Hello, I'd like to thank everyone for joining today's webinar in which we'll be discussing biomarker testing for advanced lung cancer and why it's important. Feel free to put questions in the chat as we will have time at the end for questions. That's me on the right. My name is Adam Fox. I'm a pulmonologist and clinician scientist at the Medical University of South Carolina. And it's my pleasure to introduce our speaker today, Dr. Bruce Johnson on the left there. He's a professor of medicine at the Harvard Medical School and institute physician at the Dana-Farber Cancer Institute, where he also serves as the chief clinical research officer and leader of the lung cancer program. He served as the president of ASCO, the Oncology Professional Society, and is an accomplished researcher focusing on the molecular basis of lung cancer and targeted therapeutics for its treatment. So without any further ado, I'll turn it over to Dr. Johnson. Thank you, Dr. Fox. And it's great to be here joining you in this webinar. So these are my disclosures. I'd like to point out that I get post-marketing royalties for the EGFR mutation testing, which I'm going to talk a little bit about. Please keep ordering those tests. I want to talk about biomarker testing for advanced lung cancer and why we believe it's important and how it's transformed the care of patients with lung cancer. I've broken it down into four different topics. The first thing I'm going to do is talk about the mutations for which there is targeted therapies available. That'll include EGFR, BRAF, B600E, MedExon 14 skip mutations, some recent advances with the EGFR Exon 20, HER2 mutations, and the most recent one, the KRAS G12C. I'll follow that by talking about the chromosomal rearrangements and how they're similar, but yet have a bit more of a prolonged efficacy and talk about how those are different. I'll talk about using PD-L1 or a program Def-Ligand 1 as a biomarker for potential response to immunotherapy and give an example of one of my patients. And then lastly, I want to talk about the testing rates in the United States and what's happened, and also about the timeliness of getting the testing that influences how oncologists and other people caring for these lung cancers end up influencing how we take care of people. First, I want to start about where we are. I began treating people with lung cancer in the 1980s, so I've been at it for a while. And I have to admit, for 20, 30 years, it was a little bit grim. And one of the things I want to show you what it was like two decades ago and point out a couple of things. At this period of time, it was sort of hopeful that you could rearrange the dictures on the Titanic and expect a different outcome. And this was a study that was in the plenary session. It was considered one of the top four studies done in oncology in 2000 and was published in the New England Journal of Medicine two decades ago. And this was giving platinum agents, cisplatin or carboplatin, with four different chemotherapy agents, paclitaxel or taxane, gemcitabine, docetaxel, and paclitaxel. And number one is that it didn't make any difference which of these you gave. But the second thing is that the median survival of these patients was eight months. And these were people that fit a clinical trial. And lastly, the proportion who were alive, this didn't even, the survival curve didn't, the axis there, the x-axis is months. And they didn't even bother to run the survival curves out to five years. And in these trials at the time, you know, the five-year survival was running out of between 2% and 5% of the patients with advanced lung cancer. This is where we started a couple of decades ago. And thank goodness it began to get a little bit better. And one of the things that a lot of us were able to do was that at the beginning of the 2000s, there were epidermal growth factor receptor tyrosine kinase inhibitors. There were two that were widely available. The first one that was available was a drug of Giffitt number or ERISA. And we had expanded access programs. One of the things that people observed is that there were a subset of patients who had these rather dramatic responses. Typically with chemotherapy, the response rates ran at about 20% and nobody had a complete response. And the responses lasted a few months. And these are the CT scans of one of the patients who were treated, who was treated at the Dana-Farber Cancer Institute. And the red circles are the bilateral infiltrates. So she had stage four disease, bilateral involvement of her lungs. And she was a person who'd never smoked. And one of the things that she went on the drug Giffittinib and had a near complete response for two and a half years. It eventually came back, but this was something we really hadn't seen with any of the other therapeutic agents. And the good thing was this was not terribly complicated in that the drug was aimed at the epidermal growth factor receptor. And the question came up is, is there anything going on in the receptor? And as it turns out, there was. And a few of us from Harvard Medical School, there was a group at Mass General and then a group from Dana-Farber and the Brigham, who ended up looking at these 13 patients and published it simultaneously in Science and the New England Journal, that 13 to 14 people who had had these responses to Giffittinib had a mutation in the tyrosine kinase domain of the epidermal growth factor receptor. And we published this and these two articles have been cited now 25,000 times. So this is something that people took note of. It was kind of interesting. It was kind of a simple concept that an agent directed against the receptor that had unusual activity. There must be something going on with the receptor. One of the things that really facilitated this at the time was that this was just at the time when you could begin to sequence receptors, sequence the DNA from paraffin-embedded tissues, which is one of the things that enabled us to be able to make this observation. And then we began applying