Welcome to the ISLC webinar, Highlights from ASCO 2024. I'm Rebecca Heist, a medical oncologist at Mass General Hospital Cancer Center in Boston, and I'm joined today by Dr. Joseph Greer, Dr. Alyssa Cooper, and Dr. Zosia Pietruska. We're thrilled to have you here. We will start this activity with some brief housekeeping items. After the presentations are concluded, you may ask any questions by using the Q&A button that's on your video screen, and we'll be addressing these questions after the three-speaker presentations as time permits. This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education, ACCME. The International Association for the Study of Lung Cancer, ISSLC, is accredited by the ACCME to provide continuing medical education for physicians. The International Association for the Study of Lung Cancer designates the live format for this educational activity for a maximum of 1.0 AMA PRA Category 1 credits. Physicians should only claim credit commensurate with the extent of participation 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. And to start our presentations, I'm pleased to welcome Dr. Joseph Greer, who will be our first presenter today. Dr. Greer is a clinical psychologist and associate professor of psychology at Harvard Medical School. He's the co-director of the Cancer Outcomes Research and Education Program at Mass General Hospital Cancer Center. It's my pleasure to welcome Dr. Greer. Thanks for joining us. Great, thanks so much. Share my screen here. OK, looks like we're good. So I'm very pleased to share the results of our very large-scale national multi-site comparative effectiveness trial of early integrated palliative care delivered via telehealth versus in-person among patients with advanced lung cancer. The main takeaway from this trial is that palliative care led to equivalent benefits for patient-reported quality of life, whether delivered via video or in-person visits among adults with advanced lung cancer. And these findings underscore the potential to increase access to evidence-based early palliative care through telehealth delivery. All of us in our clinical practices every day see the ways that a diagnosis of lung cancer disrupts the experience and lives of patients and their families. Even though we have many, many incredible breakthroughs in novel therapeutics over the last two decades, most patients with advanced lung cancer at some point along their disease trajectory will experience a range of physical, emotional, and other psychosocial concerns, side effects from treatment, concerns about what the future might hold. And their loved ones, their family members, and friends share in this distress. To address these unmet needs, ASCO and other professional societies have recommended the early integration of palliative care from the time of diagnosis of advanced lung cancer and other solid tumors. That recommendation and those guidelines are based on robust evidence from numerous clinical trials demonstrating the efficacy of early integrated palliative care for improving patient-reported quality of life, symptom burden, depression symptoms, and other key outcomes. And therefore, patients and their caregivers who receive early integrated palliative care once from the time of diagnosis experience improved outcomes. The challenge with that model of care, this evidence-based model of care, is that it is very difficult to implement for a variety of barriers, chief among them being the lack of available clinicians to provide that specialty care. One promising solution for overcoming barriers to delivering medical care is the provision of telehealth using video visits to help overcome these types of access barriers. And recent studies have shown that telehealth also reduces financial pressures in toxicity in patients and for the health care system. So this is what was sort of the basis for our initial hypothesis in developing this study is how could we improve access to early integrated palliative care. At the time when we did conceive of this study, this was about two years before the pandemic. So most people were not using telehealth. And so that question of whether the delivery of medical care, in this case, early integrated palliative care via secure video, was that equivalent? Could we provide that high quality care in an equivalent way to in-person palliative care? And we did this, again, in patients with advanced lung cancer. So our primary aim in developing this study was to evaluate the equivalence of delivering early palliative care using video versus in-person visits on patient-reported quality of life. We randomly assigned 1,250 patients with advanced non-small cell lung cancer in their caregivers to receive either monthly video visits or in-person visits. And then patients completed surveys regarding their quality of life, again, in terms of that primary aim. But they also completed measures regarding their satisfaction with care, their anxiety and depression symptoms. And also, we measured caregiver attendance at the study visits, both for the in-person modality as well as the video visit modality. Participants completed these measures at baseline upon randomization. And then, again, at weeks 12, 24, 36, and 48. As you can see here, this was a very large-scale trial. We conducted this study at 22 cancer centers across 18 states. We selected these cancer centers based on their capacity to provide outpatient early palliative care, in addition to trying to represent as much of a broad swath of geographic and socioeconomic diversity as well. The enrollment period went from June 2018 to May 2023. And as I mentioned, we randomly assigned patients in a one-to-one fashion to either video or in-person visits. For those patients who did not have the needed technology, we provided them with a study-issue iPad. And then the visit frequency is consistent with our prior efficacy trials of early integrated palliative care. So the patients and their caregivers would meet with the palliative care clinicians on a monthly basis at least. They may meet more often than that, but on a monthly basis at least. For patients in the video visit group, based on recommendations from our patient, caregiver, and clinician stakeholders, they've strongly recommended having patients and their loved ones meet with the palliative care clinician in-person first and then transitioning to video visits. So the initial in-person encounter in the video visit group was in-person, and then they transitioned to video. And then the clinicians, all the palliative care clinicians, documented the topics that they discussed during these encounters using a standardized survey that they completed after each study visit. So patients who are adults diagnosed with advanced non-small cell lung cancer in the prior 12 weeks who were not being treated with curative intent and who had sufficient performance status to participate in study visits and complete the surveys and were receiving care at one of the participating sites and able to complete the questionnaires either in English or Spanish were eligible to participate in this particular study. In terms of operationalizing our outcomes, for patient-reported quality of life, the measure was the functional assessment of cancer therapy lung scale. Again, completed that baseline and then the follow-up time periods