Welcome to today's webinar, World Conference on Lung Cancer 2021 Highlights. My name is David Harpole, and I'll be presenting and moderating today's webinar as the recent chair of WCLC 2021. My co-chairs, Kristen Higgins and Tan Stinchcomb, were thrilled with the success of the virtual meeting that was live September 8th through 14th a few weeks ago and had over 6,000 participants. Our goal was to create an inclusive meeting with increased global participation that updated significant advances in the treatment of thoracic malignancies. This one-hour presentation reviews a few of the most important findings from the WCLC 2021. If you would like to download today's slides, you can access them by clicking the link to the webinar page in the chat. You will also be able to find a video recording of the webinar in that link in a few weeks. An email will be sent after the webinar with instructions on how to claim your CME credit. Your camera and microphone will remain off during this webinar. Please enter the questions you have for the Q&A discussion in the Q&A section at the bottom of the Zoom webinar. You may use the chat function for other discussions. We will not be using the raise the hand function from this presentation. So our very first speaker is Dr. Tom Stinchcomb. Thank you very much. I'm a medical oncologist who specializes in the treatment of lung cancer. My presentation will focus on the medical oncology presentations from WCLC. Next slide, please. I think the topics, I sort of divide them into first-line non-small cell lung cancer, which we talked about in the Poseidon trial, the second-line small cell lung cancer, also known as the Atlantis trial, then I think treatment of brain metastasis is a common problem for medical oncologists and radiation oncologists, and I think there's been interest in the role of chemotherapy and immunotherapy in patients with brain metastasis, either as primary therapy or if there's a differential benefit. Next slide, please. This trial was presented by Dr. Johnson and her colleagues, and it was a phase three trial. Next slide, please. This represents the study design. The red on the bottom represents the standard of care arm of platinum-based chemotherapy and pemetrexin. The primary comparison was with the drivolumab chemotherapy, followed by drivolumab plus or minus pemetrexin maintenance to the standard of care chemotherapy arm. The secondary comparison was the druva, tremolumab, and chemotherapy to the standard of care arm. Of note, the tremolumab was only given for five cycles in this trial, which differs from other trials of PD-1, PD-L1, and CTLA, where the CTLA component was continued. The primary endpoint was progression-free survival by blind and independent radiological review and overall survival in the druva and chemo, drivolumab and chemotherapy versus chemotherapy arm. You can see the key secondary endpoints below. Next slide. These are the demographics, and as you can see here, it's very consistent with other trials in the first-line setting. I'd like to point out two factors. One, if you look at the squamous histology, about a third of patients had squamous histology. If you hit the next slide. We also note that 20 to 25 percent of the patients were never smokers, which has been associated with a lack of benefit of immunotherapy. About 25 to 30 percent were PD-L1 greater than 50 percent, which is associated with benefit. Next slide, please. This represents the primary comparison. On the right is your progression-free survival curve, where we see a statistically significant benefit has a ratio of 0.74, p-value statistically significant. As you can see at the landmark, the PFS rate is 24 percent versus 13 percent at 12 months. We look at the curve on my right is overall survival. A statistically significant benefit was not observed with a hazard ratio of 0.86, p-value 0.7. Next slide, please. Now, if we look at the druva, drivolumab and tremolumab with chemotherapy versus chemotherapy and the progression-free survival, we see a statistically significant improvement in progression-free survival. The hazard ratio is 0.72. We also see a statistically significant improvement in the overall survival hazard ratio is 0.77. If you look at the 24-month, it's 33 percent versus 22 percent at the landmark analysis. Next slide, please. Looking at the response rates, the drivolumab plus chemotherapy arm, the drivolumab, tremolumab and chemotherapy arm had higher response rates than the chemotherapy arm, 38 percent of the four-drug therapy, which is of greatest interest based on the previous slide. We look at the duration of response, which is presented in a tabular form on the right. You see the duration of response for the drivolumab, tremolumab arm is 9.5, and about 50 percent of patients had a response remaining at 12 months. Next slide. Next slide, please. Next slide. I wanted to take a moment to really focus on the grade three, four toxicities. Historically, when the CTLA is combined with PD-1 together or with chemotherapy, there's been concern about higher rate of immune-related adverse events. Right here, you see the immune-mediated adverse events in group terms from this trial. If we really look with the drivolumab alone and the drivolumab, tremolumab together, the adverse events rates are very similar in terms of immune-related adverse events. This might be a factor that the drivolumab was only given for five cycles versus continuously or maybe a result of the patient population. I also think that doctors are getting better at managing these adverse events. What previously would have been a grade three or four adverse event was probably a grade one or two here because we've just become so much more adept at managing these toxicities. Next slide. The second trial, and this was a presidential session presentation as well, I think this is a trial of Lubareckin and Dr. Rubison versus CAV or Topatikin presented by Dr. Paz-Arez. Next slide. Looking at this trial, it's patients who had small cell lung cancer and one prior chemotherapy and have an ECOG performance that's a zero to two and measurable disease. This investigational arm is Dr. Rubison and Lubareckin, and if you can hit the next slide. If we take a moment to look at the Lubareckin dose, it's below the standard dose that is available in the U.S. for