I'm sorry for our technical difficulties. Today's webinar is concerning meeting highlights from the treatment of lung cancer from ASCO 2022. My name is Dr. Antoinette Wozniak and I'm joining you from UPMC Hillman Cancer Center in Pittsburgh. This webinar is presented live, so you'll be able to find a video recording of the webinar within the next week. Your camera and microphone will remain off for this webinar. Please enter any questions you have for the discussion into the Q&A section at the bottom of the Zoom webinar. We won't be using the raise hand function or the chat for questions. We will have a panel discussion in Q&A after the presentations, but you can enter questions into the Q&A section at any time during the talks. I am joined today actually by two speakers, Dr. Suresh Gadgil and Dr. Karen Reckamp. And I will introduce them individually as prior to their presentations. So I would like to introduce our first speaker, Dr. Suresh Gadgil. He is Chief of the Division of Hematology and Oncology at the Henry Ford Cancer Center in Detroit. And he'll be giving us a review of some of the abstracts that are in relationship to targeted therapy. Thank you, Dr. Wozniak. Let me just pull up my slides. It's truly a privilege to do this, and I would like to thank you as well as ISLC for giving this opportunity. Again, sorry for the technical issues. These are my disclosures. And what I've been asked to do is present the major abstracts with regards to lung cancers with targetable alterations. And the six aspects I'm hoping to finish, rather hoping to review, and I hope to finish in a timely fashion, are three of them deal with KRAS mutation positive lung cancer. One is in patients with recurrent EGFR mutation one in exon 14 skipping met mutation, and then finally an abstract on CLN 081 in EGFR exon 20 mutation. So I'll start off with the KRAS mutation abstracts. As is well-recognized, KRAS is the most common driver genetic alteration in non-sponsored lung cancer with about 30% of adenocarcinomas having this alteration. And also important to note that about 30% of squamous cells also have it. However, KRAS is a much more, KRAS mutant lung cancer is a much more heterogeneous group of tumors. As you know, there are several subtypes with KRAS G12C being the most common subtype. And the biology as well as therapeutic responses in these tumors are influenced by presence of co-mutations in variety of genes, P53, STK11, and KIP1, with greater recognition that chemoimmunotherapy may not be as effective in tumors with co-mutations as STK11. So the first abstract I'm going to present or discuss is by Dr. Nakajima and colleagues from the US FDA. And what they did was they evaluated the trials that had been submitted to the FDA with regards to efficacy of IO with or without chemotherapy in KRAS mutation-positive lung cancers. And the brief background to this abstract is that there is data with pembrolizumab studies that there may be a differential efficacy with single-agent pembrolizumab in KRAS mutation-positive lung cancers as presented by Dr. Herbst and colleagues from data from Keynote 42. And then from Keynote 189, there was data showing that the efficacy is similar whether it is KRAS mutant or KRAS wild type. So there may be some difference in efficacy based on whether it's a single-agent checkpoint inhibitor or when combined with chemotherapy. Now, this is retrospective data and therefore needs to be viewed with a level of caution. And so what the FDA did was, Dr. Nakajima and colleagues did, is they looked at 12 trials, and these were trials that evaluated both immunotherapy alone or immunotherapy plus chemotherapy as compared to chemotherapy alone, and evaluated the efficacy in KRAS mutation-positive lung cancers, also analyzed the data based on PD-L1 expression. Now, one of the major limitations of this analysis is that there were a total of over 8,000, almost 9,000 patients in these 12 trials, but only on 16% of these patients that was the KRAS status available. And among these patients, 555 were KRAS mutant. So if you compare it to the overall population, based on an expectation of approximately 20 to 25% of tumors being KRAS mutation-positive, one would have expected over 2,000 patients to have KRAS mutation. So clearly a limitation is that only this analysis is based only on a very small subgroup of the total KRAS mutation patients in this population. And then the proportion of KRAS G12C, or the number of KRAS G12C patients also is much lower. So one needs to remember that limitation when viewing this data. And what the data showed is that if you just looked at KRAS mutation patients, then there did not appear to be a difference in efficacy, either with ICI plus chemotherapy or immune checkpoint inhibitors alone, or chemo alone between KRAS mutant-positive lung cancers and KRAS wild type. They also analyzed this according to PD-L1 status and found that there was a trend to slightly better efficacy with chemo and immunotherapy combination as compared to immunotherapy or chemotherapy alone in the KRAS wild type tumors, as well as in KRAS mutant tumors. And the authors acknowledge the limitation of this analysis that there were only 16% of the patients who in whom the KRAS status was known. And also the fact that there were some trials that allowed EGFR and ALK patients. And most importantly, we don't know the commutation status. And these are all important limitations in terms of this analysis. However, despite these limitations, they went on to conclude that the optimal control arm of studies of first-line therapy may be immune checkpoint inhibitor and chemo for KRAS trials. And this is relevant, particularly in the context of the fact that there are studies that are going to explore direct KRAS G12C inhibitors. And I'm not sure that this analysis per se leads to this conclusion. This conclusion may be true, but I don't know if that