it. And one of the other things that happens is that although the mutations were more frequent than people who'd never smoked and women and people in East Asia, you still had to do the test to be able to tell whether they did or did not have a mutation. And this shows the histology of two patients with adenocarcinoma. The one on your left is one that has an EGFR mutation, and the one on the right is one that has an ALKRE region. I'll talk about those next. There's no way you can tell that from taking a look at the morphology. I have to do the test. And so far, for the EGFR mutation, it's still done by assessing the sequence. With ALK, you can now do an immunohistochemical test. It's a little bit simpler, but that one's a chromosomal rearrangement, and I'll talk about that one a little bit later. One of the things that happened is that the first agents that were approved were erlotinib and gefitinib. Dr. Fox, can you see my pointer there? When this first entered trials, the progression-free survival with a doublet chemotherapy was about four to six months. In this group with EGFR mutations, which here in the United States runs at about 10 to 15 percent, this is the standard EGFR-TKI that we had available for us a decade or a decade and a half ago. As you can see, the progression-free survival is about 10 months. On your right, you can see the survival, and the survival is running at about 32 months. This is dramatically different than the eight months that I showed you before when you identify this prospectively. One of the things that's happened with the passage of time, and I'll give you another example when we get to ALK, is that there's an ongoing process of attempting to find more effective drugs. The sort of general paradigm is that you get the first drug that happens to work, you end up finding out drugs that are effective in the patients who have already progressed, and then you move it into the frontline agent. Osamartin was initially approved for previously treated patients that had the most common form of resistance, a T7-IDM. When you move it into the frontline, it increases it by 8.9 months, or almost doubling the length of time the drug works. This is what we've been able to do in these genomically defined subsets. You find a drug that works pretty well, and then once you define the mechanisms of resistance, you develop a drug that is more effective, and then it turns out it works a bit longer. Then with longer follow-up, two years later, they published the survival of this, and it shows that the patients who were treated with, as I mentioned before, the first-generation inhibitor, the gefitinib or lotinib, ended up being about 32 months, while it was about 39 months for the patients with osamartinib were about seven months longer. We hope to continue going through these paradigms. The other thing that happens is that all mutations are not the same. I'll make a comment about that with the exon 20 mutations, but in this particular one, it turns out it makes a difference about whether it's one of the two most common mutations. The two most common mutations are the ones that were described in that first article. One is a mutation that has a single amino acid change, an L858R mutation in the tyrosine kinase domain, and then there's an exon 19 deletion mutation that takes out four or more amino acids. It activates both, and you can make a drug that is more active against both. One of the things that happens, it turns out it makes a difference whether you have that exon 19 deletion or whether you have the L858R mutation. Not only do you need to know whether it's mutated or not, you need to know which specific mutation it is. Because when you take a look at this, the osamartinib compared to the standard, here in blue, when you take a look out at the 51, this is going out a good bit over three years in their survival. When you take a look at the comparator, the standard one, as we'd expect, this one's right at around 32 months that we would expect. With the L858R, you can see these things are virtually superimposed. The drug only works better in the exon 19 deletion mutants. Here, if you follow this out to about the 50 point, this thing is working for about two and a half years. One of the things that currently happens, and the research group I work with, is trying to come up with a better drug for the L858R mutants. Hopefully, you can see the same kind of prolongation with what we would think of then as a fourth generation inhibitor. The general paradigm is that you figure out these subsets. You figure out the mechanism resistance. You redesign the drugs. As an ever the optimist, we anticipate the drugs will get better and better. As they get more specific for the mutant form, they also carry fewer side effects. We had a lot of people that couldn't make it through on the first generation inhibitors because of skin rash and diarrhea, the principle. One of the things, because these drugs are relatively specific for the mutant form, we just don't see the frequency of skin rash and diarrhea. They're spared of most of the side effects. It turns out that this is effective in advanced disease. I showed you we started out with chemotherapy treated patients with median survivals of about 10 months. We're going out to about three years or more in the age of our mutants that are treated. What about if you put this in earlier stage disease? I know the title of this is taking a look at people with advanced disease, but it turns out it's becoming important in patients with earlier stage disease. The effect is even greater. One of the things that happened, and this is a study that took a look at patients with stages. The study was for 1B through 3s, but this subset is the stage 2s and 3s, who were studied for having one of the sensitized mutations of the epidermal growth factor receptor, the L858R mutation or the exon 19. They were given up to three years of adjuvant therapy. Now, there's two things about giving three years of adjuvant therapy. Number one is it's kind of