single-agent therapy. This is probably related to they had to be combined with Dr. Rubison and then they had to make a dose adjustment for the combination therapy. We look at the stratification factors, very reasonable stratification factors, particularly I would like to point out the treatment-free interval was divided into three tertiles, greater than 180, 90 to 179, and less than 90. Next slide. Due to the rate of myelodyspression on both arms, primary prophylaxis with GCSF was mandatory in both arms to prevent complications of neutropenia and febrile neutropenia. Next slide. These represent some of the demographics, and if we hit the next slide, it will highlight. This was a stratification factor, so a 12 ounce between the two arms, but as you can see, about a third of patients had a disease progression with less than 90 days. A third were in that middle core, and about a third were under and greater than 180 days. I think this is somewhat important when we interpret any trial in the second line small cell lung cancer because it's been associated with benefit from further chemotherapy. Next slide. This represents the primary endpoint overall survival. I think it's obvious that there's no survival benefit to the combination of ruberectin and doxorubicin compared to the standard of care arm, hazard ratio is 0.967. Next slide, please. This represents the stratification factors, and if we look at the hazard ratios, which are over on the far right, and if you look at it graphically, it does not look like any one subgroup benefit more or less from the lubronectin therapy, showing relatively similar activity in all these subsets. Next slide. If we look at the myelosuppression, I think if you look at the lubronectin and doxorubicin arm, the rates of grade three or greater anemia, neutropenia, febrile neutropenia, thrombocytopenia were lower in this group, and I think that there is a reduction in myelosuppression. When you look at this rate, I remind you that they all got GCSF prophylaxis as part of the protocol. Next slide. Treatment of the brain metastasis in patients with brain metastasis is an important clinical need, and what this is is a post-op analysis from the Checkmate 9LA study presented by Dr. Carbone and his colleagues. Next slide. This represents the schema. I highlight the area in red. For enrollment, patients with brain metastasis had to be adequately treated and asymptomatic for two or greater weeks prior to the first treatment dose. The patients were then assigned to Nevo, Olmab, and Ipilimumab with chemotherapy. Chemotherapy was given for two cycles versus standard care of chemotherapy. For the purposes of this presentation, I think the box on the right, and you see the magenta top heading, really illustrates that patients with brain metastasis baseline were 50 patients in the chemotherapy, Nevo, Olmab, Ipilimumab, 50 in the chemotherapy. About 300 of patients without brain metastasis in each cohort. Next slide. What we sort of look here is, and I was primarily focused on the curve on my left, which is the patients with brain metastasis, that the activity of chemotherapy and Nevo, Olmab appears to be very similar to the chemotherapy, and so it does not appear that the brain is a sanctuary site for this immunotherapies and it has activity in these patients. If you look at the patients without brain metastasis, there continues to be a benefit, but I think we're only taking one prognostic factor here. So to me, I think the important concept is that there's not any detriment. It does appear that this therapy is active in patients with brain metastasis. Next slide. I think when assessing chemotherapy or immunotherapy in patients with brain metastasis, many of the studies have been retrospective or post hoc analysis, and these can be inherently hard. And so I really commend this group for doing a prospective study. It's a phase two study of atezolizumab in combination with carboplatinum and pemetrexid in treatment IE patients with untreated brain metastasis. Next slide. This represents the study schema. Patients were required to be EGFR-alk negative, have untreated brain metastasis, and have measurable systemic disease and brain metastasis. They got the carboplatinum, pemetrexid, and atezolizumab on a very standard schedule, and then they would continue pemetrexid and atezolizumab until disease progression, unacceptable toxicity. Tumor evaluation was by CT scan for the extra CNS disease. And very importantly, there was a scheduled evaluation of the brain metastasis every six weeks, because I think this is a critical part to assessing activity in the CNS disease. Next slide, please. This represents the systemic PFS, and you see their median of 8.9 months. And if we look at the intracranial PFS, and the PFS is 6.9 months. Next slide. This represents the response rate. If you look over here, the response rate, best intracranial response by the renal brain met's criteria of 40%, best systemic response rate of 47.5%. So if you look at the brain metastasis, you see the median of 8.9 months. And if we look at the intracranial PFS, and you use the renal brain met's criteria, which is sort of the standard care criteria, it's a very similar activity in the CNS and extra CNS sites of disease. We always kind of worry about discorded responses in this situation. And two patients did have progressive disease in the extra CNS area, and stable disease in the brain. Also, two patients had progressive disease in the brain, and had a partial response in the extra CNS disease. When you look at the response rate, excuse me, median survival rate of 13.6, and two-year survival rate of 32%, which is similar to what other chemotherapy and immunotherapy combinations have done. Again, a very small trial, and a very unique patient population. Next slide. So to summarize this, I think chemotherapy with Druvolum and Tremulum will likely become a first-line option, and will join the other chemotherapy, immunotherapy, and single agent immunotherapy, and immunotherapy and CTLA combinations that are available. We're actually very fortunate to have a wealth of options at this point. I think the challenge as a clinician is figuring out which one to use in which patient. Lubronectin was given accelerated approval by the US FDA based on promising phase two trials. I