conclusion should be based on this analysis because of the limitations that I mentioned. And I think my take home is that at the present time when making decisions regarding immunochemotherapy or immunotherapy alone, one should not take into account the KRAS mutation status by itself, but base it on the PD-L1 status as we do in routine practice. Now, clearly the major advance in KRAS mutation positive lung cancers are the direct G12C inhibitors. Sotoracib is already approved in the US for recurrent KRAS G12C non-small cell lung cancer patients. And the other drug that is being evaluated is Adagracib. Phase one data was already presented. This is the phase two portion of the CRYSTL1 trial presented by Dr. Alex Pera. Need to disclose that I was a co-author on this presentation. Preclinical data suggested that Adagracib may have certain advantages in that it had a long half-life. And in preclinical setting, it appeared to penetrate the blood-brain barrier and have activity against brain metastases. And so this was the basis to evaluate this in the phase two setting, a total of about 116 patients, heavily pretreated with over 20% of the patients who had received three or more lines of therapy, and almost all patients had received both chemotherapy and immune checkpoint inhibitors. And the drug did demonstrate activity with the objective response rate of 43% and a median duration of response of 8.5 months. The median PFS was 6.5 months and the median OS was 12.6 months. And as the duration of therapy is presented in this figure, there were some patients who continued for way more than 12 months on the drug. As mentioned, co-mutations influence both the biology and therapeutic response. And what was seen is with most co-mutations, there did not appear to be a difference in efficacy when you looked at STK11, P53, or CDKN2A. However, with limited numbers, and one needs to be mindful of that, in patients with KIP1 mutation, there does appear to be somewhat of a lesser efficacy, particularly when the STK11 status is wild-type with this agent and similar data has been reported with sotoracin. The relevance of this is that in STK11 patients, possibly chemoimmunotherapy or immunotherapy may not be as efficacious. And is it possible that these drugs provide better benefit? That remains to be seen. But at least the initial data suggests that co-mutations may not influence the activity of these agents except for KIP1. Now, Dr. Pada, who discussed this abstract at ASCO, presented this slide comparing the efficacy parameters of adagrassiv and sotoracin. It's quite remarkable how similar the efficacy is in terms of the overall response rate, slightly lower duration of response with adagrassiv, but fairly comparable when you look at the 95% confidence interval, similar PFS and OS. Now, there was a thought based on preclinical data that adagrassiv may provide better efficacy, but one of the limitations of this drug is its toxicity, particularly its GI toxicity, the diarrhea, nausea, and vomiting. And this, even though it was not grade three, primarily only grade two, it did translate into 50% of the patients requiring dose reduction. And it is possible that this may have limited the efficacy of this drug. And again, Dr. Pada compared the toxicities between the two agents, and clearly the GI toxicity rate appears to be somewhat greater with adagrassiv as compared to sotoracin. Mind you, the dose discontinuation because of AEs was fairly similar, but 50% of the patients did require dose reduction with adagrassiv. Now, one of the factors in the preclinical studies as I mentioned was efficacy in the CNS. And in this study, they do look at efficacy in the CNS. Now, mind you, all these patients had treated and stable CNS metastases. And what this suggested is that the efficacy in the brain was similar to what was observed extracranially. But because of the data of this drug in the preclinical setting, again, in CNS metastases, there was a specific CNS cohort that was evaluated in the CRYSTAL1 trial. And results of this cohort were presented by Dr. Savari in a separate clinical symposium. And what they showed is that the drug did have efficacy, again, a response rate of 32%, fairly similar to what was observed extracranially, and a disease control rate of 84%. The data, when you compare among these patients, both intracranially and extracranially, there was fair bit of consistency. That is, patients, if they had a response extracranially, also appeared to have a response intracranially, and the overall disease control rate exceeded 80%. So it's gratifying to note that these drugs can have activity, or adagracib can have activity, again, CNS metastases. However, important to note that the efficacy overall is clearly not as comparable to what is seen with drugs like osimertinib and EGFR, mutation-positive lung cancers, or loratinib and ALK-positive lung cancers. And so, though it is encouraging to see CNS activity, in certain situations, such as patients with posterior fossa brain meds or large brain meds, I may still lean on using local treatments and not necessarily feel comfortable just starting them on a drug like adagracib. Data with sodoracib is also being generated against CNS metastases. Moving on to EGFR, mutation-positive lung cancers, clearly one of the major needs in this field is treatment of patients with recurrent disease following osimertinib in many patients after platinum-based chemotherapy. Dr. Hsu and colleagues presented data on amivantamab and lasertinib as part of a cohort as part of the CRISILIS-2 study. Amivantamab is a bispecific antibody that targets both EGFR and MET, but not only do this drug inhibit these receptors, but through an FC portion component, it appears to activate the immune system as well. And therefore there may be a dual mode of anti-tumor activity. Lasertinib is another third-generation EGFR TKI similar to osimertinib. And