Hello, I'm David Gandara from the University of California Davis Conference of Cancer Center. Welcome to this webinar, which will update the status of liquid biopsies and advanced non-small cell lung cancer. This will be based on our recent update of a consensus statement from ISLC published late last year in the Journal of Thoracic Oncology. We're very pleased to partner with ISLC for this webinar, and I will have our faculty introduce themselves. Natasha. Hi there, my name is Natasha Lail. I'm from the Princess Margaret Cancer Center where I lead our lung site in medical oncology. And Christian. Hi, my name is Christian Rolfo. I'm a thoracic oncologist from Mount Sinai Center of Thoracic Oncology in New York. And if we can go to the next slide, please. First just some housekeeping. We've designed this webinar to be highly interactive. You probably know if you're with us that this is going to be case-based. We have three cases. And embedded within the cases, we have questions for you, for the audience. We will have a Q&A function where you will vote on what you think is the best answer. There's only one best answer. Then our panel, our faculty, will discuss the options and why they think one or the other might be better. For some of these, there is no right answer. It will be opinion-based. And then we will proceed through the cases and we will come to another question and so forth. We may have time at the very end for general questions and answers. You can submit these through the question function in your webinar. So this is in regard to the polling questions. And then let's go to the next slide. These are our disclosures for Dr. Zerolfo first, and then myself, and then Dr. Leal. And if you can go to the next slide. And this brings us to the first case. So Natasha, please take it away. Great. Thanks so much, Dr. Banderas. So for the first case, we're going to start at the beginning and in particular talk about the role of lymphomyopathy in patients that are treatment-naive with advanced non-small cell lung cancer. So the first case is a patient of mine. She's from Angola. She's 58, a bank employee with a past history of smoking, about 10-pack years. And she presented with a cough, weight loss, and good performance status, and had a very sad history of her mother some years ago who had presented with lung cancer at about the same age, also a never smoker, but died very quickly soon after she presented without any treatment. And so understandably, this caused a lot of anxiety. Unfortunately, imaging showed stage 4 B disease with lung, liver, and bone metastases. You can see one of her lung lesions and one of her liver metastases on the right. The outside institution where she was diagnosed didn't do molecular testing, but they did do a lot of immunohistochemistry stains. But we had it called in-house, and they were able to do PD-L1, confirm the diagnosis of lung adenocarcinoma, and ordered genomic testing. Next slide, please. So in a case like this, we're actually going to ask Aubrey just to launch the questions so that she can vote. Our questions for you are, how would you proceed? Would you start systemic therapy? She's got PD-L1 at 60%. Would you use immunotherapy alone? Chemo immunotherapy? Or would you wait for the tissue testing results before starting therapy, even though it's been some time now till she presented, and she's got liver metastases? Would you send off a liquid biopsy and wait for the results to see if that helps? Or would you send off a liquid biopsy and go ahead with systemic chemotherapy? So please go ahead and vote. And I'm just going to put an answer that I actually don't choose in, just to make things simpler and to promote discussion. And then, Aubrey, let us know when we have some results. Okay, great. So we have some people who said they would start with immunotherapy, some people who would start with chemo-io or chemotherapy alone. Most people would wait about 40%, and about another 40% or so of people would send off a liquid biopsy to try and help speed things up or start treatment while waiting for the liquid biopsy. So with that, I'm actually just going to turn to Dr. Rolfo first and just ask what he would do in a case like this, and then we'll ask Dr. Gandara. Yeah, this is a very nice case, and I think it's an interesting question. I would like to wait until we have all the results, but I know that sometimes we have patients that are very symptomatic and we cannot wait a long time for the results, even because not in all the other institutions we have the results so quickly. So in that case, if I need to start a treatment before I will start chemotherapy, but preferable, I will wait until we have the results. I will not add immunotherapy in this case, from the very beginning, without knowing the results. Great. Thanks. And Dr. Gandara? First, Natasha, I neglected to mention early on that all of these slides will be downloadable by everybody who's participating through the link after the session. And secondly, that this is being recorded, so you'll also be able to watch the video. Okay, that being said, this is, I agree with Dr. Rolfo, it's a great case. And in some of these situations, that's why we need clinical judgment. In other words, because I think in this particular patient, although there are liver metastases, it sounds like the patient is stable enough that it's not an emergency. That's only maybe 10% of all non-small cell lung cancer cases. So because it's not an emergency, I think we should wait. And I actually picked option number five. In other words, that because it's going to take longer, typically, to get tissue-based results back, I would initiate a broad-based next-generation sequencing liquid biopsy, and at least have that information before I started systemic therapy. If I had to start preliminarily, it would be with chemotherapy alone, because of the potential adverse effects of immunotherapy. Great. Thank you both so much. I'm going to ask Aubrey just to go to the next slide for me, which might be another question, and I think it's just to get to know our audience today, and maybe to learn a bit more about my Dr. Rolfo and Dr. Gandara's practice. And the question for you is, when do you currently use liquid biopsy in your practice? And I'll get Aubrey just to go ahead and launch the question so you can read through. But the first option is no routine use outside trials or research, so generally not available to diagnose acquired resistance to targeted therapy, genotyping if tissue testing is insufficient, genotyping if you're waiting for tissue testing, or another scenario. So please go ahead and vote. I'm going to tell you what we do in Canada, and then when people have voted, we'll get Aubrey to bring up the results for us. Great. Okay. So about 20% of our audience today does not use this routinely. It's not routinely funded or used. About a third of people do use it to diagnose acquired resistance to targeted