I mentioned. For the findings that I'm reporting today, we are focusing on the 24-week primary outcome time points. In addition, patients completed a measure of satisfaction with care. And for that, they completed the satisfaction and care delivery questionnaire. And then for secondary and exploratory outcomes, they also completed a measure of their anxiety and depression symptoms, the hospital anxiety and depression scale. And then the clinicians documented in each of those visits using that standardized summary form that I mentioned in the last slide, they documented who attended the visits. And so this is where we were able to look at the secondary outcome of whether a caregiver was present or not. So for this particular study, 1,250 patients provided 95% power to evaluate the equivalence between these two modalities. And in terms of the primary outcome of the FACT-L, the functional assessment of cancer therapy lung scale, equivalence was established if the 90% confidence interval was within the margin of plus or minus 4 points between the two groups on that measure. You can see here that study staff approached 2,833 patients, of which 1,250 were randomized, 633 patients to the video visit group, 617 to the in-person group. And you can see the rates of data collection for the patient and caregiver reported outcomes ranging from about 65% to 75% for the follow-up time points. In addition to that, we enrolled about 558 caregivers of the 1,250 patients. On average, patients were about 65 years old, a little more than half identified as women, and the majority were white, not Hispanic, and married. About a quarter had a highly targetable tumor mutation, and about 40% had received a platinum-based doublet, plus or minus a third agent for their primary treatments. You can see over that 24-week period, both the video visit and in-person group had about the same number of visits, 4.7 in the video visit group and 4.9 in the in-person group, excluding that initial patient. Excluding that initial per-protocol in-person encounter in the video visit group, about 13% of visits in the video group were in-person at the request of the patient or the clinician, which was allowed per protocol. Prior to the pandemic, there were no patients in the in-person group who received any video visits. Unfortunately, when the pandemic hit, we did have to halt recruitment for about two months. And during that time, some of the patients who were in the in-person group had no choice but to have video visits due to the rapid changes in ambulatory care practices. And so the study staff worked very hard to really move people back into their original assigned modality when the in-person care was able to open up again at each of those sites. So we halted recruitment at each site until they could resume in-person care. And as you can see here, only about 6% of patients had 6% of the visits in the in-person group were video based on that issue of the pandemic. We had 138 clinicians who participated in this trial, and they completed about 5,200 summary forms from all of their different encounters. Interestingly, you can see here in the figure on the right that the primary topics discussed during those encounters were first and foremost establishing rapport with the patient and family, also addressing and managing symptoms, and then also supporting their adaptive coping efforts with serious illness. Less than half the visits focused on illness understanding or advanced care planning or treatment decision-making. And as you can see, whether we're talking about the video visit modality or the in-person modality, these topics were remarkably similar in frequency between the two groups. As this slide shows, we confirmed our primary hypothesis in demonstrating the equivalence between the video visit group and in-person group for improving patient reported quality of life. And as you can see on the right-hand side, for the FACT-L mean at 24 weeks, the video visit group was 99.7, and this is on a scale of zero to 136. Higher scores indicate better quality of life, and the mean for the in-person group is 97.7. And so this was statistically significant for equivalence between the two groups. We also conducted a host of sensitivity analyses to address missing data issues, as well as stratification by study site, as well as to address the contamination issue that I just mentioned of the in-person visits, the in-person modality having some video visits. And in all of those cases, we confirmed either the equivalence or the non-inferiority of video visits relative to in-person visits. With respect to our secondary outcomes, you can see here that for patients and caregivers, their reported satisfaction with care was not statistically different between the two study groups. Also, in terms of the attendance of caregivers at the visits, we did find that the in-person modality had a higher rate of caregivers participating. So about half the in-person visits had a caregiver present, whereas only about 37% of the in-person visits and 7% of the video visits had a caregiver present. In terms of our exploratory outcomes for patient-reported mood symptoms, anxiety symptoms on the left and depression symptoms on the right also did not differ significantly between the two groups. And as you can see in these figures, there's the reduction in anxiety and depression over time. So to conclude, we demonstrated the equivalence of the effect of delivering early palliative care via video versus in-person visits on patients' quality of life. Caregiver attendance was greater for the in-person versus video visits. This was actually contrary to our initial hypothesis. We had thought that the video visit arm would provide a greater level of convenience and allow for patients who have maybe family members living in distant states or more remote areas to be able to call in. But in some ways, we now have realized perhaps that convenience of the virtual modality gave them more autonomy to decide when caregivers should participate jointly in those visits. Whereas for many patients, for those who see patients in the clinic, very often a caregiver does accompany the patient to help with transportation, likely increasing their participation onsite. Otherwise, with respect to the secondary and exploratory outcomes, the study groups did not differ in their satisfaction with care or their mood symptoms. In terms of thinking next steps, the questions still remain, when are video visits essential relative to in-person visits? And I think that's still an open question. As I mentioned, patients and caregivers and clinicians in the video visit group who had requested an in-person visit when they felt that that was clinically indicated. And so follow-up interview studies, particularly with the patients and the clinicians regarding their perceptions of when those circumstances were necessary will help to answer that question. The other question is, do we see any differences in any kind of heterogeneity of treatment effects based on sociodemographic characteristics, such as age or other factors like technology experience or the presence of a caregiver? And we will be doing those follow-up analyses in a secondary report. In terms of the implications of this study, I would say one of the key messages is that patients who really from a range of locations