this combination was actually evaluated and the data were presented by Dr. Joss Bommel at last year's ASCO in patients who had only been treated with a third-generation TKI such as osimertinib. And in that group of patients, the overall response rate was 36%. But what was encouraging is that there were some patients who were on treatment for more than 12 months reaching almost one and a half years. And so it was that sustained benefit in a proportion of patients that was encouraging. What Dr. Hsu and colleagues presented was data in patients who had not only received third-generation TKIs, but had also received platinum-based chemotherapy. And again, this combination showed a promising response rate of approximately 33% with a median PFS of 5.1 months and a DOR of 9.6 months. I must point out, again, very small numbers, so one needs to be mindful. But in the group of patients where we may consider this, patients who had received osimertinib and platinum-based chemotherapy, the response rate was slightly lower at 21%. Again, this could be just a small number issue. And again, the primary sort of what I was impressed by is this sustained benefit in a group of patients extending now almost to one and a half months. So one and a half years, I apologize. And so this clearly, it's not just the response rate, but that sustained benefit that is very encouraging. And they also presented data against CNS metastases. There were 30 untreated patients, and they saw responses of 26% and a disease control rate of 74%. It is quite possible that the lasertinib addition may have led to this activity because one expects that amivantamab, that has shown activity as a single agent in this setting, may not be as efficacious in CNS metastases. So not only do we have a sustained benefit in a group of patients, but also CNS activity. Now, one of the limitations is you do see more toxicity, especially when you compare it to third-generation TKIs. Not only do you see the EGFR toxicity, such as rash and diarrhea, but you also see the MET-related toxicities of edema and hypoalbenemia. And I think it is in this context that a biomarker for this combination would be very relevant. At last year's ASCO, in the study in patients after osimert or third-generation TKIs, they presented data of evaluating EGFR and MET expression by IHC, and found that tumors that had co-expression of these molecules had a very high response rate of 90%. Similar data was not presented by Dr. Hsu and colleagues at this year's ASCO, but it's possible that if a biomarker is evaluated, that maybe this combination is used in those patients. So where are we with this combination? Very promising data, and I can tell you, at least in the US, some folks, I have not, have utilized amivantamide and osimert in patients with recurrent EGFR mutation, positive lung cancer. In my opinion, I feel that there is a little more promising data with antibody drug conjugates, such as Petritumab, Terextracan, there are newer EGFR TKIs, and there are cell therapies that have also shown promising benefit. And I feel that this combination needs to be viewed in context of all these other agents. And I feel that this particular combination may benefit from identification of biomarkers that may identify patients most likely to benefit from this combination. And the second issue is based on this data, this drug now, this combination has been evaluated in the frontline setting in the Mariposa study. And actually, this study has completed enrollment. So we'll see if the combination of amivantamide and lasertin, it provides greater benefit than just a single agent, third generation TKI. Amivantamide, as mentioned, targets MET, and Dr. Krebs and colleagues presented in the Crisalis study, there was a cohort of patients with MET exon 14 skipping mutation. And they looked at different patient populations, treatment naive patients, patients who had not received a MET inhibitor, they also evaluated patients who had received a MET inhibitor. The total numbers in each of these cohorts are pretty small, but promising response rates of 17% in patients who had received a prior MET inhibitor and treatment naive patients are 57%. How does this compare with the two agents that are approved in the United States for MET exon 14 skipping mutation? The overall median progression-free survival is fairly comparable. Now the numbers are much smaller with amivantamab, one needs to be mindful of that, but they seem very similar and one of the added benefit was activity was also seen in patients who had a prior MET inhibitor. So based on this data, clearly it's something that should be considered, that could be considered particularly in patients who had recurred after a MET TKI. One wonders whether there may be activity also in MET amplified non-small cell lung cancer. Whether this agent would be used as frontline therapy, the issue is you're comparing a pill versus IV medication and that may pose some limitations. And the question is, could there be an advantage to amivantamab plus a MET TKI like we are doing in EGFR patients, but clearly the concerns there are going to be the tolerability because the edema with these agents is fairly significant and that may be a limitation in considering this combination. I wanted to finish up by talking about CLN081 in EGFR exon 20 mutations presented by Dr. Helena Yu and colleagues. Well recognized that 2-3% of all lung cancers and about 10% of all EGFR mutation positive lung cancers are exon 20 and as we have gone to NGS testing, we are detecting these patients more and more. A potential advantage of CLN081 even compared to osimertinib, there appeared to be a differential in terms of targeting the mutations, both the classical mutations as well as the exon 20 mutations as compared to wild type. Because the major limitation in EGFR TKIs is the toxicity from inhibiting wild type EGFR. This drug did