think, obviously, this trial shows similar activities to our current standards of care, with a little less myelosuppression at this point. I think we're all sort of wondering, what's the future role of Lubronectin? I think, importantly, there are ongoing trials that might provide additional data for us to better assess what the role of this drug is in extensive stage small cell. I'm sure many of the people on the webinar realize that we have limited options in this disease, and we desperately need therapies. In regards to brain metastasis, I think chemotherapy and immunotherapy are a safe option, and active in patients with brain metastasis. I know in my practice, if someone has a small and asymptomatic brain metastasis, we will most often lead with systemic therapy and do surveillance MRIs, and also the MRIs that symptoms dictate. That concludes my section, and thank you very much for your attention. Dr. Higgins will now give her presentations. Hello, everyone. I am a radiation oncologist at Winship Cancer Institute of Emory University in Atlanta, Georgia. I will be focusing on three abstracts that I think highlight the depth and breadth of the lung cancer research that's going on within our global community. Next slide. I'll start with a presidential symposium abstract. This is a study that was conducted by the ISLC. The first author is Dr. Matt Smeltzer, and this is a survey study looking at the impact of the COVID-19 pandemic on enrollment in international lung cancer clinical trials. Next slide. I think we all here know that our clinical practices were impacted by the pandemic. This study sought to specifically look at clinical trial enrollment by surveying clinical sites and assessing enrollment during the calendar year of 2019, pre-pandemic, versus the calendar year of 2020. Next slide. The way they did this was by sending a survey to look at aggregate monthly clinical trial enrollment for lung cancer trials. They then also sent a 64-question action survey that was sent via email to look at specific strategies that sites used to mitigate the effect of the pandemic on trial enrollment. The primary respondents to the action survey were study PIs, as well as a small number of clinical trial coordinators and nurses. Next slide. This figure shows the breakdown of the trial respondents. You can see there's 173 clinical sites that were surveyed. There were 171 trials included, and there were 45 countries. The countries that were most heavily surveyed in this study were from Europe, North America, and Asia. Next slide. We know that beginning in early 2020, the cases of COVID-19 went up exponentially throughout the year. Next slide. If you look at how that impacted the average monthly enrollment globally, next slide, you can see that the clinical trial enrollment went down by 43%. The time period that was impacted most heavily was April through August. After August, you can see that the trial enrollment did start to pick back up again, which is sort of showing how the sites reacted and were able to mitigate the effects of the pandemic. Next slide. What were the most frequent challenges reported by the sites that were surveyed? Of course, fewer eligible patients that were coming in for consideration of clinical trials, issues with protocol compliance during the pandemic, and also suspension of trials by the sponsor or suspension of clinical trials by institutions. Next slide. What were the patient challenges and concerns during this period? The number one most concerning challenge was the willingness to travel to the clinical trial site, and also, of course, the fear of the COVID-19 infection. Next slide. So how did the sites mitigate these issues? The most frequently used strategies were modified monitoring requirements, telehealth visits, and then the ability to obtain clinical trial procedures at outside facilities, non-trial facilities for labs, and also for radiology studies and other trial procedures. Used less commonly but important was electronic consenting process. Next slide. And again, the mitigation strategies that were felt to be most effective were those telehealth visits and remote diagnostics and ability to really get those tests outside of the home site. Next slide. Next slide. Next slide. So in conclusion, we all know that the COVID-19 pandemic has created barriers to clinical trial enrollment, but internationally as a community we've been able to adjust our practices and rise to the challenge to continue to offer clinical trials to our lung cancer patients. Next slide. Next slide. But nonetheless, the authors of this study really felt that there should be a more flexible approach really embraced by our sponsors to try to design trials around some of these issues that allow telehealth visits, allow more flexibility with getting different trial-related procedures. Next slide. And that's really the take-home message of this survey study is that we need a more flexible approach that removes these unnecessary barriers for our patients. Next slide. And so my conclusions to this study is that really we need a more pragmatic pandemic-proof trial design for clinical trials going forward. We need to actively engage with our sponsors to create these trials. And I think that people living with lung cancer as well as study investigators should be very intimately involved in creation of these study calendars, visit schedules, et cetera, to make sure that the stakeholder voice is involved in all parts of trial design. Next slide. So the next study is a radiation oncology study that I wanted to highlight. This is from University of Pennsylvania. Dr. Gheghe Vermaan presented a study looking at death from intercurrent disease after proton versus photon-based chemoradiation in non-small cell lung cancer. Next slide. So we know that proton therapy can reduce the radiation dose to normal organs, but we are still uncertain as to what sort of clinical benefit this will produce in our patients. The authors here studied whether the risk of death from intercurrent disease was reduced with proton therapy. They defined intercurrent disease as death in the absence of disease progression. This is a single institution retrospective study, and there is about 200 patients in this study. Next slide. And if you look at their baseline patient characteristics, notably the