in a range of ages and socioeconomic backgrounds were able to successfully onboard to a video conferencing platform with minimal training. And again, when we did start the study, people were not using video visits. Obviously during the course of the pandemic that infrastructure changed rapidly, but at the time there was a lot of hesitation regarding this type of technology. Nonetheless, even in an older population with advanced cancer, we were able to successfully onboard them using this type of technology. And these visits were particularly helpful, this virtual modality for ensuring continuity of care for patients who lived in remote regions or may have a high symptom burden or maybe frail. There are ongoing challenges. And even today, despite our increased infrastructure for delivering this type of virtual care with those who have visual or audio impairments who also maybe lack needed technology to participate in video visits. We did find in the clinician summary reports that on average, the clinician saved about 10 minutes in terms of both the delayed onset of visits relative to in-person care, and then the total time in providing care was also another five minutes saved. So on average, video visits were just more efficient for the clinicians in providing care. We also observed that joint visits between palliative care and oncology, which is another key factor in this early integrated model that is critical to really ensuring continuity and support for the patient and family was more difficult to coordinate via video. So about 10% of the visits were joint visits in the in-person group between the palliative care clinician and the oncologist. In the video visit group, less than 1% were joint visits. So there's room to really think about how we coordinate virtual joint visits that needs to be addressed moving forward. And then lastly, these data provide essential evidence to support the effectiveness of high quality video-based care, and ideally will inform policy decisions, especially in this year where multiple bills are before Congress regarding making permanent the extension of these telehealth flexibilities that started during the pandemic. So we hope these data will demonstrate that high quality video-based care absolutely is effective, and that for patients who very much need this, especially those who have high morbidity and can't get to clinic, this does improve access and will ideally inform these policy decisions moving forward. So I'd just like to thank all the participating sites, those 22 sites, their patients and caregivers, palliative care and thoracic oncology clinicians and the research staff who made this study successful, our research team, my co-principal investigator, Dr. Jennifer Temel at the MGH, and then also the Patient-Centered Outcomes Research Institute for funding this study and really supporting us through all the challenges of the pandemic. Thanks so much. Thanks so much, Dr. Greer. Really great work that addresses some really key clinical questions that we face in clinic every day. So we're gonna move on next to Dr. Zosia Pietruska. Dr. Pietruska is an assistant professor of medicine at Harvard Medical School, a attending thoracic oncologist at the Mass General Hospital Cancer Center. And she will be discussing for us the late-breaking abstract for the Phase III Laura study. Great. Well, thank you so much, Dr. Heist, and thanks to the Islaq Education Committee for the opportunity to discuss this very exciting and important abstract, which we were all very eager to hear at the ASCO plenary session. Let's see. So this audience, I think, is well aware, but just by brief background, thinking about EGFR mutations in non-small-cell lung cancer, as you can see here in this pie chart, EGFR mutations comprise about 15 to 17% of oncogenic mutations in non-small-cell lung cancer when looking at a worldwide population. But of course, we also know that these are also enriched in some parts of the world, particularly in Eastern and Southeastern Asia. For patients with advanced or metastatic EGFR-mutated non-small-cell lung cancer, we've really seen a long road, now about 20 years of drug discovery in this field, and osamartinib is our current first-line standard of care with, of course, some exciting combination data coming as well. Osamartinib is a potent third-generation EGFR inhibitor, which is highly selective for EGFR. It's recognized to have overall a good safety profile, and very importantly, it has high CNS penetration. And in recent years, we've really seen the movement of osamartinib across the involvement of osamartinib in the care of patients really across the spectrum of stages of disease with EGFR mutant lung cancer. Of course, as I already mentioned, starting with patients with advanced or stage four EGFR mutant lung cancer, where first line osimertinib was shown to be superior, both in terms of progression-free and overall survival to older generations of EGFR inhibitors. And now, of course, we also have data for the combination of osimertinib with chemotherapy from fluoride 2. We also know that in early stage, resectable stage 1b to 3a EGFR mutated non-small cell lung cancer, patients who undergo surgery and adjuvant chemotherapy, if indicated, are now also eligible for adjuvant osimertinib for three years, which the ADORA trial presented at the ESCO plenary session in 2020 and 2023 showed improvement in disease-free and overall survival compared to placebo. But that leaves patients in between these two stages, those with unreceptable stage 3 EGFR mutated lung cancer, where our current standard of care is to use definitive chemotherapy and radiation, but the question has been, what should we use as consolidation therapy for these patients? And this is really the question that the LORA trial seeks to answer. So taking a step back and thinking about unreceptable stage 3 non-small cell lung cancer, we know that for a broad non-small cell lung cancer population, the PACIFIC trial showed that definitive chemotherapy and radiation followed by one year of consolidation dervalumab improved outcomes and specifically overall survival compared to placebo in the PACIFIC trial. However, we also know that very few patients with EGFR mutated non-small cell lung cancer were included in PACIFIC, and in the setting of advanced disease, PD-1 and PD-L1 inhibitors are generally thought to be inactive against EGFR mutated non-small cell lung cancer, raising some questions about the appropriate consolidation therapy for these patients. In a post hoc analysis of outcomes in the small EGFR mutant non-small cell lung cancer subset in the PACIFIC trial, I'll note this is only 35 patients, but as we might've predicted, there was no improvement in either progression-free or overall survival in the dervalumab arm compared to placebo. And in a multi-institutional retrospective analysis, looking at patients who received osmertinib consolidation in an off-label fashion and comparing those patients to dervalumab or observation, we saw with the caveats, of course, of a retrospective analysis, that real-world progression-free survival was longest in those patients who received osmertinib consolidation, as you can see here on the right side. And all of these data really laid the foundation for the design of the LORA trial, which sought to answer this