long, but we've gotten used to it in breast cancer, where women will take five years of hormonal therapy. But the other important thing is the drug is designed so that people can tolerate taking it for three years. Now, the previous iteration of this, where the drug was less specific for the mutant form and had more effects on the normal, is you had problems with skin rash and diarrhea. There were a lot of dose reductions and a lot of the patients couldn't finish it. So here you can see, and this is something we don't see very often in cancer. The top one is the disease-free survival, taking a look at when the patients relapse. And as you can see, the median duration of the drug intervention trial is about 66 months, 65.8 months. And the placebo in this group is 22 months. So two Bs and threes are sort of early, but you can see this group of patients, the vast majority of them are going to relapse and die of their cancer. But this is a hazard ratio. It reduces the chances of it recurring by 77%, which is something we really, this really is unusual in cancer, in that you can cut down the chances of it recurring by 77%. They've not yet published their survival on this yet. This was an update that I pulled. It's from last month where they showed the update in these survival curves. The other thing about the generation inhibitors, and one of the things that we're seeing now, these patients are living years instead of months, is that you worry about whether they're going to get brain metastases. One of the things that's very difficult to treat in oncology, if it goes into the brain, it's for two reasons. One is you're limited on what you can and can't resect. And if you do resect it, it's difficult to get a complete resection. Obviously, you can't take margins and such. The second is making sure that drugs can get into the brain. A lot of, especially the chemotherapy drugs, never got into the brain very well. And with a lot of medicofiptin, they didn't get in that terribly well either. But one of the things, when they've taken a look at this, and take a look, this is the central nervous system disease-free survival. So 100% would mean that nobody is going to recur in the brain, and zero means everybody's going to recur. And as you can see here, the vast majority of people have not recurred in the brain. So the drug is both controlling the systemic disease, as well as preventing the recurrence in the brain, which is one area, as I mentioned before, that's particularly difficult to treat. And as you can see, this is a potential common site of relapse with up to a quarter of the patients developing brain mets by four years out, if they're on the older tyrosine kinase inhibitor. I'm sorry, if they're just observed. So here you can see you've cut it down by about 15%, which is a big help. So this was approved by the FDA three years. When the data was first released, this was a study that was stopped early because of the magnitude of benefit, and the patients were allowed to cross over to commercial drug supply on this. So some of the patients got put on the drug, and they're still seeing this vast difference in outcome. So we await the survival data, but certainly my patients who have stage 2 or 3A, I certainly want to put on the osimertinib. So it's very important to discover these not only in advanced disease, but also in earlier stage disease as well. Well, you know, the EGFR mutations were approved for doing it in 2013. From testing one a decade ago, there's now 10 or 11 different changes for which one should be tested for which there's FDA-approved indications. And, you know, I put osimertinib in here. There's quite a few others that are approved, but I haven't listed them all here because osimertinib is clearly the drug of choice for these patients. And you can see, as we go down here, V600Es, you know, this is approved in melanoma, and it was approved in 2017. MedEx and MedExon 14, it's got two different drugs approved, capmatinib and tapotinib. And as you can see, the response durations and the progression-free survivals are running, you know, typically, you know, between 10 and 11 months. MedExon 20, it's one that's not sensitive. That particular mutation is not sensitive to the drugs that I showed you, but it turns out they've developed two different drugs that work about 40% of the time. Now, granted, you know, this is about the same or about somewhere between the same to twice as active as what you'd see with conventional chemotherapy in these populations. And the Exon 20s, the duration of response, 10 to 14 months, and the progression-free survival of eight months. Trastuzumab directs a TCAN response rate of 58%, once again, in this area that's between 8 and 12 months. And probably most importantly, you know, BRAF runs at about 1% of lung cancer. Exon 14 is about, you know, 2 to 3. Exon 20 is relatively rare. ErbB2 is about 2 or 3%. KRAS G12C is about 12% of adenocarcinomas of the lung. So this one's pretty clear. And as you can see, the response rates are about 20%, duration of response 9 to 11, and seven months. So it's important to identify all these. You can't tell them apart by any clinical indications. All of these, with the exception of the KRAS G12C, are ones found more commonly in people who have never smoked. KRAS G12C is the one that's associated with smoking. And you'll also see BRAF B600E occurs in some of the people who have smoked in the past. And I'll mention why that's a bit important when we get to the immunotherapy section. I've talked about the different point mutations for which there's targeted therapies. I will go through these four different chromosomal rearrangements briefly and talk about them. And as I did in the previous one where I focused on EGFR, I'm going to focus on ALK or anaplastic lymphoma kinase. And I thought I'd show you one of my patients. This was kind of an interesting person. She was a lady who was in Germany and showed up with brain mets in the summer of 2011. And they resected the brain mets. She had a single set of mets. And they empirically started her on an EGFR regimen because she hadn't smoked. And the whole point of this is that you can't tell these on clinical characteristics. You've got to do the test. And it wasn't going well. She didn't respond to the EGFR inhibitor. They tried to give her chemo. And she was originally from the U.S. And she decided the best way to go see the doctor was to get on an airplane. So, she came here to the Boston area. She ended up finding out she had an ALK rearrangement. 