patients that received protons were older. They had a heavier or more severe cardiovascular comorbidity, and they had a higher history of pack years of tobacco use. Next. And here, this table on the right shows the radiation dose to organs at risk for patients that receive proton versus photon thoracic radiation. And not surprisingly, we see that the dose to the normal organs, including the heart, the lung, the contralateral lung, and the esophagus are lower with proton therapy, and that's been shown previously. Next. So, they then looked at death from intercurrent disease. So, if you look at just the raw data, there were nine events in patients receiving proton therapy versus 16 in patients receiving photon therapy. Most of those deaths were related to respiratory failure. They then looked at the Kaplan-Meier curve for death from intercurrent disease at three years. We see 14.6 versus 7.1% favoring protons, but not quite statistically significant. Next slide. And there was no difference in overall survival or disease progression on this first analysis. Next slide. They then adjusted for age and performed a multivariate analysis for death from intercurrent disease. And here, they found that there was a statistically significant difference in patients receiving proton versus photon therapy. The three-year death from intercurrent disease was 15.6% versus 6.7% lower in patients receiving proton therapy. There was also differences in survival based on the mean heart dose. Next slide. Next slide. And so, the authors concluded that proton therapy is associated with reduced radiation dose to normal tissues and reduced risk of death from intercurrent disease after adjusting for age. And they believe this endpoint may be clinically relevant if disease progression decreases with immunotherapy. Next slide. So, my take-home for this study is that it's a very interesting hypothesis-generating retrospective study, but I think that RTOG 1308 will be the definitive trial to determine the role of proton therapy in locally advanced non-small cell lung cancer. But this study and other studies are pointing to the fact that proton therapy can certainly reduce the side effects of radiation. We've seen this for acute side effects of therapy, and also now the risk of intercurrent death, which is likely related to exacerbation of those comorbid conditions that these patients have. And we know that patients with locally advanced non-small cell lung cancer are very times medically frail with a host of other medical problems related to sometimes prior tobacco use, age, and so forth. So, potentially, proton therapy could be another tool in our toolbox when we're treating patients who may not be eligible for our standard therapies. But more to come as we look for those results of the randomized trial that's underway in the United States. Next slide. Okay, so this is my last abstract. This was also in our presidential symposium. This was presented by Dr. Berg. The last author is Dr. Schiller. And this abstract looked at the global lung cancer deaths attributable to air pollution. Next slide. So, from prior work, we know that air pollution is a risk for lung cancer. Globally, air pollution accounts for 14 percent of all lung cancer deaths. In the United States, that number is lower, about 5 percent, but still significant with 1 in 20 lung cancer deaths attributable to air pollution. Next slide. So, particulate matter is a group 1 carcinogen. Next slide. And this is carcinogenic by way of breathing in this particulate matter that then causes an inflammatory response in our airways and the alveoli, leading to the carcinogenic process that can take years. But certainly, this has been well worked out and shown in prior studies. Next slide. And so, the authors here sought to look at the estimates of death from lung cancer in countries across the globe. And they used a database that is publicly available and that has been published before, the Global Burden of Disease. And here, they were able to get estimates of particulate matter exposure globally across the world using satellite measurements of surface measurements, transport and geographical data, and aggregate exposure concentrations. And they then looked also at population attributable fraction and looked at an estimate with combination of this exposure and relative risk to try to understand what was the risk of lung cancer from air pollution across the world. Next slide. And here, you can see a figure. This shows their results in patients ages 50 to 69. You can see the hot spots are really in China and Eastern Europe. Next slide. And here, this is a tabular form of the results. The number one country with the highest numbers of deaths attributable to lung cancer from air pollution is Serbia. Poland is also very high as well as China. The United States ranks 176 within these countries. Next slide. And the sources of particulate matter are also important. The sources are largely considered to be related to transportation, indoor cooking, and reliance on coal for energy sources. Next slide. And the authors concluded that, again, 14% of lung cancer deaths are attributable to air pollution. This air pollution is coming from fossil fuels, transit, and indoor cooking. Of course, both smoking and air pollution are important causes of lung cancer. And really, we need to concentrate on eliminating both. As lung cancer professionals, the authors put forth a call to action for us to really raise awareness about the risk of air pollution and lung cancer, and I commend them for bringing air pollution to the forefront. We really haven't seen an abstract like this before, and it was, I think, additive to our presidential symposium. And that concludes my abstracts, and we'll end with Dr. David Harpole. Good afternoon, or evening. I'm Dr. David Harpole. I'm a professor of surgery pathology and thoracic surgical oncologist at Duke. Go ahead, Mike. Next slide, please. So our initial plenary was to understand more about the disparities in lung cancer care, not only in regions, but also globally. And this was an excellent presentation discerning some of the issues with respect to lung cancer care in the United States. Next slide, please. The objectives of this talk were to describe the multilevel framework of healthcare disparities in the US, to