question in the context of a prospective randomized phase III study. So this is the design of the LORA study, which Dr. Ramolingam presented on behalf of his co-authors in the ASCO plenary. This design will look familiar. It's really quite similar in many ways to the PACIFIC trial. These were patients with locally-advanced, unresectable stage III EGFR-mutated, non-small-cell lung cancer. These patients had classic activating EGFR mutations, exon 19 and L858R. And following completion of definitive chemotherapy and radiation, they had to have no evidence of disease progression. And those patients then, after chemoRT, were randomized in a two-to-one fashion to osmertinib 80 milligrams once daily or placebo. And you can see the stratification factors here. Now, a key factor of this study design is the duration of osmertinib. Unlike the adjuvant setting where osmertinib was given for three years, here in the unreceptable stage III setting, osmertinib was planned to be given until disease progression or toxicity. So essentially indefinite osmertinib until progression. There was also a crossover allowed. Open-legal osmertinib was offered to patients with progression in both treatment arms. Tumor assessments were by CT, but also, importantly, by brain MRI to monitor for CNS progression. And the primary endpoint of the study was progression-free survival, with overall survival and CNS outcomes as key secondary endpoints. These were the characteristics of the patients enrolled in LORA. You can see that 143 patients received osmertinib and 73 received placebo. The arms were fairly well-matched. I'll just highlight that over 80% of patients in each arm were of Asian race, and the majority, as we would expect, had stage IIIb or IIIc disease. And this is the primary endpoint of the study. I'll pause here because this received a standing ovation in the room at the Eskil Fennery session, and I think these results are really worth, you know, spending a moment on. You can see this was the progression-free survival blood-blinded independent review, which was 5.6 months in the placebo arm and 39.1 months in the osmertinib arm. The PFS hazard ratio here was 0.16, corresponding to an 84% reduction in the risk of progression when osmertinib was used. Now, if we look at overall survival, this was an interim analysis with only 20% data maturity shown here on the left, and there was no significant difference between the two arms. But it is important to note that there was a high rate of crossover, which was great to see. Among the patients randomized to placebo, 81% of them crossed over to osmertinib at disease progression. I would say that we don't always see such high rates of crossover, and this will be really important. It's the best thing for patients, but will also be important to keep in mind as we look at subsequent overall survival analyses. Now, as I mentioned, a key factor, a key feature of osmertinib is its excellent CNS activity. And so one of the expectations was that the success of osmertinib in early-stage and unreceptible stage 3 disease may have to do with a CNS protective effect. And indeed, when we look at the sites of disease progression on the LORA trial, there was significant decrease in CNS progression in the patients treated with osmertinib. 29% of patients treated with placebo had progression in the brain. I think this is a notably high number, and only 8% of those treated with osmertinib. This is important not only for survival, but also because of the morbidity and mortality that can go along with symptomatic CNS progression. And so this is really, I think, a key thing to keep in mind as we make decisions for our patients. It does seem that osmertinib has a CNS protective effect, which is probably key to its success across all stages of disease. Now, when we talk about treating patients indefinitely with a drug that they may be on for many years, of course, safety and adverse events will be incredibly important to keep an eye on. Broadly speaking, I think the safety profile of osmertinib in this study was as expected. We saw higher rates of diarrhea, rash, paronychia, all toxicities that we are used to seeing and managing with osmertinib. We did see that 48% of patients in the osmertinib arm and 38% in the placebo arm had radiation pneumonitis, and these were all largely low-grade. And interestingly, this was grouped separately from interstitial lung disease, which was reported in 8% of the patients in osmertinib and was also largely low-grade. From a clinical perspective, I can say that it's not always easy to distinguish radiation pneumonitis from ILD. And so I think this is something that we will have to keep a close eye on in the clinic. And when we're faced with patients who have evidence of pneumonitis and are thinking about a potential longer treatment duration of TKI, I think this is something we'll have to understand better of what's definitely radiation pneumonitis, what's drug-related pneumonitis, and how does that impact our care of these patients going forward. But overall, I think the take-home here is that there were no major unexpected safety signals with osmertinib. So at the ASCO plenary, my colleague, Dr. Sequist, discussed this trial, and then, of course, there was a great amount of discussion in the hallways of the McCormick Center after the meeting, and I just wanted to highlight two major questions that were key points for discussion that I thought it would be worth spending a moment on. One were the outcomes in the placebo arm of the study, and were they reflective of what we expect in stage III EGFR-mutated lung cancer, or are they poorer than we might expect, and does this suggest a propensity for EGFR-mutant disease for early metastatic potential? The second is this issue of indefinite, the duration of osmertinib. What is the optimal duration of therapy, and can we say that all patients need indefinite osmertinib? So to address this first question, it's always hard to answer, to compare the placebo arm of a randomized large phase III study to other data sets, which are often retrospective case series or post-hoc analysis of Pacific. I will say that the two-year landmark progression-free survival rate on the LORA placebo arm was slightly lower than what we saw in that data I showed you from Pacific and retrospective case series, but given really the dramatic magnitude of observed benefit in the LORA study, in my opinion, it seems unlikely that even a slight improvement in the placebo arm's performance would have meaningfully changed the overall study outcome here. I will also note that a PET scan was not required at study entry for all patients, and this was highlighted as a limitation. It's possible that some patients may have had more advanced disease, and from a practical perspective, I think what this emphasizes is that complete staging of patients with PET scan, brain MRI, and I would also add here invasive mediastinal staging prior to starting treatment, are truly essential to delivering the best care for our patients, to selecting optimal therapy and really knowing that you have a patient with unresectable stage three disease versus those who may perhaps have a stage four disease. So staging will really be important here. Now, what is the optimal duration of therapy? You know, a big point of the discussion by my