demonstrate activity with a response rate of 41% in the 100BID cohort, which is the cohort, which is the dose that is expected to be recommended as the phase two dose. And interestingly, it also demonstrated CNS activity, limited data, but quite encouraging that CNS activity was observed. But there is toxicity, possibly the toxicity of rash and diarrhea is less than what is experienced with mobisertinib, but nonetheless, this toxicity is observed and it remains to be seen with larger numbers, whether the slightly lower rate of toxicity with CLN081, particularly compared to mobisertinib, it holds up. This is slide presented by Dr. Tan in the discussion, demonstrating that the efficacy is fairly similar with amivantamab and mobisertinib. The two other agents approved for exon 20 mutations, but possibly the toxicity is less and it may potentially have CNS activity. So sorry for being a little rushed, but thank you very much. Thank you, Dr. Gadgil for that comprehensive discussion. As a reminder to the audience, please feel free to type any questions to Dr. Gadgil or Dr. Ekhemp in the Q&A section at the bottom of your Zoom screen. I'd now like to introduce Dr. Ekhemp to give our talk about immunotherapy. She's a professor of medicine. She's director of the division of medical oncology and associate director for clinical research at the Cedars-Sinai Cancer Center in Los Angeles, and she's joining us very early in the morning to give this talk. Okay. Thank you, Karen. Good morning. Thank you. And I will be covering the ASCO 2022 highlights in immunotherapy. Our abstracts will cover things from neoadjuvant therapy from the NATAM-2 trial to brain metastases and a pooled analysis of PD-L1 greater than 50% at the frontline setting. And then moving on to patients who have received prior immunotherapy with the ramiciribab, pembrolizumab, and cabizantinib and atezolizumab studies. And then finally moving into small cell lung cancer with a So we'll start with the NATAM-2 trial presented by Dr. Provencio. And again, this was a trial looking at neoadjuvant therapy, very similar design to the Checkmate 816 trial. It was locally advanced and respectable patients, specifically stage 3A and 3B. So this did not include early stage 3A and 3B patients. And so we'll start with the NATAM-2 trial presented by Dr. Provencio. It excluded patients with ALK and EGFR alterations. They received nivolumab with carboplatin and paclitaxel and the control arm chemotherapy alone. Following surgery, though, the arm that had received nivolumab went on to receive adjuvant nivolumab, and this was for six months. And you can start to see that some of these studies are slightly different in the way that they're designed. Here we get with the primary endpoint of pathologic complete response. You see there's a significant improvement in pathologic complete response when we add nivolumab to chemotherapy, nearly 40% versus about 7%. And also looking at the major pathologic response is 52% versus about 13%. So overall significant improvement in those responses as this primary surrogate endpoint. Looking at PD-L1 expression, what they did see on the right-hand side were significant increases as PD-L1 expression went up. 15% pathologic complete response in the less than 1% versus 40% and then 60% in the greater than 50%. And just putting this into context in the checkmate 816, this is on the bottom right side. We see the event-free survival by PD-L1 specifically, and what we see here is for the less than 1%, a little bit closer to the one mark, and then with greater than 1% and 1 to 49, a little more significant event-free survival benefit and most significantly seen in the greater than 50%. Remember this was for stage 1b through 3, so hard to directly compare. But overall, the NATM2 study, this supports this improvement in the surrogate outcome of a pathologic complete response with immunotherapy and chemotherapy treatment as new adjuvant therapy. And again, and this is for resectable stage 3 disease specifically in this study. The pathologic and major pathologic responses were improved without surgical delays or significant toxicities that weren't expected, and we hope to see this survival and event-free survival data. We know that there are many, many trials in the neoadjuvant space and adjuvant space that are going to report out soon, and again, many of these have slightly differing schemas, and some include neoadjuvant and adjuvant immunotherapy for these patients. Then moving on to the frontline setting, again here is a pooled analysis from the FDA looking at patients with PD-L1 scores greater than 50% and looking at outcomes in patients who received chemoimmunotherapy versus immunotherapy, and this was presented by Dr. Agambaro. These are the trials that they included, and it really is comprehensive of the trials that have led to FDA approval for combination chemotherapy and immunotherapy or immunotherapy alone. They did include the nivolumab, ipilimumab checkmate 227 in the I.O. only trials, and they did include Empower 150, including bebacizumab with chemo I.O. in the combination trials. This included more than 9,000 patients over these 12 studies, and again, their analysis is including chemo I.O. and I.O. alone. Here we see the primary outcomes, overall survival numerically improved in the chemo I.O. group, though not significantly different, 25 versus about 21 months. Progression-free survival slightly higher in chemo I.O. with a hazard ratio of 0.69, 9.6 versus 7.1 months, and overall response rate, again, numerically higher in the chemo I.O. arm, which may not be surprising, 61 versus 43 percent, but not, and with odds ratio 1.2. Then looking at some subset analyses, overall survival is on the left-hand side, and we see maybe a slight benefit for I.O. only in our patients who are greater than 75 in overall survival, and then interestingly in our never smokers, a slight