therapy. Dr. Rolfo's got a great case on that. Another third of people use it if the patients are under genotyped, or testing is in tissues insufficient. And another 20 or 25% of people have expanded access to this, so they can use it if tissue testing is pending, or some other uses, which will be interesting to hear about. So maybe this time we'll start with Dr. Gandara. When do you use liquid biopsy in clinic? When can you access it? When do you routinely use it? Well, Natasha, I actually selected other. And the reason is I use it in multiple situations here. So, of course, the most common use these days is to look in patients with oncogene-driven cancers for what are the mechanisms of acquired resistance. This is incredibly important. It's growing importance, because whether there's a secondary mutation or a bypass often dictates how you would manage that patient. Obviously, number three is also a good choice. And number four, I think, is also a good choice. I do want to say that this is an ISLC webinar, and the I is international. So we realize that some of you on this webinar may not have liquid biopsy readily available in January 2022. But I can tell you, it is coming. And as you will hear from Natasha in a few minutes, it is also, I think, going to be a very cost-effective way of increasingly being able to personalize therapy. So I'll pass it on at this point. Great. Thanks. Dr. Rolfo, anything different in your clinic in New York? I say I agree with David, because I also choose number five. So I do offer, because actually what we are doing here is a complementary approach. So trying to get tissue and liquid at the same time. And in that case, you have a good baseline to follow the patients during the treatment, in case that this patient have any drug-able alteration. I think in the liquid biopsy, you have also the opportunity to test very quickly with the results, and you don't wait, coming back to your former questions. So in my opinion, we are using also not only in driver, and we can address that in the discussion, not only in driver alterations, but we also are using in other situations like David explained before. So I will say three and four are OK, but I would like to do a complementary that is the number five. Great. Thank you so much. So I'm just going to ask Aubrey to advance to the next slide for us, please. And this is a great paper. If you haven't read it, Aubrey's put the link in the chat, please do. This was really thanks to the leadership of both Dr. Rolfo and Dr. Gandara, but really updates for 2022, what we should be doing with liquid biopsy and how we should be using it in clinic. And so in particular, I'm going to focus on the first line treatment, naive, advanced non-small cell lung cancer indications. And as you can see here, you know, liquid biopsy is potentially indicated in all patients. So on the far left, a sequential approach, if tissue testing is not enough, you could certainly reflex to liquid biopsy to help and make sure the patient gets complete genotyping, a complementary approach. And I'm going to talk a bit about a study that we did in Canada that looks at this, you know, where you could do tissue and liquid at the same time, and whichever, whichever finds you the alteration first is what you use. And also even a plasma first approach. So when you know you're not going to have enough tissue, when you know that there are going to be delays with tissue testing, you can opt for a plasma first approach, which I think is really fantastic for all of us in the clinic. Next slide, please. So molecular testing, you know, it is a challenge. There's this really nice survey from the ISLC that was global. And really, the big things that people have challenges with are costs, you know, so especially if we're adding a liquid biopsy, that's, you know, twice as much as adding the cost of tissue biopsy, and also, you know, getting access to good quality MGS. Time is also an issue, as you can see in blue there across the different bars, with a lot of people indicating that we're not able to get the results in the recommended 10 or so business days that are that are in the current ISLC guidelines. Next slide, please. So in Canada, we conducted what we call the value study, where we really wanted to show the value of liquid biopsy, you know, you knew that it was really helpful, and, you know, often a real boon for patients in the clinic, and could really rescue patients, but we wanted to demonstrate the value and the cost effectiveness. And so, in particular, I'll focus on cohort one, we looked at 150 patients that were treatment naive. Now, we did really select this population, they had non squamous, non small cell lung cancer, and a 10 pack year or less smoking history, because we really wanted to maximize our ability to capture targetable alterations, we looked at clinical outcomes, and, you know, response, overall survival, progression, free survival, but we also looked at system outcomes, how many patients didn't save, and allow to have targeted therapy, and what about costs and consequences. Next slide, please. So, we found that pretty consistently, as you've seen in the literature, and as you'll read in Dr. Rolfo, and get to this updated paper, that liquid biopsy is incredibly helpful, you know, and often perform performs at least as well as tissue in terms of detecting alterable alter actionable alterations, there is very high concordance. So in our study, you know, we found eGFR and ALK alterations, the most common in Canada, in 40% of our patients using tissue 39% using liquid, and we were able to actually find a few more alterations using a broad spectrum NGS liquid biopsy panel than we were with standard tissue testing. Now, we were quite lucky in this study, usually in Canada, I would say that 10 to 15% of our patients don't have enough of a diagnostic tissue sample to get them through all the biomarkers we need to test in this study, it was only 6%. And about 13% of our patients didn't have any cell free DNA detected in liquid biopsy, which is also a challenge. So, some patients have tumors that don't shed, or they have smaller tumors where you might not find something. Next slide, please. But by and large, you know, in the top there in red, there was very high concordance, whether we use liquid or tissue to make decisions, you know, we could get patients to where they were going significantly faster, as I'll show you on the next slide. But there was also the potential to rescue patients. So, about 60% of the patients in our study had results using liquid biopsy that we couldn't find using tissue, whether the tissue ran out, or we couldn't afford the testing in tissue, or we just didn't find it in tissue. And these patients were able to go on targeted therapy. But conversely, also, you know, liquid biopsy is not perfect. And so, about 10% of patients had actual alterations identified in tissue, but we didn't have enough cell free DNA in the liquid biopsy