colleague, Dr. Sequest, was that this trial design really assumes that stage three disease, unresectable stage three disease, is really not curable, and that an indefinite duration of TKI therapy is required to suppress mycomatostatic disease, and that this is really perhaps a practical and patient-focused approach, because we know that if we, you know, deliver TKI for some period of time and then re-challenge that disease recurrence, not all patients are gonna access subsequent therapy of recurrence. You know, even in this study, we saw that 81% of patients had crossover to osomertinib, which is great, but there are a subset of patients who may not access TKI recurrence, and so the early and continued use of TKI therapy ensures all patients access to the best therapy and may protect some patients from the morbidity of symptomatic disease recurrence. But on the flip side, it also exposes patients to the side effects of osomertinib for a long period of time, to the financial costs of this drug, the practical considerations of having to have monitoring, and we know that there is perhaps a small, but a subset of patients with stage three disease who are cured with chemotherapy and radiation and may not need that indefinite TKI therapy, and so I think a future direction of research that will be really important is the identification of this patient population who may need de-exhalation of treatment, who may need a shorter time on TKI therapy, and this will need to be a focus of future research efforts to identify biomarkers of this population. So to conclude, what are the conclusions from Laura for our practice today? I think we all agree that the results of Laura are clinically meaningful and practice-changing. You know, pending regulatory approvals, consolidation of osomertinib will become the new standard of care after completion of chemotherapy and radiation for patients with unrespectable stage three EGFR-mutated lung cancer, and really, I think a key point is that these results underscore the importance of molecular testing across all stages of disease. We have to identify these patients to be able to select those who may benefit from osomertinib therapy, but equally importantly, to avoid the inappropriate use of immunotherapy for patients who have EGFR-mutant non-small cell lung cancer. As I mentioned, I think future studies will be needed to identify biomarkers that may help us tailor our treatment approach, but for now, I think the approach will have to be to give osomertinib until disease progression, or of course, until tolerability issues arise after chemotherapy and radiation. And this emphasizes the need for careful toxicity management, which will be essential to the success of the strategy. And finally, I think for this global audience, it's really important to say that another key point will be ensuring equitable access and reimbursement to osomertinib after chemotherapy for our patients around the world. When we see data of this magnitude, I think it's really essential that we try to ensure that all patients who need it have access to this therapy. So with that, I will thank you for your attention. I'll thank the abstract authors and all of the patients who participated and to all of you for joining us today. Thanks so much, Dr. Piotrowska. So our final presentation today is going to be delivered by Dr. Alyssa Cooper, Dr. Cooper is a thoracic oncologist based at Memorial Sloan Kettering Cancer Center in New York. And she will be discussing ASCO LVA-5, the Adriatic Study. Thank you, Dr. Cooper. Thank you very much for the opportunity to present the Adriatic Study, Dervalumab as consolidation treatment for patients with limited stage small cell lung cancer. And I just want to take a moment to thank all of the authors on the abstract and investigators on the trial, especially Dr. Spiegel, who was the presenting author at ASCO. So to start with some context for this study, our current standard of care for limited stage small cell lung cancer has been the same for decades. Concurrent chemoradiation with four cycles of platinum-based chemotherapy and radiation, either twice daily radiation over three weeks or daily radiation over six weeks. And as you can see here that the outcomes have been far less than ideal, especially when treating patients with a potentially curable illness, five-year overall survival of approximately 15 to 25%, and median overall survival of 25 to 30 months. Over the past five or so years, there's been a revolutionary innovation with the incorporation of immunotherapy into the treatment of lung cancer, more specifically non-small cell lung cancer, where PD-1 and PD-L1 blockade has markedly improved outcomes for patients with metastatic non-small cell lung cancer. More so, as you can see here, this is the Keynote 189 study with the addition of pembrolizumab to a carboplatin or a pemotrexate backbone, where you can see the benefit was mostly highlighted in the PD-L1 high group, but also was still present in the PD-L1 negative group. There was improvement across the spectrum and this basically completely changed how we think of immunotherapy incorporation into lung cancer. When this same tactic was applied to metastatic or extensive stage small cell lung cancer, I think there were mixed feelings. On the one hand, it had been so long since any study had shown any benefit in improvement in outcomes for small cell lung cancer. So this was immediately practice changing. This was one study, Dervalumab plus platinum-based chemotherapy versus platinum-based chemotherapy alone. But this made a difference here really in the durability of outcome for just a few patients, kind of lifting the tail of the curve for a few and really only extending the median overall survival by just a couple of months for the population as a whole. Still, it was, as I said, sort of the first improvement in such a long time and immediately changed our practice. When considering what gains can be made in the locally advanced space with the addition of novel therapies, it's worth considering the studies that have been performed in non-small cell lung cancer. Laura, as was just expertly reviewed by Dr. Pietruszka, demonstrated not only the power of additional therapy in this space, but unfortunately still the poor outcome of locally advanced lung cancer. And as she just described, there may have been some differences with the placebo arm, but even if it had performed a little bit better, we still would say these outcomes are still not acceptable for our patients. The Pacific trial, which changed the standard of care of locally advanced non-small cell lung cancer and was the precedent for the Adriatic study, demonstrated a marked improvement in the addition of Dervalumab after concurrent chemoradiation compared with placebo, though you'll still note that it was still under 50% overall survival at five years, which I think we can all agree is not enough for our patients. So to dive into the Adriatic study design, this was a phase three randomized double-blind placebo-controlled study of patients with limited stage small cell lung cancer that was inoperable. Patients received concurrent chemoradiation with four cycles of platinum and atopicitis as the standard of care. Patients were allowed to have three cycles for toxicity reasons, and they could have either a radiation plan