emphasize the need for comprehensive, proactive approaches to correct these issues, and to exemplify innovative programmatic solutions to the problem of inequities of lung cancer care delivery, which have, on a local area, have been able to overcome some of these. And finally, to highlight the social policy interventions, which are the greatest levers to equalize care across the spectrum. Next, please. So first of all, let's look at lung cancer, and these are two very demonstrable maps. The left-sided map is a heat map showing lung cancer mortality rates from 2009 to 2013, with the blue states, the dark blue states being low, and the red states being hot. And you notice that there's certainly a focus of high lung cancer mortality in the southeastern United States, and less problems in the West and upper Midwest. And next to that is a heat map of the percentage of change in age-standardized mortality rates for lung cancer between 1980 and 2014. In other words, the areas that were able to make the largest impact in improving lung cancer care are those in green, and the ones that had the worst impact were those in pink or red. And you notice that if you can almost superimpose these maps, that areas like California and the Northeast and New England area were able to have much better decreases in lung cancer mortality, whereas in the Southeast and Midwest, which looks exactly like the other map, in fact, the lung cancer mortality increased over that same interval. Next slide. So, you know, how do we define healthcare disparities? Well, it's a difference in the incidence, prevalence, mortality, and burden of disease, and other adverse health conditions that exist among specific population groups in the same geographic area. Avoidable differences are patterns that are predictable and similar, that emerge or worsen with discovery and innovation, and that multi-level etiology, whether it's patient, provider, organization, or social policy, can, in fact, impact these avoidable differences. That there can be multi-level clustering across geographic disparities, and overcoming these requires active interventions on preventing, eliminating, and narrowing the cause. Next slide, please. And so, let's look at what we've done in the last 10 years. Well, lung cancer screening has been approved for about a decade in North America, the United States, and so it has stimulated the development of lung cancer screening programs. The right-hand panel shows, with each blue dot, where all of the lung cancer screening programs are located, and not surprisingly, it mirrors those areas with decreases in lung cancer mortality seen in the previous slide. Unfortunately, if you superimpose that with the left-hand panel, which is where the lung cancer burden is highest, you see that there's almost complete disparity. In other words, in the areas that are black or dark gray, where there's high lung cancer prevalence and mortality, there are virtually no screening centers. So, we're screening in areas that have the least burden, and we're not screening in areas with the most burden, which just highlights the issue with disparities, not only geographically, but potentially for other causes. Next slide. And so, we all believe that the best treatment are treatments on clinical trials. Our colleagues in child oncology have 80 percent of the children with cancer in North America are placed on a clinical trial, and these are data for black patients in the U.S. You can see that in the U.S. Census, shown in dark blue in the left-hand panel, 12 percent of the population is black, but if you look in the orange panel, only 2.9 percent of participants in pharmaceutical trials are African or black, and 9 percent in all the SWOG trials. And if you look in the right-hand panel, this holds true for not only lung cancer, seen in the left panel, but breast cancer, colon cancer, and prostate cancer. The orange bars are far less than the overall percentage of the population that is black. Next slide, please. And so, why? So, one would assume that there are major issues. The first issue is structural barriers. In other words, a lot of the population in our country where there's disparity are in rural areas or in urban areas that lack clinical trial structures, so 56 percent of the barriers were due just, frankly, that the trials weren't available. But even more interesting is people have said, well, maybe there's a reluctance by different groups not to participate in trials because of their biases, but if you actually look at in patients who are presented trials, 55 percent overall of patients agreed to participate in trials, and when you break it down by ethnicity and race, in fact, blacks were just as likely as Hispanic and Asian people and even more than whites to participate in trials, so it is not a reluctance. It's probably that the trials are not available. Next. So, the take-home message is that for healthcare disparities, they can be reversible if we have a correct political and social construct. In other words, if we overcome the educational issues and we allow access in areas that are underserved, we can create a situation with which a more level playing field. And so, correct interventions, we need to reverse the situation that we have now where individuals and providers have most of the impact and need to have social policy and organizations in charge of this so that on a global front that we can decrease these disparities. Next slide, please. So, this is a presentation by Dr. Altorki of our president, Dr. Wakely's overall trial on Empower 10, which characterized the adjuvant use of atizolizumab in stage 1b to 3a resected lung cancer patients. Next slide. So, we know that stage 1b now in the eighth version, stage 2 to 3a, surgically resected patients followed by adjuvant chemotherapy is the standard of care. The phase 3 Empower 101, I mean the Empower 10 trial, evaluated atizolizumab and antipedial 1 versus best supportive care after adjuvant chemotherapy for patients with completely resected non-small cell lung cancer. And at the DFS interim analysis, which was presented earlier by Dr. Wakely, we found that adjuvant atizolizumab showed significant DFS benefit versus best supportive care for PD-L1 staining 1 plots, 1% or greater, and the statistical boundaries was not crossed in the intentions