to detect it. Next slide, please. So, in this study, you know, because we'd selected these patients based on smoking status and non squamous pathologic subtype, the vast majority, about 56%, went on to some form of targeted therapy. But some of the patients did go on to checkpoint inhibitor therapy, checkpoint inhibitors plus chemo, chemo alone, of course, those without actionable alterations. Also, another group of patients were really observed, because I think for a number of our patients even today you know we desperately want to offer a targeted therapy you know there's concern about chemotherapy or their ability to tolerate it and so 10 percent of our patients basically had no treatment because they couldn't withstand any of the standard options. The turnaround time is much faster for the liquid biopsy assay that we used seven days versus 20.5 days and in the vast majority of cases liquid biopsy really helps with the decision process. Next slide please. And in terms of outcomes you know we've seen this in the literature I think it was Dr. Jeff Oxnard who presented one of the first papers in T790M positive patients where we can see that whether you find the alteration in liquid or tissue the outcomes are really the same response rates of about 62 percent with targeted therapy either with tissue in blue or liquid in red and similarly for non-targeted therapy response rates of 40 and 36 percent with tissue in blue and liquid in red and on the at the right side in green those patients access targeted therapy and of course we had more patients accessing targeted therapy and therefore better progression-free survival with liquid biopsy because we were able to find it more often in red patients receiving non-targeted treatments and then at the very bottom of course our patients that receive no therapy again so important to remember that we really want to diagnose patients as early as possible and offer them the best possible treatment. Next slide please. And the last piece and of course this is very Canadian but I think very relevant to to a lot of a lot of delegates that might be attending today is you know how can we afford this and so Dr. Azafeh from Calgary presented our economic model where we looked at the outcomes and costs based on tissue biopsy alone in our study with tissue testing or adding liquid biopsy so this complementary approach that Dr. Rolfo and the team describe. Next slide please. And what we found was that patients did better if they were able to access targeted therapy, more patients were able to access targeted therapy if they had a liquid biopsy than if they had tissue alone and when we looked at costs what was really surprising to us was adding the liquid biopsy to the tumor biopsy in fact did not increase the total costs or you can see 1.3 million versus 1.34 million for tissue biopsy alone for the whole study which really I think speaks to you know the costs of repeat biopsy and the the expense of immunotherapy when when patients have to have immunotherapy when in fact they truly have a targetable alteration so in the Canadian system it was cost saving and we're looking forward to moving that into standard practice. Next slide please and we'll all as soon as I'm done we'll address some of the questions at the end I hope. So for our patient we put her on the value study on day five the pathologist called and said you know we just don't have enough tissue for genomic testing the patient was very upset we repeated we booked a repeat biopsy but as you can understand you know she was thinking about what happened to her mother during the three-week wait between diagnosis and her mother passing we were very lucky the liquid biopsy result came in at seven days and she had an exon 19 deletion mutation and she was able to get begin treatment the very next day. Next slide please and you know I think around the world everyone wants to use osemertinib not all of us have osemertinib funded we were lucky to get this lady osemertinib in 2019. Now we have much better access to it and you can see a nice improvement in her lung lesion resolution of her liver lesion and she's actually still ongoing but in the next case Dr. Rolfe is going to talk to us a bit about what to do when these targeted therapies fail. So just to sum up just going to get to go to the last slide for me please Aubrey. You know our takeaway certainly in the first line setting is that this is an important and valid tool for genotyping it complements tumor tissue profiling and treatment naive patients with particular value in those with insufficient tissue under genotype samples or not enough time and in selected populations adding liquid biopsy can actually save costs or at least be cost neutral by avoiding inappropriate immunotherapy and extra biopsies in patients with oncogene addicted lung cancer. Now with that I'm going to turn back to Dr. Gandara and I think our next case will be from Dr. Rolfo. David you are mute. Sorry sorry we'll we'll move to Dr. Rolfo. I just wanted to interject thank you Natasha that was a beautiful case. I just wanted to say this is the first webinar for 2022 for ISLC. We want to thank you all for joining us because we have over 700 registrants for this webinar so we are very happy to have you all aboard. Our second case I think will be as instructive as the first and it will be presented by Dr. Rolfo. Cristian. Thank you thank you David and a very nice case Natasha we will discuss also over this one. It's a little bit long case but it's really interesting and illustrative how we can tailor the treatment with the use of liquid biopsy. So the next slide. So this is a 52 years old female former never a smoker that's also important but in July 2018 she had some flank pain dyspnea and cough and was arriving to the emergency with pleural effusion. So the pleural effusion was checked it was a drain that was positive for a lung adenocarcinoma. She did at the at the moment of the drain a PET CT scan that show a left upper lobe mask left-sided pulmonary nodules left-sided pleural effusion as well they are still and lymphadenopathy along the left ilial mediastinal left mammary chain portal parties and retoparietal region. So as you see a very diffuse a very spread disease and also the brain metastasis a single brain metastasis was confirmed a very small very teeny eight millimeters in the right frontal parietal location. So we send the tissue at that time and we send liquid biopsy and as all know that the liquid biopsy arrived before we received the liquid biopsy and the result of the liquid biopsy was an EGFR exon 19 mutation collection that was with a 41.2 percent of the allelic fraction variation that is the quantity of DNA that we have in the sample. We started the treatment and I will go there but that was surprisingly because when we started the treatment and she was already responding we received the result of the tissue and that is another advantage of liquid biopsy. Next