2011 was about the time we were doing the trials for crizotinib for ALK. She got put on. This is her lesion here on the right side. And as I mentioned, she also had a brain met. And we put her on crizotinib for four years. And she progressed. And it was four years later. So, we'd come up with a new drug, electinib, which is the agent of choice for newly diagnosed patients. And she's still going in March of 2023. She's lived. Her kids were in junior high when all this started. And they've all finished grad school. They haven't gotten married yet. She doesn't have grandkids. She's gotten a decade out of it and still going pretty strong. And she lives a pretty normal life. So, this is, you know, and I showed you how well things work. This one so far is the one that is one where you see these very long and very sustained responses, particularly to the third generation inhibitors. And just to show you how this works, this was the study that showed that where they compared this third generation inhibitor, electinib, to the first drug that was active was crizotinib. And once again, here I put red. They were able to do this just on an immunohistochemical test, not having to do the genomic test. And put it on, and they put about 150 patients on each one. And the primary endpoint was progression-free survival. And these are the progression-free survival curves. Once again, you know, as expected, you get that sort of 11-month progression-free survival with the first generation inhibitor. And here we get a specific, a relatively specific inhibitor that's potent that was specifically developed against the ALKRA arrangement. It works for almost three years. And, you know, in our world where we started out with about three or four months, this is quite a change. And this is followed up five years after the trial started. And this is a survival. Now, about two-thirds of the patients crossed over. So, you don't see a huge difference. And these patients are doing pretty well. And this is one where the majority of people are living longer than five years. So, you know, I love to show this one because being a person who was around treating people where we had, you know, when I first got in the business, we were having between 2% and 5% of people alive at five years. And we didn't bother to run the survival curves out beyond three and a half years. This is quite a change in being able to do this. Now, granted, this is only 1% to 3%. But, you know, when you lump all these things together, we're getting, you know, somewhere around about 30% or 40% of the people are going to have one of these drivers for which you can give these targeted agents. And a good number of them have a rather substantial impact on the patient's outcome. And the part you don't see is that people can be on these treatments for years and function pretty normally. So, these are the rearrangements that I wanted to show you. The L to the Ntrek and RET. The thing about the chromosomal rearrangements is the tyrosine kinase domain remains intact. By and large, these are not agents that are terribly active normally. So, you can give relatively potent and specific inhibitors. So, as I showed you before, the progression-free survival of lectinib is about 35 months, close to three years. Ntrek is a rare one. It's less than a percent lung cancer. ALK is about 3% to 5%. And as you can see, the progression-free survivals are running between 11 and 28 months. And then RET, there's two different agents that are approved, as well as two agents for Ntrek. And the progression-free survival is running about a year and a half. So, this is pretty good. We await the mature survival. And as you can see, the response rates, if they have these rearrangements, run at about, on average, about 70%. The duration of response running at about two and a half years. And progression-free survival at about two years. So, when you find these things and you give them the drugs, they work pretty well. So, what about the other biomarker? PD-L1, it's Programmed Death Ligand 1. Some of the checkpoint neighbors, a class of the immunotherapy agents, call for having 1% or higher to be able to treat. And others, you don't have to test. It is actually somewhat of a confusing field because a lot of use different points. You know, as far as getting the test, you just have to order the test. The medical oncologist can sort out, you know, what that means and what the treatment indications are. But the thing I want to point out is PD-L1 greater than 50%. So, that represents about a quarter to a third of lung cancer. Now, one of the things about PD-L1, it's a little bit opposite the ones that I've already talked about. Most of these mutations or chromosomal rearrangements occur in patients who haven't smoked very much. PD-L1 tends to be higher in the cigarette smokers. So, there's some, it's getting me close to something for everyone. And when I see the patients in clinic, I tell them this is one time that, this is one of the few times where it's good to have smoked. Because if you're going to get immunotherapy, the more you smoke, the more likely the drugs are going to work. So, there's going to be, as I said before, there's going to be something for everyone. I'll show you some of what happens with the people based on that PD-L1 testing. Once again, it's about a third of patients who are going to have this value. And it's an immunohistochemical test. So, it's relatively simple to carry out. Now, I'll show you some stuff on the testing rates that show you, this one seems to be a