to treat. In other words, all randomized patients, not only those with 1% or greater staining. The OS data at the time was immature, but one of the questions was, does surgery type and the other factors potentially impact these outcomes? And that was the purpose of this presentation by Dr. Altorki. Next slide. So, this is the schema very briefly, completely resected stage 1b to 3a by version 7. We're given four cycles of cisplatin plus hemotrexid gemcidabine, docetaxel, or venerelbine. There were 1,280 patients and they were randomized one-to-one. A thousand patients met randomization of best supportive care or atizolizumab for 16 cycles. Now, this was a hierarchical statistical testing to make sure that each hypothesis were met before the next stage. So, if DFS was met in the 1% PDL people, then if that were positive, they looked at DFS in all randomized patient. If that were positive, they look at DFS in the intention to treat. And then finally, overall survival. Next slide. So, there were again, 1,280 patients enrolled and there were 275 patients that were discontinued prior to randomization. So, our honesty, this is a consular diagram showing the reason people withdrew. Now, a third of the patients withdrew because of preference of the patient due to the, due to their overall status at the completion of chemotherapy. But I think importantly, 20% of the patients relapsed or progressed during therapy prior to surgery. And so therefore, did not go in to the randomization of the trial. And in fact, there was a 7% mortality rate of therapy, which is not unusual in patients in for adjuvant therapy after resection. Next slide, please. The characteristics, however, for the Atizo arm and the Best Supportive Care arm with roughly 500 patients in each were well-balanced. And importantly, the median time from surgery to the first Atizo or the placebo was about five months in both arms. And the completeness of lymph node resection and type of operations were also similar between the arms. Next slide. I think what is important is the initial adjuvant trials, which have been published for more than 15 years, demonstrate around 70% of patients completing therapy. And what is important is in this more modern trials, you can see for the cystocetaxel arm, for the cyst venereal being arm and the cyst pemotrexate arm, virtually 90% of patients receive therapy. I highlighted the cyst gem arm, which was in 78%, but still significantly higher than the previously reported data, probably demonstrated the more efficace ways we can give chemotherapy and better monitoring during therapy for our patients. Next slide. So the DFS arms here with the left-hand panel with the greater than 1% PDL, the center panel with all randomized patients and the right-hand panel with attention to treat. The blue curve are those who received Atizo. And you can see that in the 1% staining and all randomized patients, significance was met. And in fact, it appears in attention to treat, the P-value is 0.04, although the curves are close together, that likely this is also gonna be significant. Next slide. When we look at this way, if you're doing some subset analysis, we want to see all of the effect on the left side of the identity line. And you can see that all of the blue dots are, with the exception of a couple of points, the gemcitabine arm, and as well in the type of surgery, those that had a pneumonectomies or bilobectomies. These probably were concurrent for larger central squamous tumors and the gemcitabine seemed to associate with them as well, which may denote that that was just a larger tumor burden. And so the responses were less than expected. Next. So in conclusion, at the DFS interim analysis for the Empower 10, Atizo showed significance for disease-free survival compared to best supportive care for the PD-L1 1% stainers and all randomized patients. In the intention to treat population, the arms were well-balanced. The majority of patients had lobectomy and lymph node dissections, and were able to obtain all four cycles of adjuvant chemotherapy prior to the immunotherapy. And the median time to surgery to the start of randomization was similar. So in this exploratory analysis, it appears that everything was well-matched and we look forward to the overall survival in future studies. Next slide. So S1619 is a trial by Dr. Stowe and colleagues from the SWOG, which was looking at the feasibility of a neoadjuvant approach of adding atezolizumab to neoadjuvant cisplatin and pemotrexid in plural mesothelioma. Those of you that know the data that there've been several small phase two and then cumulative trials that have demonstrated that neoadjuvant cisplatin and pemotrexid for two to four cycles prior to pleurectomy and decortication has not improved survival. And it appears that it may actually be detrimental because the response rates are so low that there's a lot of progression of disease during the treatment interval. And in fact, less patients are allowed to have R1 or R0 resections with worse outcomes. So this trial was looking at, does the addition of upfront immunotherapy improve that? Next slide. So again, it's a phase two feasibility to review a mesothelioma is an orphan disease with limited treatment options. A neoadjuvant chemotherapy has not shown much benefit. It is an immunogenic tumor and PD-L1 targeting has been identified for some advanced studies that show when it may be useful. And so the rationale was wondering if the addition of anti-PD-L1 upfront was beneficial. Next slide. So here's the schema. There were 24 patients accrued from a number of institutions that were SWOG and participating other cooperative groups. The patients received PEM and CIS plus a TISO. If they had no progression, they underwent a pleurectomy decortication or an explanumectomy based on the surgical preference. An optional XRT was given out back. And then the patients received maintenance of TISO. Next slide. So 24 patients were accrued, as I said earlier, the regimen was considered safe and tolerable as no patients experienced grade four to five immune related adverse events, either perioperatively or late. The feasibility was demonstrated with none of these toxicities. And the feasibility written of the trial was with 18 of 24 patients received at least one dose of maintenance therapy that