benefit toward chemo I.O., and for most of the subgroups, we're seeing a slight benefit for chemo I.O. For progression-free survival, again, slight benefit toward I.O. only for the greater than or equal to 75, and never smokers slightly over to chemo I.O., and all of the rest for progression-free survival slightly better with chemo I.O. So again, this is a retrospective exploratory analysis, really hypothesis-generating and does not fully take into account the heterogeneity across the trials, and there are multiple differences in the PD-L1 assays, as we know. There are differences between the clinical trial populations, and we noticed in this study there were only 1 percent of patients who were Black enrolled on these studies, which is pretty impressive given the large number of patients that were enrolled and really shows that we have work to do. The Hispanic and Latinx population was not necessarily reported in all the trials, and we do see some discordance between progression-free and overall survival, but that is often seen when we use I.O. alone, so I think the overall survival is really where we want to look, and we know that performance status, age, smoking status may have some effect on the treatment and the tolerability of treatment, and so some of these outcomes in the subset analysis are not significantly surprising, but some information that can help us move forward. Then looking at another question of chemotherapy plus immunotherapy in patients who have untreated brain metastases, and again, there have been data utilizing immunotherapy with responses in the brain, maybe around 20 to 30 percent, and this was now looking at patients who had untreated brain metastases, asymptomatic, no neurologic symptoms, low-dose dexamethasone only, did not include patients who had leptomangial carcinomatosis, and did not include patients who had EGFR or ALK, but could be any PD-L1 status, and they received carboplatin, pemetrexid, and atizolizumab, and followed by pemetrexid and atizolizumab maintenance. They enrolled 40 patients, and looking at the patients, some of the notable pieces of information, the median, the total number of brain lesions per patient, the median was five, but it was one to 20. The majority of patients, over 50 percent, were on baseline corticosteroids, and PD-L1 expression was negative in about 45 percent of these patients, so not potentially the patients we might think as being highest to have responses in the brain. Then looking at the outcomes, the overall response rate here, systemically, was about 45 percent, and intracranially, 42.5 percent, so similar response rate in the brain and systemically. This is just looking at the concordance of response rate by the waterfall plot, and we see here that the majority had some concordance, but obviously there were some differences and some additional progressions in patients who had systemic responses. The survival analysis and progression-free survival analysis is shown here. Systemic progression-free survival, about nine months. Intracranial, about seven months, so slightly lower. Overall survival, shown on the far right, about 12 months, which is lower than we would expect with a chemo-IO combination. Then I guess what we're really trying to look at is, do these patients ultimately need brain radiation? Here we see the event, any brain radiation, or patients who died before receiving brain radiation, and that is the majority of patients, so over 90 percent of patients did go on to need brain radiation. The median time to brain radiation was about 11 months. The majority of patients in this group received whole brain radiation when they did receive radiation, so I think it's hard to say whether we're improving or delaying here. Potentially we're delaying the radiation, but if more patients move on to whole brain radiation, we may not be improving their outcomes, so I think this gives us some information that we can see responses in the brain, but whether we can really hold off on radiation in patients is still left to be seen. Whole brain radiation is something that we may be able to hold off on, but understanding that in the future they may need whole brain radiation when they recur. So this was a trial, the lung non-match sub-study, S1800A, that I presented at ASCO this year. This was a randomized phase 2 trial evaluating pembrolizumab and ramicerumab versus standard of care, which included docetaxel ramicerumab, docetaxel, gemcitamine, pemetrexid. Our primary endpoint was overall survival, and patients had previously received PD-1 or PD-L1 inhibitor therapy and had to have progression at least 84 days after the initiation of immune checkpoint inhibitor therapy. They also had to have had platinum-based doublet therapy, so this was an acquired resistance setting and ECOG 0 to 1. We stratified by PD-L1 expression, histology, and the intent to receive ramicerumab in the standard of care arm. Here we see the patient characteristics at baseline. Some slight differences in patients who had ECOG performance status 1 were higher in the standard of care arm. PD-L1 less than 1 was higher in the ramicerumab pembrolizumab arm, and the TMB median range was slightly higher in the ramicerumab pembrolizumab arm. Here we see overall survival, which was improved with a hazard ratio of 0.69 with a standard log rank p-value of 0.05, which meant its statistical significance at that point, and this was improved from the beginning of therapy. The median for ramicerumab and pembrolizumab was 14.5 months versus standard of care at 11.6 months. I think importantly, the majority of patients, two-thirds of patients, received dosetaxel and ramicerumab as the most efficacious treatment in this setting at this point in time for patients, so this is against the best therapies we have. In looking at overall survival subgroup analyses, PD-L1 status hazard ratios were similar across the board, not