one. So in this case that is this is a elusive case but when you use liquid biopsy in advanced and small cell lung cancer and here we have some options you use only at the baseline and to establish the pressing of oncogenic drivers and that was represented the case of Dr. Lei only a progression to the termite mechanism of resistance. There is also the possibility to do after six weeks to treatment monitoring and I use liquid biopsy in all the situations so one two or three or never. Please vote. I don't know David and Natasha if you will vote as well but we will capture there. Okay so I see here that the 48 percent of the people is using liquid biopsy in the three situations so that's very good. Only at the progression and that is obviously depends of what David was telling before the access in the different regions of the world is completely different and the good thing is that nobody was doing never selecting never and that is a good opportunity for the patients as well. So next slide. So in this case she have a very spread disease with a enter paroxysm 19 deletion and a small asymptomatic brain metastasis. What will be your choice for therapy in this case? So we have SBRT for the brain metastasis and start Ocimartinib. Go for Ocimartinib alone. Use EGFR-PKI first generation and the Basismab or the combination with chemotherapy double platinum and EGFR-PKI. Please vote. Here could be some some options that that are possible acceptable I would say and we can discuss. Ocimartinib alone and SBRT. So David what is your your opinion about that? We have only a small asymptomatic brain metastasis in a EGFR patient. Well Christian I think this is a great question and I think the fact that this is an international webinar for an international audience there are a lot of right answers here. You know what I would do in this case is use Ocimartinib alone because this is a small single asymptomatic brain metastasis and Ocimartinib is highly effective in treating brain metastases if there's an EGFR activating mutation and also in preventing them we know now in the adjuvant setting from the ADURA trial. However I also know that in some areas of the world and this may be around 40 percent from the latest figures that I've seen Ocimartinib is not available for first-line therapy. So in a case like this I know there are data quite compelling data that using an EGFR TKI second at least first generation like Erlotinib with platinum chemotherapy or with Bevacizumab or even Ramiserumab could be an option if you do not have Ocimartinib available. But I think at least in our practice I would use Ocimartinib alone and monitor the brain metastases and only use SBRT if there were progression in the brain. Now that's good. Natasha what is your comments about this case? So it's a great case and like Dr. Gandara I would use Ocimartinib up front as well. You know it's interesting we do have a trial that Dr. Cheryl Ho in Vancouver is leading where we're randomizing patients to either Ocimartinib or stereotactic radiotherapy to a limited number of brain metastases and then start Ocimartinib because you know I think there's still a real sense out there that we don't know the value of radiotherapy long term in brain even with such a great drug like Ocimartinib. So you know a case like this I'd probably just start Ocimartinib by itself. Someone with more brain metastases or larger lesions I would discuss with our multidisciplinary brain team and if possible try to get them on this trial. Yeah no that's as we see and the people here can see there are several right options and depends also of the access that you have in your region. But if you are using a TKI of third generation that doesn't mean that we'll not be acting in the brain or crossing the metabolic barrier but it's not the activity that we are expecting with Ocimartinib obviously. So the next slide. So she started to have a good response and I would like to to stop here to check a little bit better this slide because when we are looking for a report generally as oncologists we are going to fix our eyes there or our view in the driver mutation and we don't see generally the rest of the report but we don't see carefully the rest of the report and that is something that is very crucial because in this case as you can see here look at in the the part that there are the allelic frequency she have a variant of allelic frequency of 41.2 but then she have also a TP53 mutation. The patient have also an IVRAF amplification, CDK amplification, EGFR amplification. So all these companion mutations or commutations are able to give us some idea how will this case will go because patients who have for example TP53 or EGFR amplification could have a bad prognosis in terms of short depression for survival. So she was responding actually she have a spectacular response in the brain so this teeny lesion was completely disappeared at the moment that we received the tissue biopsy so with only with the liquid biopsy. This is part of your presentation Natasha when you say a liquid or blood first so that is the example and so taking considerations and read carefully all the commutations because are very important. Next one. So you see here a next one that was the baseline after the the brain of the pleural effusion and that was a very short time that was actually after one month and a half of treatment so very good response and we expected. Next one. So here we enter in another concept at the moment of this case was 2018 we just published at that at that time the first statement paper we recommended at that time liquid biopsy only for the detection if the tissue was not available and we don't have the concept of monitoring but this concept was added later on and actually in the new paper we include this concept of monitoring and there are several data this is the data of the FLARA super analysis where this clearance of the mutation after six or in this case for three or six weeks we have a good surrogate to speak about progression-free survival and it's something that some members are offering right nowadays to to give us a combo covering in the same package the baseline and if the patient have a TKI or drug-able alteration suitable to TKI we can do another detection of six weeks to see how this DNA is detectable or not or there isn't a decrease at least. It was not this case but this is an important concept to incorporate. Next one. So in February 2020 you see that you can see here she have a 0.3 of allelic fraction variation very very minimal but there is a new mutation that was 797s that was also doing a CT scan and showing a minimal left ilial lymph node. You see here was between parenchyma and an ilial lymph node was difficult to describe that. We did a bronchoscopy. Next one. We repeat the liquid biopsy and we did a bronchoscopy and was positive for adenocarcinoma. We did also the tissue of this relation and was also T797s EGFR mutation and we know that this is unfortunately