would prove it. And that in fact was reached. So it's anticipated that 28 patients will continue to be accrued so that they can have 24 eligible patients for evaluation of potentially moving this into a phase three setting. Next slide. So here is the consort diagram showing that most patients were able to have the treatment that 19 of the patients, 29 of the patients underwent the planned surgery and that 16 of the patients received a maintenance registration. Next slide. So of the 21 patients who've completed all therapy, it appears that the toxicities were tolerable, that at resection, stable disease or partial response were seen in 18, which is a certainly a higher percentage than was seen with just PIM and CIS given an induction method. And 16 patients are receiving their TISO. So it appears that this has been a successful phase two trial and we again, await the further final analyses of these data in the future. Thank you. All right. I think that wraps up our slide presentation and we're gonna move now to the question and answer. If you have questions, please put them in the question and answer box and then we'll go through them one by one. The first question is for Dr. Stinchcomb. In the Poseidon trial, did they do any comparisons for the first and second treatment groups? They did not compare the chemodrovolumab to the chemodrovolumab and tremolumab arm. Both independent arms were compared to the standard care arm. Yeah, the plan on the trial was to look at immunotherapy versus standard chemo, but not between the combination versus single drug. All right. We have another question for Dr. Stinchcomb. Will the failure of the Atlantis trial affect the development of lerbanectin in combination with arenatequin or nivolumab or other drugs for that matter and their chances in general in the small cell space? My hope is it does not. I think it's one trial in a disease that's desperate for new therapies. And you know, when we talk about the comparative arm of topatequin and CAB, those were really developed in the 1990s and we need some therapies. I guess the questions remain with this trial was did the lower dose, the combination with doxorubicin adversely impact the outcomes or the tolerability? Is there a patient population that may be better suited to it? So I hope those trials continue to develop because as we get more and more data, we'll probably have a more accurate picture of the activity of lerbanectin. Yeah, no, I definitely agree with you. This question is from Greg Frazier. Do you think the mitigation strategies used in the pandemic can continue to be effectively used in trials post pandemic to increase recruitment? So, I mean, I think I'll just pose that to all of the panelists. I would say in general, the onus is on us as investigators to really demand that we improve the flexibility of our trials and we keep some of these mitigation strategies in place. I think telemedicine is a great example of something that can be easily applied and it can make patients more likely to join a clinical trial if they know they don't have to come back to the enrolling center as frequently. I know that, sorry, go ahead, Dr. Harpool. Well, I was gonna say, I think that this is hopefully going to nudge the regulators because the European and FDA have been very rigid in their definitions how trials have to be monitored, how reporting has to be done and all these things. And I think if anything, the pandemic has forced things for us to on the fly adapt. And so hopefully it will allow a little more flexibility. Those of us who do clinical trials, it's been incredibly frustrating, how difficult it is to get trials approved at your institution, how much more they cost and how it's more difficult to get patients to comply to the trials because they're so onerous and having some flexibility of where you get your studies and where you follow up and all these things I think is gonna help. I mean, Tom, do you agree? No, I mean, I think that this has been a problem before the pandemic. And like many things, the pandemic exposed our fundamental weaknesses. And I think we really need to look at how many of these extra study visits are really necessary. I can, the shipping of oral drugs, I think electronic consents are all advances. My fear is I don't want us to sort of lose momentum because I think we really need to fix this across all of our trials, because frankly in the US our participation in the cancer trials is very low. And I think that's a sad statement on our effectiveness of delivering clinical trials. Yeah, and Dr. Marina Garasino did the discussion for this abstract and she noted that in Europe, given all of the demands of clinical trials and the rigidity of the clinical trials, young investigators are now swayed to do other things with their academic careers because a career in clinical trials is felt to be onerous. And that's really disheartening. We don't wanna lose our talent as a field because people feel like they can't succeed in this environment. So I just think the environment needs to change and I think we're at a tipping point and hopefully things will change. I think it's happening. All right. So we have a question about the air pollution abstract. Can you please explain what is meant by the risk of indoor cooking modules? So yeah, that's a good question. So this is relevant to other parts of the world where when people are cooking in poorly ventilated spaces, there is a high concentration of particulate matter that can then put them at risk to develop lung cancer. So it's really more applicable to other areas, not so much in the United States, but when you're cooking in small areas with poor ventilation. So that was what was meant by that. The next question. Were there any discussions of chemotherapy in stage 1A non-small cell lung cancer as these cancers are often treated by surgery and may reoccur? Boy, we have an expression in the South called preaching to the choir where that you're not really, you're preaching to people who already believe. For the last 25 years, Tom and Kristen, all of us have been saying in breast cancer, adjuvant therapy is giving to women with a 92% survival in lung cancer. We accept an 80% or 75% survival is something that doesn't need treatment with a 20 to 25% recurrence rate. So the answer is, of course, we