lot, like the uptake on getting this test is a bit quicker than some of the other tests. So, once again, this is another one of my patients. The guy was, this gentleman was in his middle 80s when I first met him. He was on oxygen in the hospital. And I saw him, and this is what his CT scan looked like, because he had involvement of the right upper lobe, but extensive bilateral involvement. And he ended up getting up to 10 liters of oxygen to keep him going. And I gave him a single agent checkpoint inhibitor, and he had a complete response. And I took him off therapy after two years. That's something also I thought I'd never see. Now, about a third to a half of the people who get two years of therapy look like they have a complete response are going to recur. He recurred about nine or 10 months later. The first time I gave him a checkpoint inhibitor alone. The second time when he didn't respond, I gave him chemotherapy plus a checkpoint inhibitor. Now, interestingly, the chemotherapy we give now, at the time I started, he was 88, and he tolerated it fine. And I've had him on immunotherapy, and it looks like we're going to try to take him off the therapy in another few months to see how he does again. And when I saw him back this month, he still doesn't have any evidence of disease. And the interesting thing, he's got some problems with back pain and things, but you make it to be 90, something's going to give. So, not only does this work, but you can give it to people. We used to exclude people from the clinical trials who were older than 65. And now you can treat the treatments, people can tolerate this up into the 90s, which as I age is becoming more important. So, what does the trial show in this? And remember, I told you about two to 5% of people were alive at five years when we had the first rounds of doublet chemotherapy. So, this was the trial that showed this happened. And it was one of the checkpoint networks, Pembrolizumab versus chemotherapy, and those that had a PD-L1 of greater than 50%. And this is the survival curve. As you can see, it's a 40% reduction in the chances of death. And as they followed people, you can see here about 32% of the patients were alive at five years, as opposed to 16%. Now, it turns out, once again, about a half to two thirds of the people crossed over. So, not only is it important to get the immunotherapy, it's important to get it early in the treatment course, which means you need to have the testing to be able to identify these people. Now, one of the things that's sort of confusing for those of us medical oncologists, I have to keep this straight, is that different of the checkpoint inhibitors have different cut points for where you give this, and it's for drug approvals. But in truth, it's not a dichotomous variable, it's a linear variable. So, this is from my colleagues here at Dana-Farber, who took a look at the progression-free survival. And when people were treated with Pembrolizumab, who had PD-L1 values of greater than 50%, and they broke it down into two areas. One is those that had it between 50% to 89% versus 90% to 100%. 90% to 100% makes up about 10% to 20% of the patients. And here they've broken it, and the blue line is the patients who have 90% to 100%, which is roughly, it's a little bit less than half, and those that have between 50% to 89%. And as you can see, the hazard ratio of progression-free survival is 0.5, or you essentially double the progression-free survival in the patients who had the values between 90% to 100%. And when you take a look at survival, obviously it's not reached versus 16 months. So, rather than thinking about this as, you know, 50% or greater, and I use this, is that the higher the PD-L1 value, the more likely I am to give these patients a single agent checkpoint inhibitor. So, look, this is kind of the focus of this talk about biomarker testing for advanced lung cancer, and why it's important is that not everybody's getting it. So, I want to show you three different studies that have looked at this, and including some that I've worked on. So, the first thing I wanted, this is a little bit wordy, but you take a look at our, the thing that a lot of us go by, the short for this is NCCN, which more people may know this as, compared to the National Comprehensive Cancer Network. And one of the things that happened, I've shown you there's, you know, there's 12 different markers for which there's FDA-approved agents, and there's more coming all the time. And one of the things you don't want to have to do is go back and retest every time there's a new drug that's approved. So, and the guidelines that we use for the cancer evaluation and treatment is these NCCN guidelines, and they're pretty similar with a number of different professional societies, but it's recommended that when feasible, testing should be formed by a broad panel-based approach, most typically by a next-generation sequencing. And for patients in the testing who don't have an identifiable driver, you can consider these RNA-based NGS if it's not already being performed. For some of these chromosomal rearrangements, it's tough to do, and some of the commercial providers automatically go to an RNA-based NGS, which is a better way of detecting the chromosomal rearrangement. So, I showed you that chromosomal rearrangements, you know, some of the drugs work particularly well in there compared to the mutations, and that the broad molecular testing is defined as molecular testing that identifies all biomarkers. This is just the ones where there are all the FDA, and also the emerging biomarkers. So, what I was talking about is that, you know, I showed you, and I didn't show you the pace at which they're happening, but right now there's between one to two different genomic markers every year for which there's new agents that are approved. And so, as I said before, you don't want to have to go back and test, so you hope that the panels that the commercial providers, as well as maybe your own homegrown ones, have not only all the ones for