significantly different across PD-L1. Squamous or mixed potentially had more significant benefit with ramicerumab and pembrolizumab. There was no significant difference in performance status 0 or 1, and potentially, the numbers are small. There was a higher benefit for ramicerumab and pembrolizumab in our SDK11 population, though, again, very, very small population there, and more patients had benefit who had received chemo followed by IO, which may be a parameter that indicates time on prior immunotherapy. Looking at progression-free survival, there was no significant difference in progression-free survival, though numerically longer at 12 and 18 months, and there were no significant outliers for progression-free survival in the subsets, though there was a slight benefit toward ramicerumab and pembrolizumab in all groups. Moving on to cabizantinib and etizolizumab in patients, again, as a VEGF receptor TKI now, and so this was presented by Dr. Neal, and these were patients who had received prior immunotherapy again and had received two or more lines of prior therapy, or two or less lines of prior therapy, but many of these were third-line patients, and they received cabizantinib and etizolizumab, and this is an evaluation of the extended enrollment. Again, the patients that were randomized to cabizantinib and etizolizumab, but we are only looking at the cabizantinib arm, but we are not looking at a comparator. There are just multiple arms where patients could be randomized, and patients with other alterations were not allowed. Looking at the prior lines, the majority of patients were third-line plus, 52%, and so, again, this is a highly unmet need in patients who have received prior chemo, I.O., and subsequent therapies. The majority had received prior platinum-based therapy, and looking at this, the response rate, about 20% overall in the main group, progression-free survival, 4.5 months, and overall survival, about 13 or almost 14 months in the overall group. So some benefit for this highly retreated population. There are a number of trials evaluating cabizantinib with other immune checkpoint inhibitors. The cabizantinib atezolizumab versus docetaxel contact O1 study has accrued and we await the outcomes of that study and the phase two ECOG alliance or 5191 study cabizantinib versus cabo-nevo versus standard of care. And this has some selected patients with MET and RET and ROS1 cohorts. So overall ramicerumab and pembrolizumab in patients with advanced previously treated with immunotherapy, non-small cell lung cancer improved overall survival compared to the standard of care which most included docetaxel and ramicerumab. The further evaluation of the approach is warranted and we hope to move on with a phase three trial. Multiple trials are evaluating immunotherapy and VEGF receptor TKIs. They're ongoing and results are anticipated shortly for many of these. Combination of VEGF and receptor or VEGF inhibition and immune checkpoint inhibitor therapy are really some of the earliest trials showing signs of benefit in patients who have received prior immunotherapy both in the acquired and primary resistance settings. Then finally, we'll move on to small cell lung cancer. And the skyscraper two study was a highly anticipated study evaluating the standard atizolizumab, carbapen and atoposide with or without turigolumab, the TIGIT inhibitor in patients with untreated extensive stage small cell lung cancer. And again, in this study, this was first line therapy for extensive stage small cell lung cancer. They had no prior treatment for the extensive stage disease and patients with treated or untreated asymptomatic brain metastases were eligible. Somewhat different than some of the other studies previously done with immunotherapy. And again, simple design utilizing the standard carbapen atoposide plus atizolizumab either with turigolumab versus placebo. And primary endpoint was the progression-free survival and overall survival. So here we have the primary analysis sets, the progression-free survival seen on the left-hand side and we see really no significant differences. The median is 5.4 versus 5.6 months, but really quite similar. And here on the right-hand side, we see overall survival. And again, very similar outcomes in both arms, really cannot tease those out at 13.6 months and hazard ratio of 1.04. In the full analysis set, again, we see a similar pattern of similar progression-free survival in the five-month range and overall survival on the right-hand side is about 13 months and similar in both arms. So again, these studies are different and it had different inclusions. And I think the Skyscraper-2 allowing patients with untreated brain metastases was significantly different than many of the other trials. But here we see the outcomes and really the outcomes are really quite similar across the board. And we don't really see a benefit to adding the Teregolumab and have further to go with our patients to understand how we can improve outcomes in this patient population. So future studies really must focus on selection as we start to understand the small cell lung cancer biology and subtypes better. The small cell lung cancer inflamed subtype may benefit the most from immunotherapy regimens, whereas other subtypes may require alternate approaches and alternate combinations. But really moving toward biomarker selection in small cell lung cancer will be essential to move the needle forward. We're always limited in this setting because tissue acquisition, as we all know, for small cell is a huge challenge to have sufficient tissue. And so I think we still have a ways to go to get to this ideal selection, but many trials are moving in that direction. So again, one of the barriers to clinical trial participation that we're all working on is trying to understand how to get more diverse patients on these trials, as we've seen, especially