would love to see that. It is certainly the next step for us to do that, especially now that we have adjuvants that aren't as toxic as platinum-based doublets. As you know, from the adjuvant trials, the treatment mortality was 0.8% in the three large randomized trials, which is not for chemotherapy. And that's a reasonable number for a 5% benefit. You have to weigh that. And now that we're getting treatments that are much less toxic, I think hopefully we'll start seeing some more of these trials. I don't know if Tom and Kristen want to add other information. I mean, I think that this is a, I think the problem is that the small population event rates is low, so these require long-term follow-up in a lot of patients. I mean, that doesn't mean we shouldn't do it. I mean, like you cited those relapse rates, and I think this is the best opportunity to cure, and I'm hoping that some of the newer agents will move into this very early-stage disease. And it also is a very opportune time to look at prevention agents, because many of these patients develop second primaries. And so, I mean, I think there's a wealth of opportunity in that patient population. And we did have a session on CT-DNA and measurements of mental and residual disease. And I think as those bespoke DNA plasma tests become more and more sensitive, we are going to get to the point where maybe we could use those to separate the patients, the early-stage patients who actually have demonstrable disease and might benefit from additional therapy. Now, I'm not saying that the presence of disease definitely means they'll respond to therapy, but if you were going to select a population, you want to treat only those who may benefit. And so, if we have a way to separate that 75% who don't need it, that might make these trials more appealing. All right, we have one final question. How is ISLC supporting more effective conversations on clinical trials between clinical teams and patients from underrepresented groups, both recently and in the near future? I think that one of the big things that ISLC has done between the last World Lung and this one is the Lung Ambition. And Lung Ambition has gotten together industry and our group and advocates to try to not only come up with better ways to diagnose lung cancer, that we're helping worldwide screening programs, but to really come up with more effective treatment strategies. And in areas where, say, the latest and greatest aren't available, we still have effective therapies. And to make sure that those effective therapies are able to be delivered, educating providers throughout the world about this, educating countries about smoking cessation. And I think, as Kristen said, this presentation on pollution is just eye-opening that 20% of what, 14, 15% of lung cancers in part of the world are actually not related to smoking, but related to air pollution, even 5% in the U.S. So I think all of these things ISLC is trying to do, but this is a grassroots effort. And so nothing will happen without our membership getting involved with these different processes. I don't know if Kristen and Tom have other things they might want to add at the end. Yeah, I mean, I second what Dr. Harpole mentioned about the Lung Ambition Alliance. I think that's a great effort to really accelerate the pace of the progress in lung cancer. And it's a way to incorporate the patient advocates into what really needs to be done to move the needle in lung cancer faster. But I think your point is well taken that certainly we do need to make sure that we're having these conversations with underrepresented groups about clinical trials and clinical trial moments. And it needs to be something that we prioritize. I also think, to add on to what David and Kristen said, you know, we had this long conversation about how onerous the trial infrastructure is. We gotta sort of reduce the cost of these trials if they're gonna be made available to health systems that maybe don't have the resources to do them. We can't get the trials to people if we're not actually having the medical centers in there as underserved minorities have access to the trials and access to the things. And I think we really do need to look at our economics of the trials and see if there's any way we can reduce the price. And I think this is so important because unfortunately, if you look at the worldwide global trends in thoracic malignancy, especially lung cancer, the biggest growth are in the developing world. And these are the areas that have the least amount of screening and the least amount of trials and the least amount of providers and access. And so we have to look at this as a very important task for us to participate in. We need smoking cessation programs and things around the world so that everyone has the same opportunity for a healthy life. Absolutely. It looks like we have one minute left. So should we wrap it up? Well, I think I really appreciate you all listening and participating in this. This was a wonderful conference. Of course, we all would have liked to have been together in Denver and we all hope that we'll all be able to get together in Vienna. But I finally wanna say, I wanna thank my co-chairs for all of their hard work and especially the staff of ISLAC for all of their Herculean efforts to put together this meeting and which I thought was a terrific success and almost went off flawlessly in spite of literally thousands of participants. Tom and Kristen, any last words? No, I would like to thank the staff as well in this, sorry, a tremendous effort. And I think people don't realize that a virtual meeting is actually, I think, more work than a live meeting, it seems to me, just because there's so much coordination in time zones. And so I think they did a tremendous job. Thank you. Yes, and it was a great pleasure working with you all. And I think the meeting was fantastic. And remember, you can download the slides to this webinar and you can replay the webinar. It'll be available online. And also, as Aubrey wrote in the chat, keep an eye out for the program evaluation and CME information. All right, take care, everyone.

World Conference on Lung Cancer 2021

lung cancer treatment

Poseidon trial

non-small cell lung cancer

chemotherapy

Druvolumab

Tremolumab

Atlantis trial

small cell lung cancer

air pollution