which there's FDA-approved agents, but also the ones that are likely to emerge in the next several years that are going to have an impact on being able to select the therapies. So, what I want to show you is, this was one that was done in the U.S. oncology. So, they looked at the biomarker testing among the metastatic non-small cell lung cancers getting first-line treatment in the U.S. oncology network, and there were patients, non-small cell lung cancer patients, initiating first-line systemic treatment between April 1st of 2018 through March of 2020. Now, at the time, there were five biomarkers for which there are FDA-approved agents, and that's EGFR, ALK, ROS1, BRAF, and PD-L1. So, within the U.S. oncology network, they had 3,474 with advanced non-small cells, 74% adenocarcinoma lung. Most of them had a good ECOG performance status, so it was a group that was important to know this. 90% of them had at least one biomarker, but only 46% of them got all five biomarker tests that we were talking about, for which there were FDA-approved agents during the time frame that they examined them with a one-year lag. All of them improved for at least a year. And these are the rates. Now, the part that interests me here is that, you know, they're running at about typically in the 70s or 80s. The uptake of the PD-L1 is a bit higher in the 80s, but these three all had approved indications at the time they looked for eight years or longer. BRAF was approved in 2017, so it was a year before, and so the uptake is okay, I guess, but it's not incredibly high, at least as far as I'm concerned. Now, one of the things that happened, and Dr. Fox's boss and I worked on this, and that we did one that was similar to what was done with pulmonary physicians, and that is take a look at the biomarker-related testing and treatment practices for advanced non-spots on lung cancer, and it was done by surveys. The one I showed you before was actually taking a look at the patient records to show it was actually done. So, we sent a survey to 2,374 patients or physicians, nurse practitioners, and PAs who are members of ASCO. 49% or about half are lung cancer specialists. I was one of those. I filled it out, and so I knew what it was like. I didn't know for sure I was going to be working on it when I filled it out. It was available for several months, and 170,000, I'm sorry, 170 responses were seen, or 7%. So, I think one of the things this shows is ASCO physicians and healthcare providers aren't very good at filling out surveys, because these are all people that agreed to be contacted, and they're eligible for analysis, and the thing I wanted to show you here is a little bit different than the others, because it asks how long you're willing to wait. So, this is the average wait time for getting the biomarker testing, and eight of them, or 5%, wanted it within a week. The majority of them wanted it within two weeks. Not a few people were waiting to wait three or four weeks. Interestingly, the older a person was, the more likely they were willing to wait to get the results before embarking on treatment, and then the last one I want to show you is, you know, this one shows what happens with the passage of time. So, this is a flat iron EHR. They looked at 30,631 patients with advanced non-small cell lung cancer from 280 U.S. cancer clinics, and they identified patients between January of 2015 and July of 2021 who initiated treatment, and the records were examined for EGFR-RAS1, KRAS, BRAF, and PD-L1. KRAS didn't have an approved medication for it until two years ago, and BRAF was in 2016, so, but all the others were available by 2015. So, this takes a look at the uptake in these 30,000 patients with the passage of six years, and this is what it looks like. Now, the one that I'd like to point out is one that changed quite a bit, and that is, this one is the one for ELK. So, you can see this one, there wasn't much uptake, but by 2016, there was an indication that you had to have a PD-L1 of one percent or higher to get treated with a checkpoint inhibitor, and then that 50 percent came in. So, it looks like about 70 percent of the patients got it, and it doesn't change very much between 2017 to 21. The top one is EGFR, is any of the above, but the, and the others, the green one, EGFR, was the first one. It hasn't changed a great bit, and then when you take a look as these new ones are either being studied or indicated, it takes a long time for these to be uptaken. As you can see, the bottom line, where all of the above, only 40 percent of the patients get tested for all of them. So, I, you know, the thing I take from this is that we could do a good bit better. So, I've talked about, you know, all these different mutations for which there's agents, and the difference it makes in doing them. For the mutations, you know, you can expect a patient with EGFR mutant lung cancer to live about four years, and this is the first one where we've seen efficacy in the adjuvant setting. The chromosomal rearrangements, these, the drugs tend to work better in this, particularly the ELK is very mature now, and we're seeing effective agents that work for about three years. The PD-L1 testing, and it's something I thought I wouldn't see, and that is that there's a certain proportion of patients who appear to be cured of their non-small cell lung cancer. They're surviving free of cancer for over five years from the stop in the checkpoint inhibitor, and the testing rate still can be a bit better in the U.S., even in the oncology populations, and that we would hope that as new agents are introduced, that the testing rates for those specific genes increases, and that we also hope that we can get these results in sometimes, sometimes in two weeks or less for getting these all from our broad panel of tests. So with that, I'd like to thank you for the attention and open it up for questions. And please, everyone, please put your questions, there's a Q&A in the Zoom to put your questions. Thank you, Dr. Johnson, for that excellent talk. I