from the FDA-approved analysis that we are not getting a representative cohort of patients on these trials. One of the studies published in the past few years looked at if a patient was offered participation in a trial, whether they would agree to participate. And the majority of the patients agreed, but there was a differential in who was asked to participate. So in asking people to participate, we are getting more patients onto trial and potentially more patients of diverse and more representation of our true populations. So continuing to work on that. And I thank you and happy to move on to the question and answer and answer any questions. Okay, thank you, Dr. Ecktemp. That was an excellent discussion. As a reminder, please type your questions into the Q&A box at the bottom of your screen, because we won't be checking the raise hand function or the chat box during this discussion. We have about 10 minutes, so let's go to the Q&A and see what we have. I think this is for Dr. Gagel. What will KRAS inhibitors need to overcome in order to move it to the first line? So clearly that is of interest with the data that has been generated in the second line setting. What I can say is that these drugs are being evaluated in the first line setting, both as single agents and in combination with cytotoxic chemotherapy. There are also efforts in combination with checkpoint inhibitors. I must mention that the initial data, there are some concerns, particularly with sotoracib and immune checkpoint inhibitors that there could be toxicities. I think once we have a sense of what these drugs, both as single agents and in combination, what clinical benefit they provide in the first line setting, can we really plan the sort of phase three studies and what should be the threshold that these drugs, either single agent or combination, need to meet or exceed for them to move into the first line. This is my sort of impression based on the available data that these agents are likely to have better benefit in combination. It is possible that in some specific subsets of KRAS G12C, these drugs may be beneficial as first-line therapy. As single agents also, not just based on co-mutations, but possibly based on performance status as well. But I think as such, these drugs would be evaluated in combination. And I think as far as meeting the threshold, I believe that we would need to compare it with checkpoint inhibitors, either single agent or combination with chemotherapy or combination IO therapy based on PD-L1 status. So I believe at the end of the day, the drugs either as single agents or combination have to exceed the benefit that is observed with checkpoint inhibitors today in this patient population. Next question, Dr. Rickham. For the NATEM trial, how did they define resectability? And was there any indication that chemo IO converted borderline resectable to resectable tumors? So I actually don't have those specifics. I think it had to do with the surgeon identifying the patient as resectable. And I don't have the specifics of surgical outcomes as we saw with the Checkmate 816 trial. I think those will be future subsets that we will be evaluating. We really saw just the primary outcome of pathologic complete response. But again, according to the Checkmate 816, it is interesting to see that there were patients who had lesser surgeries and potentially more patients who could get lobectomies. In this stage three setting, if we could show that and that data comes out, that would be, I think, highly significant for our patients. Another question, in light of the FDA analysis, would you recommend frontline mono IO for PD-L1 high? So, yeah, I mean, I think that for the PD-L1 high, 50% or more is relatively easy to recommend IO alone for the greater than 75 group of patients. We do know for many of these studies that the higher the PD-L1 goes, we still have benefit, that chemotherapy does add benefit. And so I look at the patients who may have more rapid tumor growth, more symptomatic disease, and do move toward chemo IO. I think that this is a subset retrospective analysis. So to say that all patients should get chemo IO upfront, I think I'm not ready to go to that place yet. There are still patients who have long-term benefit from IO alone, rather small, but still some patients. And so some patients can forego chemotherapy. So I don't think I'm ready to move there for all patients. Okay, Suresh, a question for you. What is the best targeted treatment for EGFR exon 20 insertion mutation, TKIs or antibodies? So I'm going to just sort of assume that the person asking the question is trying to compare amivantamab or mobisertinib, because those are the two agents at least approved in the US and possibly in some other countries. And I think there are pros and cons for both agents. Clearly the advantage with amivantamab is at least initially it is somewhat better tolerated, though there is the issue of infusion reaction that in most cases can be managed quite easily. The issue, the con with amivantamab is that it needs to be given weekly for the first four weeks and then on every two week schedule intravenously. And so clearly that impacts delivery of the drug as well as causes a lot more inconvenience. The issue with mobisertinib is that it's an effective drug, but because of the toxicities observed due to inhibition of wild type EGFR in terms of rash, but particularly the diarrhea. And in my experience, the diarrhea, even if it is grade one or two can cause significant, can have a significant impact on the patient. It is not just about the diarrhea, but it results in weight loss and fatigue. And despite interventions, the diarrhea can persist and the only way to manage it is drug hold or dose reduction. And so in general, my preference is to go to amivantamab, but it's a very kind of, I just lean only slightly more towards amivantamab. As mentioned with drugs like