an unmet medical need because even though we have some drugs that are in trials we don't have actually treatment for this mutation. So next one. So this is a clear example and that's one of the figure of our paper how the liquid biopsy can complement or give the idea about the heterogeneity and also the clonal evolution of the disease. And obviously, the possibility to repeat over the time and tailoring and monitoring. Next one. So this is a question. So in June 2020, the CT scan showed this progression. The MRI showed no brain metastasis. We continue to have a very good control in the brain. So at that time, with the spectacular response that you have, what do you do? Continue or subordinate local treatment radiotherapy and continue or subordinate? Switch to chemotherapy or start chemotherapy and immunotherapy? If you can, launch the vote. Aubrey? I'm sorry, you know, I don't think this one got built out in time. I apologize. I just noticed it's not the right question. I apologize. Sorry. But we have here, David and Natasha, that we'll discuss. Natasha, start with you. What you would do in this case? Great. Thanks. And Kristen, so these are always judgment calls. You know, I'm not even sure I make the same decision for the same patient. For me, the options really are continuing with the osomert nib and continuing to watch if it's very small progression and the patient's asymptomatic or stepping in and asking the radiation team if they could offer some local therapy and then continuing. So sort of like the old days when we only had Jafet nib, we would either just, you know, we wouldn't look if there was just a little bit of progression, we'd continue or we'd try and offer local therapy. And, you know, there's some very nice data from the CINDIS trial and other trials that suggest that maybe offering local radiotherapy to oligoprogressive sites may improve survival. So my favorite would probably be number two, but sometimes I talk to my patients about number one as well. Yeah, that's a very good option, and David, what are you doing in your practice for this kind of case? Right. Well, I think in regard to this question, you know, sometimes there's not one right answer. There are options, as Natasha said. Sometimes there's a wrong answer, and sometimes there's one that's like really wrong. So I'll take it from the backwards end and say what I think would be really wrong is to start chemotherapy immunotherapy in this case. I personally would not switch to chemotherapy. This is oligometastasis. However, it's pretty minor. So I actually voted with a continuing osmertinib, although I think you could easily make a case for giving SBRT. Sometimes, you know, I'm saying what is the benefit? You know, randomized trials are ongoing. We had some phase two studies, but, you know, we don't know for sure that that will make the patient live longer. Yeah, and I think the decision making for me in this case was the fact that in the liquid biopsy, even if it was small, the 797 mutation was there. So that means it was not there before, and we have a good decrease, and these images is disappearing, and there is no real confirmation of mechanism resistance, and given the good response, I will continue osmertinib alone, but it takes place. So, Christian, let me just ask you another question then, real quick. So do you think that C797 is coming only from the hyaluronimth node, and that you're going to eradicate that with SBRT? To be honest, I was surprised because the amount of disease was very minimal to get this. So I think it was something more cooking there. That was my impression as well. So for the reason I say, if you go for the next slide, you will see. So we give radiation to her, and we continue with osmertinib. Next one. But as you can see here, in very short time, she have a good, and this is July, and if you do the next one, she have this liquid biopsy with C797 that was increasing, and also the mutation, the baseline, the election, I think, was also increasing. So we know that these mutations are part of the mechanism resistance. Next one. And it's important that we discuss also the subclonal evolution of disease, and I think here we are focusing one of the mutations. Next one. But this is minimal compared with other in the flower data. Next one. Here is just to confirm that we need to use broad methodologies like next-generation sequencing approach for liquid biopsy. There are some questions that I see here in the chat that they say that the commutations were before in the tissue. Yes, some of the commutations were there, and then there is an interesting question that say the intracranial response was better than extracranial response. I will not say that. So she have a very good extracranial response, and a very minimal amount of disease in the brain compared with the big amount of burden of disease that she have in the extracranial setting. So next one. I say the next one. There are some of the typical mutations that we have or other mechanism resistance, and 787 is one of them, but we learn also that when we are passing us from the second line to the first line, we discover the new mechanism resistance like metamplification was also there. It was 15% in the flower case, in the liquid biopsy portion of the data as well. So next one. Here we have a good question. Was it in cis or in trans? What is this means, Natasha? Why we have here somebody who is asking if it was in cis or trans? Oh, so I think there's been a lot of interest, especially in these subclonal populations, for the ability to combine first generation kinase inhibitors back with the third generation kinase inhibitors and see response. And I know you're a nice case. You'll tell us how your patient did. I think for most of us, although I think it's an interesting strategy, I think for many patients, response is short lived. And so certainly our team and others are looking at other ways to target 797S. But of course, if we could go back and recycle and reuse these first generation kinase inhibitors, I think that would be interesting. But I think you're going to tell us what happened to your patient. It's not something we use in Canada off study, but it has been used. There are some case reports. Again, duration of response can be a challenge. David, any comment about this question about if this was in a cis or trans mutation? I agree with Natasha. I'm not sure it makes a difference here. Okay. So in this case, we have, after the radiation you see in a very short time from July 16 to August 27 that we did the liquid biopsy and the PET scan, she had a big progression, also increasing of the allelic fraction variation. And that was very important. At that time, we decided to go for another treatment. So next one. And here is a pool again, due to the impressive response to Osimertin and the small amount of disease progression in the brain control, what is your treatment for? That was before, sorry. I think that was another