wanted to reflect on a couple spots while we look through any questions we may get here. One of the big points I think was illustrated by some of the patients that you brought to this talk was that the toxicity seems to be much lower for some of these agents compared to that traditional chemotherapy. Can you speak to some of the toxicity that you may see compared to standard chemotherapy, and who may be eligible for these patients who may not be eligible for maybe traditional chemotherapy? Yeah, so, you know, one of the things that that happened is that up until about 15 years ago, we stopped the therapy after six courses of treatment. And about the median number of cycles that our patients could tolerate was three to four. So, and they, when they added Bevacizumab to the regimens, it was the first time in a trial that we ended up seeing that the majority of people got all six cycles of therapy. So it was tough to make it through those agents. And as a person, you know, the people looked like they were getting chemotherapy. You know, they had hair loss, nausea and vomiting, fatigue. Finally, when the drug Pemetrexid came out, one of the nucleoside analogs, that was the first drug that you could give for longer than the four to six cycles. And there was a maintenance therapy study where it made people live a bit longer. And the median number you could give in that setting, you know, was somewhere around 10 to 16 doses. So the median went up a bit. But other than that, the standards, you know, the tax scenes that they still use in breast cancer, people have a tough time taking those for a long period of time. As I mentioned to you before, you know, granted, these targeted agents, particularly the first generation ones, will have quite a bit of toxicity. So when we first used Gifidin and Verlotinib, there were serious problems with skin rash and diarrhea, prompting a lot of dose reductions. And we used to have a special group that helped manage the skin side effects. And you got this bad acne form rash on your shoulders and face. People could tell you're getting treated. And the drug Osimertinib, they ended up engineering it so it was more preferential against, preferentially active in the mutant form, and it spared the skin, and so it was less. There's the others, you know, and Electinib is pretty easy. Interestingly, it affects the light, dark adaptation on this, and it also causes a bit of GI distress. There's some, like, for instance, Sulfurcatinib, the one for Rett rearrangements, it can cause hypertension, it causes hypertension and diarrhea, and, you know, you end up having to manage hypertension. But frankly, I'd rather manage the hypertension than the nausea, vomiting, diarrhea, and hair loss. So, and the one thing that does happen is that these have enough side effects, they'll keep the oncologists in business because nobody wants to try to remember all the side effects and how you manage these things. So, and, you know, the other thing that happens is, you know, you don't see these people all the time. I got my second person with a Rett rearrangement that I'm getting ready to start on treatment. You don't see them every day. And it took a while to figure out that they get hypertension that you have to manage through this. Yeah, that's incredibly interesting and insightful. One of the other things that came up that I thought was really interesting was the focus on biomarker testing for patients who have smoked. That's always been a kind of a controversial topic for the last 10 to 15 years of the importance of biomarker testing for those who've smoked. And I think that the cases you brought, especially with perhaps that patient who got immunotherapy who had the exceedingly high PD-L1 score was, I think, incredibly insightful and hopefully a really good illustration for that concept. The one thing that does happen, as I mentioned before, you know, these EGFR mutations and Alkary rearrangements, you know, they tend to be more common. That said, they are found in people who smoke. And you can't, so that like all of our, all the professional societies who have weighed in, have said you shouldn't use clinical characteristics for deciding on biomarker testing. It's just that they're less frequent, but the people who have these, have these genomic changes that can occur in almost anybody. And, you know, we find these in people who have smoked in the past. But also, as you correctly mentioned, you know, you want to know the PD-L1 values. It turns out that, you know, both things are true. Number one is that the people who haven't smoked very much, who have these targeted therapies that can get the, typically they're getting pills instead of chemo that work quite a bit longer. But also in here, this group, and because they typically haven't smoked for much, the immunotherapy doesn't work very well. So, you really have to have the test for two reasons. One is so they get the targeted therapy. But the second is you don't want to put them on the immunotherapy because they don't work. So, for instance, you know, with this Rett rearrangement, I had to get the guy, a guy I put on study. It only worked for about six months and he had to get irradiated. So, it didn't work for him. And I put him on immunotherapy and he ended up having a complete response. I took him off and he recurred after seven months. I want to put him back on the Rett inhibitor because I'm worried that the immunotherapy is not going to work as well in this setting. So, please don't use the clinical characteristics because there is a subset of people where these will work, even in the smoking folks. And I think even the decision making that you just illustrated for us with that last patient really speaks to how important it is at the time of diagnosis to really make sure that these biomarkers are being assessed for. Because myself, you know, I participate in our multi-disciplinary tumor board weekly. And this is, I mean, this is the topic for every patient with non-small cell lung cancer is what are their