CLN-081 and there are other drugs coming along, hopefully the differential between wild type inhibition and exon 20 inhibition is greater, resulting in less toxicity. And I think that would be a better way to go. But at the present time, both agents are effective, both have their limitations. Me personally, I tend to lean a little bit towards amivantamab. So based on the toxicity data. Okay, any other questions? Let's see. Yes, we do have another question. For a young patient who refuses clinical trials, EGFR-L858 mutation, brain mets control on Ossie, Mertinib, but systemic progression, what would be your best next line of therapy? She has had carbopen with progression. So systemic progression and post-Ossie-Mertinib and chemo. So this is a very common scenario. And I would say that there's so much variability in these patients. So first of all, it would be important to note what sort of progression the patient has, because if there is oligo progression, then potentially addressing the area that is progressing with a local treatment would be an option. Generally in these patients, I prefer to find out if there is any specific resistance mechanism, particularly after progression on Ossie-Mertinib. And if there is a targetable alteration identified as a resistance mechanism, either through blood ctDNA analysis or a biopsy of a progressing lesion, then I do evaluate the possibility of combining Ossie-Mertinib with a agent targeting those resistant pathways. One needs to be mindful of small cell progression as a possibility in these patients. And I can tell you that initially I thought it tends to occur more commonly after TKIs, but I have seen it occur even after they have been off TKIs and just on chemotherapy, quite uncommon, but one needs to be mindful of that. But this is a space where there are several agents that are being evaluated. I mentioned the amivantamab-lasertinib combination, and I can tell you there are some colleagues I've heard have utilized evaluated amivantamab-Ossie-Mertinib. I would be interested in knowing whether Karen has tried that combination in this setting, but there is data with patritumab-derixtocan, a HER3 antibody drug conjugate that has shown promising benefit, and it appears to provide benefit irrespective of resistance mechanism. Also, there are now TRP2-ADCs such as DS-1062 that are being evaluated in this situation. And there are now more potent EGFR TKIs that are being evaluated. I shouldn't say necessarily more potent, but drugs that can address resistant mutations that can emerge such as the 797S mutation that may emerge post-Ossie-Mertinib. So I think that one needs to take into consideration the sites of progression, the molecular mechanisms of resistance, clearly the clinical status of the patient, and really try and look for a clinical trial that the patient may be eligible for. Karen wondered if you have used amivantamab-Ossie-Mertinib. I have not tried that combination off of trial. We have a number of trials that we're doing that include amivantamab, but have not used that type of combination off trial at this point. We're getting toward the end, but there is another question. So let's see. If this same patient had a high PD-L1 expression, would you ever considered IO in the third line setting, assuming biopsy shows no other transformation and no new target? Go ahead, Karen. I have used the Empower 150 in these types of patients because we don't know well whether immunotherapy is really benefiting them, but at least in the Empower 150 study, there was some evidence of benefit in patients who had EGFR mutations. This would not be for a patient who had received prior platinum-based doublet therapy, but I do in some cases use this on patients, even if they'd had a carboplatin pemetrexid in the past. I would just add one other thing that it is possible PD-L1 expression may not have the same relevance for EGFR mutation positive patients as in others in that PD-L1 expression is used as a surrogate marker for presence of T cells in the tumor microenvironment, whereas in at least some EGFR mutation positive patients, the PD-L1 expression may just be a downstream signaling effect and may not correlate with presence of T cells in the tumor microenvironment. And as Dr. Rekha mentioned, if I were to use immunotherapy, I would use it with chemotherapy. And what I have done is in patients who have had carbopem, I have felt comfortable in some patients, very limited patients who really don't have any other option of using a taxane, anti-VEGF, and atazolizumab. I've been able to have insurance approved in a couple of patients, but that's something that is absolutely no data, but it is taking off the Empower 150 study. Okay, just for a last comment, this is a follow-up to the young patient who had systemic progression. And basically it says, thanks, we did do RT to an isolated liver match. She now has growing hyaluronic acid. We did do a bronc to exclude small cell progression. The last time we did a biopsy, she had an L718V resistance mutation. Any thoughts? I have no idea specifically about that mutation, but I can tell you that there are several newer TKIs that are being developed to address these resistant mutations, but I'm not sure that if any of the ones that I'm familiar with specifically addresses that. The other thing would be interesting, one thing to note is that many of these patients can have double mutations and that become mutations that are resistant to several TKIs. Okay, I think we have to end the webinar. I'd like to thank Dr. Rettkamp and Dr. Gagel for excellent presentations and an excellent discussion as well. Please keep an eye out for an email with a link to the recording. And I want to thank you all for your participation. Thank you.

webinar

lung cancer

ASCO 2022

neoadjuvant therapy

immunotherapy

EGFR mutations

small cell lung cancer

chemotherapy

personalized medicine