over six weeks or over three weeks. And interestingly, same study design as Pacific and these patients could not have experienced progression following the conclusion of concurrent chemoradiation. There were 264 patients then randomized to Dervalumab and 266 randomized to placebo, and treatment continued for a maximum of 24 months. But as you'll see, many patients did not receive up to that either due to progression or due to toxicity. And the dual primary endpoints of the study were overall survival and progression-free survival. This was the first interim analysis, and both the overall survival and progression-free survival met the pre-specified efficacy boundaries for declaring statistical significance for Dervalumab versus placebo. So when looking at the baseline characteristics of the population, these were fairly evenly matched arms. And what you'll note is obviously both arms were comprised of patients who had a current or former tobacco history. But as you can note, actually just under 10% of patients were actually never smokers, which might indicate that the population of small cell lung cancer might be changing. I'll draw your attention to the fact that most of these patients had stage three disease, and just about two thirds of patients in each arm received a cisplatin-based chemotherapy regimen versus a carboplatin-based chemotherapy regimen. As I said, only about a third of patients in the Dervalumab arm and just about a quarter of patients in the placebo arm completed the maximum of 24 months of treatment. And the most common reason for discontinuation of the study treatment was disease progression in both arms, though the incidence was a bit less in the Dervalumab arm and followed subsequently by adverse event much lower down the list. And here too, as Dr. Pietruszko said, this received a standing ovation and applause with a lot of applause at ASCO. So please draw your attention to the fact that these overall survival curves demonstrate a statistically significant but also clinically meaningful difference in the arms with 55.9 month overall survival for Dervalumab and 33.4 month overall survival for placebo with a hazard ratio of 0.73. And this benefit held up even when looked at multiple subgroups, so including prior chemotherapy regimen, including the radiation schedule, and including the best response to the concurrent chemoradiation. So this benefit was really seen amongst all arms. The progression-free survival also was statistically significantly different and clinically meaningful with a median progression-free survival of 16.6 months in the Dervalumab arm, 9.2 months in the drivalumab arm, 9.2 months in the placebo arm with a hazard ratio of 0.76. And similarly, everything held up in all subgroups for the PFS analysis as well. In terms of safety, so I've mentioned this a couple of times but I do wanna draw your attention to the fact that the median number of cycles administered was nine in both the drivalumab and placebo arm which is really interesting to note and we'll play into our discussion later. There were similar rates of grade three or four adverse events as well as serious adverse events. And of course, the immune mediated adverse events were higher in the drivalumab arm as would be expected. Radiation pneumonitis was sort of a pneumonitis in general was an adverse event of special interest. And so here it is sort of separated out on how clinicians tended to describe this. So radiation pneumonitis, the incidence of this was similar in both groups. The pneumonitis not being attributed to radiation per se was a bit higher in the drivalumab group with 10.7 versus 6% and still low incidence of grade three or higher events. And here they're pulling out the pneumonitis data to show you that 38% of patients in general had any grade of pneumonitis or radiation pneumonitis in the drivalumab arm versus 30% in the placebo. And there was, as you can see, a higher rate of treatment discontinuation in the drivalumab arm, almost 9% versus 3% in the placebo. The overall conclusions from this study were that the addition of drivalumab as consolidation treatment after concurrent chemoradiation in limited stage small cell was statistically significant but also clinically meaningful agent in terms of achieving benefit in overall survival and progression for survival and should immediately change the standard of care and be translated into practice. But this study also raises a number of questions in how we will actually translate it into practice. So the duration of therapy came up as sort of an ongoing question and has come up as you saw in the Laura study, but also here because why was two years chosen? That study was asked at ASCO and Dr. Spiegel had basically described that the recurrence risk does increase after about two years. So they were hopeful to sort of extend across that timeline so to protect as many patients as possible. I think we'll have yet to see whether there will be an increased risk of recurrence after terminating treatment at two years and will there be a sense of escalation of therapy for some patients or might there be a place for de-escalation of therapy because the benefit that was presented here was really seen after a median of nine cycles. So how much treatment is really necessary? And we think of this in the Pacific regimen too when we see patients in clinic. Sometimes those patients also don't complete the entire 12 months of therapy as was recommended in the Pacific trial. And sometimes we think that they still have achieved as much if not the clinical benefit as completing the entire thing. We also are going to need to navigate the incorporation of novel therapies. So Tarlatumab is Amgen's T-cell DLL3 targeting T-cell engager, which was just approved in the extensive stage space after progression on a platinum-based chemotherapy regimen. And there is a study now looking at how to incorporate Tarlatumab into the limited stage space. But the question is going to be, the ongoing trial is looking at Tarlatumab versus placebo. But now if Dervalumab is becoming the new standard of care in the limited stage space, how could we incorporate something like Tarlatumab? Should there be a trial of Dervalumab versus Tarlatumab? Should there be a trial of Dervalumab plus Tarlatumab? So these studies, I think, and these questions are going to be ongoing as we gather more information. Incorporation of novel monitoring. So something, lessons that we can draw from the non-small cell lung cancer space, specifically in the concurrent chemoradiation for stage three cancer. Max Dean at the Dean Lab in Stanford is looking at a lot of cell-free genetic testing, DNA and RNA to sort of understand what happens to these markers in patients who undergo these treatment modalities. And might there be a way to identify patients who might experience progression before seeing it on radiologic findings? Or are we able to sort of prognosticate or predict how patients might do by incorporating novel monitoring strategies into their surveillance? So this is going on in non-small cell lung cancer, but I'm interested to see whether this might, this might be incorporated into future trials for limited stage small cell lung cancer. And indeed, novel paradigms of therapy as well. As we know, induction chemoimmunotherapy, as in CHECKMATE 816 with