question. So we will cancel this. We can just go to the next slide, Aubrey. So in this case, what we did, we was using Erlotinib because actually the mutation was in a position biologically, following a biological rationale. We was discussing that and we felt that was a good opportunity to go for a TKI in first generation. In this case, Erlotinib. And we started Erlotinib. Next one. Next one. So you see here, when we are using the first generation TKI, in the beginning, we have this and at the end, that was a problem. Osimertinib was overcoming this resistant mechanism. But then we have, if we are focusing the second part of the graphic here, we have the third generation TKI that when we have these mutations that are in cis or in trans, and this is an important question because biologically we can combine some of the alterations. And for example, some of the target in this case, for example, when we have this alteration, we went to Erlotinib that theoretically there is a biological rationale to work. So next one. And that was happened, you see, from August to October was non-detectable. She had a very good response in the CT scan. Actually, in the bed, we discussed this because it was a pneumonitis due to the radiation. Actually, she was treated with cortisone and recuperating that. So she was almost in a complete response. Next one. And we continue to follow up this patient. And as you can see here in the follow-up, since October to January, we push another mechanism of resistance here and we have T7-9PM coming as a mechanism of resistance of the Erlotinib. So in this case, we have a triple mutation and that is a very difficult situation because we don't have a treatment for this even if we are in the position of the mutations that allow us to go for a combination. So we decided at that moment, next one, to go for chemotherapy, chiroplasty and chronotherapy without immunotherapy. Next one. And she was in a very good response for a long time. Then the history continued, but I will not continue with the case. The important is why we are not adding immunotherapy here. And there are several trials, several studies. I just put these images from Dr. Macias that I think is a very interesting retrospective analysis showing why we don't need to use immunotherapy in all the driver mutations. So there are some cases and there are some exceptions. And there are some trials that are saying, the contrary. What is your opinion here, Natasha, about this immunotherapy? Yeah, it's very challenging. I mean, my experience, by and large, especially for an ischiopharyngeal lung cancer patient is that they don't do well at all. You always hear about that one case of someone who did so well. But unfortunately, you know, I think for the most part, it's not the case. And I think that's why we are not adding immunotherapy here. I think for the most part, I, like you, leave it sort of as my treatment of last resort. And in particular, I wonder if this is a group of patients where when we get to the stage where immunotherapy is something we're considering, or perhaps even earlier, should we be enrolling these patients in cell therapy trials or some of the newer, more interesting immunotherapy approaches? So for me, again, this remains a last resort for many of these oncogene-addicted patients, you know, ROS1, RET, ALK, EGFR. Although I think for things like KRAS and NET oncogene and BRAF oncogene-addicted patients, you know, obviously this is different and immunotherapy is potentially much more active. David, any comment about this? No, just as a reminder, when we asked early on about would you start therapy empirically, instead of waiting for testing, a lot of people, when they start empirically, they start with chemotherapy plus immunotherapy. And then if they find there's an oncogene driver, like shown here, it alters the subsequent response. And there's emerging data quite strong in this regard. It reduces the chance of the patient responding to the TKI. So just going back to that initial point, I think it's because immunotherapy is relatively ineffective. PD-L1, I would say, is a false marker here because these patients, in lung cancer, we only use TC. We don't use IC plus TC. In other words, a CPS like are used in other tumor types. There are very few in some of these, very few infiltrating lymphocytes. So you can have 60%, 80% TC, PD-L1 positivity, no IC, patients do not respond. There are some of these though where it's maybe, there is a little more activity. And I would suggest maybe BRAF could be one, but I agree entirely with Natasha here. Yeah. And also I think this is a very interesting area of research because we was actually working always separate target therapy for one side, immunotherapy for another. And maybe we need to start thinking in the microenvironment, the immuno-microenvironment of these patients with targeted alterations. And there are already some research ongoing to answer that question. So the next one. And that's my take-home message from this case. And so CT-DNA is a very good tool for all the patient journey. And we saw in the case of Dr. Lei, we will see also the case of Dr. Gandara, so in this one, it's important that we do a validate comprehensive platform. So next generation sequencing in order that we know also different commutations, important that we have also baseline determination to monitoring these patients. It's important also to report any anecdotal case because we need to do a process of learning curve. And I think every case is valuable here. And it's important that we use testing for our patients at least to discover which one will not respond to immunotherapy. So with that, I pass to David for the next case. Okay. Thank you, Christian. This is case number three. We see that we have a lot of questions. Some are in the chat, others in the Q&A. I just want to say that we may not get to these or to all of these during this live presentation, but we will address these and post the answers. So Aubrey from ISLC will be able to do that and we will address all your questions one way or the other. So we'll move now to this additional case, case three, 64-year-old male, previous 15-year pack smoking history, presents with cough, shortness of breath. You can see one of the images from the CT scan. There's left upper lobe primary. There are mediastinal and hilar adenopathies as well as bilateral lung nodules. You can see some of these and bone metastases. This is a adenocarcinoma consistent with a lung primary TTF1 positive. Brain MRI shows no metastatic disease. Next slide, please. So this is a new case. The performance status is one. You decide to perform a broad comprehensive next-generation profiling, and there is inadequate tissue. Remember this was an FNA. So in the face of inadequate tissue, how would you proceed? And you can see the choices here. Would you send a plasma only where you expect a seven-day turnaround time? Would you repeat the biopsy and send tissue