biomarkers? What were the, what was the pattern that we saw and what has been their response to therapy? It really weighs in the decision-making, it seems like. Now, I mean, just this week, I had a guy who, he ended up getting a relatively small biopsy. They sent it off to a commercial provider and there wasn't enough to do the testing. And so then they told, you know, we got the message that they're having to recut the bronchoscopic biopsies to try to get enough to do the genomic testing. I was worried that we would not be able to find out what he had. So I repeated a percutaneous biopsy on him to make sure we had enough adequate amounts of tumor tissue to do the testing. And then I was lining him up to, he had smoked in the past and he had a pretty good PD-L1 value. So I was lining him up to get a novel immunotherapy regimen. And then after I was near done with the screening, the testing came back, they had a RET rearrangement. So, and knowing that the RET rearrangement, say we only got a 6% response rate to the immunotherapy, so I switched him over to the targeted therapy cohort instead of the immunotherapy. And there's also, there's also some evidence about getting both increasing likelihood of complications such as pneumonitis and things like that. Is that correct? So I see there's a question in the chat about what's the likelihood of pulmonary fibrosis. So almost all the agents that we have cause pulmonary fibrosis. You know, the one thing that happens because we image, you know, typically for people on the targeted therapies, we image them every couple of months. So even people with people who are asymptomatic will end up seeing if they're developing interstitial infiltrates. And they're pretty characteristic. And, you know, the ones that, you know, the targeted therapies, you know, for instance, Kefenton and Asimertinib, you know, they run, you know, interstitial lung disease ran at a rate of about 1% to 2% in the U.S. and 3% to 5% in patients who are of Asian descent. And it held up the adjuvant therapy studies for a long time. With Asimertinib, there's less of it. And so it was able to be put into the adjuvant treatment. But, and the part about those is that it's pretty easy to treat. You just drop the drug and then put them on steroids. The one that's tougher to treat is the pulmonary fibrosis or the interstitial infiltrates you get from the checkpoint inhibitors. They tend to go on much longer than the radiation, the pneumonitis that we see with combined modality. And, you know, you typically have to treat them for months. I have a lady right now that's coming off of having gotten, having gotten the bilateral infiltrates associated with the checkpoint inhibitor. And I've just got her tapered off after about a month and a half of it and she's doing okay. So, so these are something we commonly see. The one thing I always do, and anybody that gets, gets pneumonitis associated with the tox is I have them see one of my pulmonary colleagues to help in case they need to be biopsied. To follow up on the second part of that other question about early stage disease, the role for these therapies, you know, that it seems like there's evidence for EGFR and for immunotherapy in early stage and resectable lung cancer. Do you see the roles for these other targeted therapies expanding into early stage as well? Well, I mean, they're, they're, they're started now. I mean, the elk, the one thing is these are really in the rare ones, you know, elk's one to 3% and the rare ones, they're pretty tough to get enough patients to be able to answer the questions. So now the one thing is about, about looking at drugs and earlier stage disease, you know, there's drug approvals for, with, with atezolizumab in the, as well as pembrolizumab in the adjuvant setting, not in 1As, but typically start at 1Bs at the current time for it. So, you know, the, so there's approvals both for EGFR inhibitors, as well as for checkpoint inhibitors in early, at 1Bs and higher. The other question that came through about thoughts of single agent immunotherapy of PDL negatives who don't have any actual mutations. We don't, it's, it's kind of interesting. Pembrolizumab, Merck, who makes pembrolizumab, stacked the deck a little bit and got rid of the bottom third of the patients with the PDL1 of zero and did them on 1%. And there's approvals for atezolizumab with 1% or higher. And, and, and it took fewer patients due to the trials. Bristol-Myers-Squibb that makes nivolumab always wanted to get a broad indication. And so they included people with PDL1 negative. In general, you know, as far as a single agent immunotherapy, we don't give, most of our patients get chemotherapy plus immunotherapy based on the trials. They do a bit, they do a bit better in that setting. The, the, the only people I give, for me personally, the only people I give single agent immunotherapy to are the people who have typically have very high levels and have some sort of medical contraindication where I'm not real enthusiastic about giving the chemotherapy. If I think they can tolerate the chemotherapy and immunotherapy, I'm more likely to treat them with, with it. I think that's all the questions we've had. We're, we're rounding up to about four o'clock here. So I'd certainly want to thank Dr. Johnson for a really great talk. Really, really took, took a lot of the main points around biomarker testing and really some great illustrative points around some of these patients who can gain a lot of benefit. I'd like to thank CHEST and the, and the organizers from CHEST for helping us put this together. And we do have two more webinars in the series, one on tissue acquisition and also one on multidisciplinary coordination and issues related to pathology. So we'll be looking forward to those in the next month here. Thanks everyone. And have a good evening. Thank you, Dr. Fox. And my thanks to the audience and the folks who posed the questions.

biomarker testing

advanced lung cancer

targeted therapies

EGFR

ALK

ROS1

BRAF

PD-L1

patient outcomes