chemotherapy and Nivolumab for unresectable, or sorry, for potentially resectable non-small cell lung cancer has completely changed the field. And we really now always sort of think about that for our patients who are potentially resectable with non-small cell lung cancer. Might we think about an induction therapy now for patients who are potentially resectable in the small cell lung cancer space? And these trials are ongoing, looking at patients with limited stage small cell and looking at induction with platinum-based chemotherapy and immunotherapy agents combined. And there are a number of trials ongoing in the limited stage setting that I think will be helpful to sort of help us fully understand how we might be able to fully apply these to our patients moving forward. So where is immunotherapy gonna have its best fit? You know, in the study that was just presented in Adriatic, it was consolidation only. There are some studies looking at the incorporation of immunotherapy as frontline with combined chemoradiation or others looking at frontline and then incorporation of novel modalities or of changing of the radiation schedule as well. So once these studies, in addition, start to read out, I think we'll have a fuller data set to really appreciate how we might best be able to treat our patients. So in conclusion, Adriatic was a groundbreaking trial. It immediately changes the standard of care for limited stage small cell lung cancer. I am immediately putting this into practice in my own clinic. I do think that there are a number of lessons that we've learned from the treatment of non-small cell lung cancer over the past several years that I'm hopeful we can apply to the treatment of small cell lung cancer, knowing that the field of non-small cell lung cancer is unfortunately a bit ahead of where we are with small cell lung cancer and in understanding how best to treat patients. And, you know, it goes without saying, but, you know, we need to continue to improve upon current therapies for cancer in general, small cell lung cancer in particular, especially with all of the strategies that I've outlined in terms of novel paradigms and modalities and monitoring and agents. But I think ultimately, you know, these outcomes are still not quite good enough for our patients when we know that there's still less than ideal survival in these diseases. So ultimately, I think we'll need to develop increased surveillance strategies, detection modalities to help intercept cancer before it spreads. Thanks very much. Thanks so much for that presentation, Dr. Cooper. So I am going to invite everybody to submit questions into the Q&A section of their video screen. If they have questions they would like to share and ask of the discussants. But while we wait for some questions to flow in, I'm gonna get started. And Dr. Greer, you presented your study of the telemed versus in-person palliative care visits. I think one of the most fascinating things and was surprising, I think, to you, as well as to many people hearing was the difference in caregiver presence at the video visit. You know, now with post-COVID, we're used to using video visits a lot. We think of it as a convenient thing where we can easily loop family and caregivers in. And in fact, there was less caregiver participation in the video visits. I can see pluses and minuses of that, right? And I'm just wondering how you're thinking about that. And is that finding changing what you're doing in your practice or how you're thinking about designing future studies? Yeah, it's a great question. Thank you, Dr. Heiss. You know, we, like you, we had hypothesized that caregiver attendance would actually be higher in the video visit group. And given all those convenience factors, so we were a little surprised when we did see the finding that there was such a difference between the two modalities. And I don't think we have a good answer to know really what is sort of the optimal engagement of caregivers and visits. So it was clear that, you know, for in-person visits, assistance with transportation really did increase the likelihood of the caregiver being in the actual visit. But I do think there, like you noted, there's pluses and minuses to that. There are oftentimes, I think, when patients do want to have a visit with the clinician alone. And when there is a caregiver who is there with them, that can be challenging and it can change the nature of the conversation and the clinical encounter. And so in one way, we could say that the video visits, as much as there's a convenience factor, and I would also argue having a conversation in the comfort of your own home where you're not in a, you know, sterile medical environment, and it's really one-to-one between you and the clinician, I wonder if the nature of the conversations, both with palliative care or with their oncologist, are different in allowing for maybe more frank conversations sometimes that patients want to have with their clinicians. And so on one level, I appreciate that there is more autonomy, and I would make the other argument that there's reduced burden for caregivers. What I was a little concerned about this, because we want to make sure that caregivers' experiences also between these two study groups was also equivalent. We did look at their own quality of life. We also looked at their mood symptoms and their coping. And despite that differential in attendance at the palliative care visits, we did not see any differences in the caregiver-reported outcomes. I didn't present those outcomes today, but we did look at those. So that was reassuring. So we were happy to see that the caregivers overall were also experiencing equivalent reported outcomes between those two groups. And so I think it's an open question. I think we have more research to do. And I mentioned at the end of my presentation, some qualitative interviews might get at some of this, and we're gonna incorporate those questions when we talk to patients and caregivers about what that experience was like for them and why and how they decided to participate in video visits versus when they didn't. So thanks. And I know there were structured questionnaires about what was covered during the visit that you looked at in the study. Did the study also allow for listening to the conversations to get a sense of if there was a qualitative difference or not? Unfortunately, that would be a wonderful addition in terms of the study if we'd have an opportunity to do some audio recordings. The scope of the study kind of was prohibitive for that. So we don't have actual audio recordings. So our best bet with this, we'll just be talking and doing some interviews with the clinicians and the patients and the caregivers. Unfortunately, we don't have any audio recordings. And this was a well-resourced study in terms of you were able to provide iPads for people and also some training. What do you think about in less well-resourced settings? How does this translate? Do you think this is something that would translate to phone visits? Or what do you think about that? Yeah, that's also a great question. So phone visits also were permitted for any scenario in either arm, like if for whatever reason, if they couldn't have a visit within that four-week timeframe. So per protocol, we were asking the clinician and the patient and the caregiver