only where you anticipate? And I think this is a really real world, about a 20-day turnaround time. Or would you send both? And again, the turnaround time would be based on the tissue. Please vote. And I'm sorry, can you still hear me? I had a momentary lapse in my picture. So you can see the majority of people are going to send both and I think from a cost effective viewpoint, one thing practically that I do is I am arranging for the tissue biopsy, but it's going to take a week or so to get it done. In the meantime, if I get the CT DNA and it gives me an answer, then I cancel the repeat biopsy and don't put the patient through that. So Natasha, what would you do in this situation? Do you think these turnaround times are in line with what you would expect? I agree. I agree with you completely. So this is a patient where if I could access with the biopsy, I would send that off. I would book the tissue biopsy. But of course, if we found something in the liquid sample, that would be actionable and we'd act on that. And of course, the bigger challenge then becomes, you know, if you don't find anything in the liquid biopsy and you have to wait for tissue, you know, you have to wait that for six weeks, you know, 20 days is great. In theory, we have a 20 day tissue NGS turnaround time in practice. It's probably more like 28 to 30 plus days. So that's one of the great things about plasma, right? You don't wait for the biopsy. And then, you know, if you're using an assay with quick turnaround time, it can be so much faster. And Christian, any additions? No, I think it's perfect for the time sake, we will continue that. Okay, next slide, please. So molecular testing is done by a plasma based NGS assay. And it reveals that there is a KRAS G12C mutation, of course, highly interesting these days compared to a few years ago. Plus there is an STK11 mutation. And in this particular case, tissue was sent and it subsequently comes back and confirms these results. The PDL1 by the DACO22C3 is a TPS of 1%. Next slide. Now, this is a slide that has already been shown and I won't belabor it. If you can, there's animation here, advance. Albrey, okay, great. This is the typical classic approach, sequential, next. This is a plasma first, which as we've said, is most utilized in the acquired resistance setting. And then this complimentary approach, when we published our paper, we know this is a little controversial, but I think studies such as that by Natasha and others coming out say, actually, this may be the future, where if you have it available, you're going to try to send both, you're going to match them up and then you're going to come out with the best information. Next slide. Back to our patient. So this is, again, now you've found a KRAS G12C plus an STK11 mutation, the TPS is 1%. What would you recommend for first-line therapy? Would it be the G12C inhibitor, sodoracid? Would it be chemotherapy plus immunotherapy as in Keynote 189, immunotherapy combinations as in Checkmate 227, or including an anti-angiogenic as in the Empower 150, or lastly, what I call chemo light plus dual immunotherapy as in the Checkmate 9LA. What would you choose for your treatment in this particular patient? Okay, so interesting, 51% say they would go right to sodoracid. And you can see another 35% are going to go with a combination of platinum-based chemotherapy and pimbolizumab. And then we have some votes really for all the other selections. So Natasha, what would you do here? So I think as a standard off trial, you know, in Canada, we would offer, you know, whether it's number two, or number five, which is also approved, but I think most of us would go with chemo plus one agent or pimbolizumab. You know, I think the sodoracid, you're going to show us some of the nice data, which I think pushed a lot of people to vote for that. But certainly in Canada, still, it's approved only second line. And so, you know, I think for us, we would really still favor a standard approach outside a clinical trial. Of course, a patient like this, I'd love to get them on a trial, you know, especially a trial with a KRAS inhibitor, and perhaps some other combination therapies. And Christian, what would you do? Yeah, in that case, in this case, I would like to do option two, because it's what I use generally, but there are the other options that we can enter here in the discussion, which kind of the other options is better or not, but I think all the other options are available and valid. The first one, the sodoracid, no, because we don't have still data in first line. And actually, this is not a target that we expected that we'd be responding like EGFR, for example. So I will wait for the results very patiently to have all the results in first line before we use this kind of inhibitors in KRAS. And I agree with the comments of both my colleagues. My own opinion would be that sodoracid would be used as second line here. And the reason is that, you know, the response rate is reasonable. It's in the high 30s percent. We'll talk about whether the STK-11 affects that. But the main thing is the duration of response with this drug and the other G12C inhibitors that are being reported is not in the same degree. The duration of response is not like an EGFR TKI or an ALT TKI. It's in the range maybe of eight months. So I think because of that, it's hard to say this should be first line therapy as standard of care today. Maybe that will change, particularly with sodoracid combinations, which are under study. Let's go to the next slide. So this just emphasizes what we talked about in terms of the immunotherapy landscape. As you can see, it is very complex these days. This shows all the studies that we just talked about in our question and answer, plus the studies that were single agent immunotherapy and is updated to include the mPOWER with a E, LUNG-1 with semiplimat, which is now approved in the United States also for the high PD-L1, greater than 50%. So lots to choose from. Next slide. And so if you are using all the data available, you might look at an algorithm like this, where first you would test for oncogenes, and if you find one, you would use therapy. Otherwise, you would pick one of these options. And because we are running short on time, I won't belabor this at this point. Let's go to the next slide. So sodoracid was approved based on a series of studies coming out of the code break analyses, where it was administered as a single agent, and you can see the design here. Next slide. And the response rate, as the data increased with an increasing sample size, shows that by RESIST criteria, the response rate was 37%. Next slide. So going back to our patient, our patient was treated with pemetrexid carboplatin and pembrolizumab, and the patient achieved a partial response. However, at six months, there was progressive disease in three sites, two new bone lesions and growth of a pulmonary nodule from about one centimeter to 2.5. Remembering