered postoperatively. I think it's worthwhile discussing the adjuvant component. And the other element, although it wasn't, they were subgroup analysis. What stood out to me was that perhaps those patients who are higher risk in general, who have a higher risk of relapse may derive more benefit from the adjuvant component. And at least in this analysis, it suggested those patients who had PD-L1 negative tumors who probably don't derive as much benefit from the neoadjuvant component. And also those patients who don't have a PCR at the time of surgery perhaps derive more benefit. So for those patients, I would definitely keep it in mind and discuss it with them in some depth. And, but I still think a randomized trial would be helpful. And there are several attempts at that ongoing both in the U.S. and in Europe and probably in Asia as well in terms of trying to address the question of preoperative versus neoadjuvant. Thank you. For practice, Dr. Fork, is there any subgroup that you would offer the neoadjuvant exclusive treatment upfront before having the results of the pathological response? Yeah, I think, so I think that the pathologic response we're still kind of trying to incorporate it into our practice. And to my mind, it's one element of kind of a general clinical assessment of the patient postoperatively. The patients for whom I think perhaps more intensive therapy makes sense in general are those patients so with stage three disease who make up the majority of patients in these trials. And also perhaps those patients who have PD-L1 negative tumors. I think those are patients for whom adjuvant therapy, so surgery upfront followed by adjuvant chemo, plus or minus immunotherapy probably doesn't confer as much benefit as neoadjuvant or preoperative may. So I would tend to divide patients into those who are risk categories, I suppose, and also comparing it with their comorbidities and other kind of competing risks in terms of mortality and morbidity in the future, which we've done for many years in the adjuvant setting. Really, if you have a healthy patient who has a resected lung cancer, we often recommend adjuvant based on the fact they don't have another competing disease risk. I think we may have to kind of individualize it even a little bit more in the future based on the characteristics of the tumor, but also on the kind of dynamic changes, such as PCR and maybe even liquid biopsies and clearance of ctDNA, which we're seeing emerging data there as well. Thank you. So I'd like to ask Siyuning about the HER2 inhibitors. So there is a very good choices for the HER2 inhibitor reported. Please give your opinion on the sequence of the using the already existing tractum of the acousticon and tyosin kinase inhibitors. Yeah. So thank you, Hedi Hito. Those two TKIs currently, neither of them are approved. They got, some of them are FDA breakthrough designation and also got the Chinese equivalent FDA breakthrough designation. As you can see, both of the drug are hoping to go into the frontline because their confirmatory study were both designed for treatment naive patient population compared to the chemo treatment. I personally think if those drug, both of the TKI can demonstrate similar efficacy as we're seeing now, I would incline to offer TKI upfront because I felt like HER2 biology, HER2 tumor biology, it might be very similar to EGFR tumor biology. If we can have the patient receive upfront TKI benefit for beyond a year or a year or so, and we save chemo and ADC as the next line of option in term of the quality of life, I think that's probably the best preserved. But we have to see what the data look like because in the end, we want upfront as much benefit as possible. Yeah, that's great answer. So maybe too much progress in advance, but please let me ask your opinion also about the possibility of the combination of the TKI and ADC because toxicity profile is somewhat different in between. Yeah, I think that's definitely a area I think we should continue to do research. I think you're not the first one. I got this question a lot of times. The idea is a vertical blockade of both blocking cell surface receptor using the ADC or chemo approach, and as well as block the ATP binding pocket. So we might be able to achieve a very deep suppression upfront for patients like we see in FLORA2 trial. For HER2, we need to be very mindful of two toxicity. One is a cardiac toxicity. The other is interstitial lung disease. As long as we're careful in designing those trials, I think those direction definitely is worth going for. Shirley, regarding the PAC mutations for the FURTA trial, we have a lot of retrospective data suggesting that cosomergenic could have some activity in some of these mutations too. And from the community, we hear a lot that people are trying to use the FLORA2 schema sometimes for these patients. What's your opinion regarding the... What would you consider today the first line for these patients and how does the new drug would compare to chemo and the smertinib, the fatinib, the other drugs? Yeah, so PAC mutation is under-recognized until recently because NGS testing become more popular worldwide. So this uncommon group start to be recognized. We knew that osimertinib for this PAC mutation works, but not great. So the response is in the 30, 40% and PFS six to eight months compared to the classical mutation. A fatinib works better, but quite toxic. If there's a new drug that, for example, formalinertinib or any new EGFR-TKI can give us much benefit similar to osimertinib, but not as much toxicity, I will argue monotherapy TKI for this patient population upfront will also be appropriate. Of course, when we evaluate a patient, we probably have to factor in the very high risk patient population, such as brain and liver metastasis, large tumor burden. But I'm still also hopeful that we can have new TKI that's good enough that upfront monotherapy for this patient population. As we're all practicing physicians, those patients who are receiving Tagriso or a effective fusion TKI, their quality of life is really good. Like they're amazing. They can maintain their really day-to-day life. So we're hoping we can see benefit for both HER2 and EGFR-PAC patient population. So can I return to Dr. Sanza about the small cell? So I'm very excited about the efficacy of the Taulatin lab. And I have experienced a patient with no response at all to those who experienced a durable response for about one or two years. So are there any studies underway to determine the predictors of these efficacy, such as a DLL3 or something like that? Well, this is obviously an important question for so many different, and any trial we lead as far as better determining who's gonna truly benefit and have these kinds of durable responses. The DLL3 expression in this study was about 95% of patients that had DLL3 expression. So it's very, very high in small cell lung cancer. I think that's an especially important question, though, for extra pulmonary large cell neuroendocrine. We saw at the same session, there was a discussion of obriximib for large cell neuroendocrine. It's another bispecific T cell engager that's currently only available in clinical trial. And in the large cell neuroendocrine population is about 70% of patients that have tumors with DLL3 expression. And we saw an impressive response rate in that group. And I suspect this class of drugs is gonna, I mean, it's showing efficacy in other tuber types beyond small cell lung cancer. And DLL3 expression might be an important component of that. You know, the other thing is that in the small cell paradigm we're looking at small cell subtypes and whether different subtypes may benefit more from some of these. Now the subtyping is not yet really ready for prime time. I think there's still more refinement to that. Even just the scaling of testing all tumors is not yet widely done, as well as ideally ways of doing this through blood-based testing that might make it more feasible given that we see some plasticity to subtypes and it's hard to use just the initial biopsy from diagnosis. So ongoing work is important. The other component is at resistance or at progression, what are we losing DLL3 expression? This is of course, particularly relevant for other DLL3 directed therapies that are multiple in development. So there's a lot of work to still do in this arena in identifying those that are gonna have durable responses as well as at the time of resistance for other DLL3 directed treatments. Thank you. I think it's almost time maybe. So I'd like to explain some additional information for the audience. So just before closing this session, I'd like to thank all the speakers and also my co-chair, Clarissa, to do the very great work, to very shortly summarize, very condensed summary of the Well-Learned 24. And also that there is many other sessions and many other informations shared in the Well-Learned 2024. So please check the Well-Learned 360 in the ISNC website. And also to discover the more educational activities being covered or offered by ISNC, please visit the website at ISNC.org. Thank you for joining us today. Thank you for joining. Thank you and bye everyone.

advanced lung cancer

Ivanesimab

Pembrolizumab

NSCLC

Harmony 2 trial

Tropion Lung-01

datapodimab

tarlatumab

SCLC

targeted therapies