to meet on a monthly basis. And if that couldn't happen for any reason, maybe the patient was hospitalized or any other factors, they could do phone calls. And looking at the phone call summaries as well. So the clinicians similarly would finish their post-visit surveys, even for phone calls. It was optional, but the vast majority of phone calls, they did complete them. And interestingly, we didn't see any differences in those topics either. So I do think there is an easy translation across these different modalities. Anecdotally, talking to the clinicians, I will also say they did appreciate being able to see the patient's home. There's just additional data that you get when you're actually able to see what a person's experience is in their own home. And so that would be one limitation that telephone doesn't provide. Similarly, obviously in-person business doesn't provide that either. So I would make the argument that in terms of like how a clinician thinks about what to use and when, for the most part, these modalities really do allow for these types of conversations to happen with no significant differences. But I will acknowledge that the data you get, the information, the sense of who the person is, and also the comfort for the patients is different when they are in their own homes. Yeah, well, thank you. That's just an amazing study. And I think something that really is gonna impact how we practice and approach things in clinic and on video and phone. So thanks so much. I'm gonna do, I don't believe, oh, let me just check. So I do want to address a question that came in through the chat. So one question that's asked is for small cell lung cancer. So Dr. Cooper, do you think devaluumab consolidation would be as effective after sequential chemo radiation? So if you're in a situation where you're giving the chemo and radiation sequentially for whatever reason, do you think that would be as effective? And also as a corollary to that question, what about during the radiation? Yeah, those are such good questions because this is the real world and we often find ourselves in many situations not akin to a trial. With regards to sequential chemo radiation, I mean, I think you'd have to think about the patient who within whom that strategy is being applied and why. So if that is because of fitness of the patient, clearly they wouldn't have been enrolled in this trial, but this is the real world and oftentimes people can't tolerate the full concurrent chemo radiation. I would think that they would still achieve a benefit. I just, I'm not sure if we can compare apples to oranges in that way because I think we are not totally sure if concurrent, how much better of a benefit does concurrent get you versus sequential. And so I think, I do think that devaluumab would add something, but I'm just not sure if they would achieve the full survival metrics achieved in this study. And then with regards to during consolidation, or sorry, during concurrent chemo radiation, well, that's the really interesting question that was just attempted to be answered in Pacific II that was presented in non-small cell lung cancer in which there was not a benefit with devaluumab added up front in the frontline setting, which was really interesting and I think brought up a lot of questions about the trial design and the recruitment to try to understand why that might be. But I think as far as we know, we do have some data in the non-small cell lung cancer setting where that was not recapitulated. So I think we're just gonna have to wait and see and see how it's, you know, how is that played out in the small cell lung cancer setting where we already know that this is a tumor type that is not as immunotherapy responsive as non-small cell lung cancer. So I think, you know, if the benefit wasn't seen in the non-small cell lung cancer setting, I'm skeptical it will be seen in the small cell lung cancer setting, but I think we'll just have to wait and see for those studies to read out. Thank you. And for Dr. Pietruszko, another question from the audience, do you think stage 3b and c non-small cell lung cancer with agent for mutations in treatment of that disease, do you think we still need chemo and radiation or are we heading to OC only? I think a very astute and great question, you know, and again, I think one that was discussed a lot at ASCO after the presentation, you know, I would say that the design of the trial, again, suggests that there may be micrometastatic disease that is present at the outset, but I would say that still, you know, if we look at the median progression pre-survival achieved in this study with osomertinib, it was 39.1 months, significantly longer than what we see with first line osomertinib in stage 4 disease. I think that one reflects the fact that these patients, even if they have metastatic disease, it's a more limited disease burden, but I think it also tells us that probably chemotherapy and radiation are still providing additional benefit. You know, I think that in the future, what I hope we will achieve is a world where not all stage 3b and 3c diseases may be approached in the same way and that we will be able to develop better biomarkers to understand, you know, which are the patients where the chemotherapy and radiation is really leading to long-term disease control or dare I even say cure, and which are the patients where, whether by MRD assessment or other kind of more in-depth biomarkers beyond our current staging, we can identify those patients who are high risk or perhaps we can, you know, spare them from the inconvenience and the risks of chemotherapy and radiation. But for today, I think we are still, you know, for an unrespectable stage 3 patient, I think that, you know, still chemotherapy and radiation followed by osomertinib would be my standard of care. I wouldn't yet exclude that though. I imagine that there may be some trials addressing that in the future. Thank you. So I do want to be mindful of time. And so one last question that I'm going to ask you to address quickly. For those who progressed after chemo radiation and OSEQ for unrespectable stage 3 lung cancer, what would be the treatment option? Yeah, so very briefly, I mean, I think we're going to have to consider those patients as having really more acquired resistant to TKI therapy if they're progressing on the TKI. So I think looking for resistance mechanisms, the same way that we would do for a patient progressing on osomertinib in the advanced disease setting will be important. And I hope we'll see more data for that from Laura. But outside of any targetable resistance mechanisms, I think this will be a scenario where, for example, FLORA2 with the addition of chemotherapy to osomertinib would have a lot of appeal because, you know, you want to do something other than just treat them with a TKI if they're having recurrence on that drug. So thank you everyone so much for presenting today and to all the attendees for your engagement and your questions. Discover more educational activities being offered by IASLC. Please visit their website at IASLC.org. Thank you for joining us today.

ISLC webinar

oncology advancements

palliative care

telehealth

lung cancer

osimertinib

consolidation therapy

EGFR-mutated non-small cell lung cancer

dervalumab

limited-stage small cell lung cancer