that this case has G12C plus STK11 mutation and a TPS of 1%, what would you recommend at this point? First choice would be SBRT to all the sites, and I'm, looks like we, there's a glitch here. So the first bullet there, when you vote for that, you're voting for SBRT to all sites and continuing the same treatment. The second is switching to sodoracid. The third is switching to docetaxelramaserumab, and the last is going to nevo-ipi. Please vote. Again, the first choice will be for SBRT to all sites and continuing the original treatment. Okay, so the vast majority of people, 74% are going to switch. That's what I would do. And 7% said give SBRT to everything and continue. I don't think I do that in this particular situation. It's not, well, it does fit in many people's definition of oligometastasis, but this is not a classic oncogene driven cancer such as EGFR. So just very quickly, Cristian, Natasha, what would you do in this case? Yeah, in this case, I will go for Sotorazib if it's available. If it's not available in my country or in a clinical trial, I think one of the options of the Staxel will be useful. And I know that, for example, Ramosilumab, but also in Europe we haven't needed any. So that those options are, or even the Staxel immunotherapy, if they don't have any other options, is a valid option. Natasha, what do you think? I agree with the majority. I would try and get this patient on targeted therapy with Sotorazib or a trial. And I think so much of why we make these decisions is what comes next, you know? So if we didn't have anything after Sotorazib, for example, or we only had Dosataxel, you know, then I would have probably picked number one. But because we have this exciting new option for number two, that's what I'd choose. And you know, in places like Canada, if we don't have that option, our alternative second line, unfortunately, is still Dosataxel. And Nevo-Ipi is not approved in that setting. So we wouldn't use it. Agreed. David, can I? Yes. There were some questions in the chat. I don't know how much time we have, but, you know, some people were talking about, you know, is this SDK 11 commutation data that we've seen at meetings? Is it enough? Most of it's been retrospective. Should we be recommending that people use that in their decision making or what to do with that? Right. I think that's my next slide. So let's go to the next slide. I think that's actually, okay, and this one we can skip. If you can go to the next slide, Aubrey. Okay. So this addresses that question. Now this is in terms of response to sodoracid based on whether there is a STK 11 or keep one. But in terms of immunotherapy, and I don't think I probably have that in this deck, it is controversial now, whether STK 11 in particular is just prognostic or predictive of poor outcome with immunotherapy. And I think further studies are ongoing such as our own to sort that out. But in terms of the G12C inhibitors, you can see in this analysis, and this is again, a small group of patients still, you can see that STK 11 doesn't seem to portend a lower response rate with these G12C inhibitors, but keep one may well. And you can see that in the right sided figure. So in my opinion, we would still give a G12C inhibitor if it's appropriate, regardless of the commutation status. But I think this is going to play out in more detail. We have a study that is just completing within the lung master protocol, which is specifically designed to see what the activity is of sodoracid in the various commutation subgroups. Any final comments on this issue, Natasha or Christian? Sorry, Natasha, go ahead. Oh, sorry, Christian. Thanks. I was just going to say, you know, I think the data are so exciting. But the truth is, I mean, most of it is retrospective or small subgroups. And so, you know, to change practice in Canada, we're going to need those prospective trials. But no question, I get a little nervous with PEMBR alone, if my patient has commutations with STK 11 and KRAS. And you know, I might push a little bit harder to get that patient on a trial, but you know, is it ready for primetime? I think we could argue. I think we could argue. Christian, go ahead. Oh, I absolutely agree. I would say the same. But there is also a question here, David, the radiation for oligometastatic evolution is not feasible. That is, in this case, what is your opinion? I'm sorry, I'm not sure what the question is, Christian. The radiation, because one of the questions that you have was doing radiation of the multiple sites. Oh, it's, you know, this is a situation where to me, it's not, it's not, can you do it? Should you do it? And you clearly, you can do it. You can give radiation to 10 sites, if you consider all of those oligometastases. In my mind, it's probably not the best option for the patient. And there's one last slide I will just show, if we can go to the next slide. And this is the commutation status with the other G12C inhibitors. One of the others that is far along in development, and that is with adagrassib. And here you can see for STK11, for KEAP1, P53, you can see maybe the data are not so clear, even for KEAP1. So you can see maybe there's a difference in the drugs. My own opinion would be probably this is not a difference in the drugs. It's just small populations at this point. And that's the reason I would not deselect a patient to get one of these drugs based on a commutation at the present time. And I think with that, we will end this symposium. We're just a little bit over time. Those are just my take-home messages. But I would like to thank ISLC, and in particular, Aubrey Hsu, and our co-faculty, and all of you who joined us today. As a reminder, these slides will be downloadable on the website through the link, as well as you can listen to the video if you want to re-listen to that, or for the folks that haven't seen it. And also that there is CME associated with this, which you can get through the link. Any final comments, Natasha or Christian? No comments, OK. And so, Aubrey, did you want to make any final announcements from ISLC? Again, we will try to address your questions and put them within the link so that those of you that ask questions, we get them all answered. But I hope you enjoyed this truly interactive session, three great cases, and lots of discussion here. Thanks to all. Thank you so much. Yeah, I'll send an email out later today with information on claiming CME credit. A video of the recording will be uploaded to the site hopefully in the next day or two. And I'll also make sure to send you the questions. I've copied those, and you can maybe include those on the email I sent out. So thank you so much. Thank you, everyone, for being here. Everyone, have a great day. Bye.

liquid biopsies

advanced non-small cell lung cancer

genomic profiles

systemic therapy

immunotherapy

tissue testing results

EGFR mutation

acquired resistance mutations

KRAS G12C mutation

comprehensive genomic profiling