Insight Molecular Diagnostics Inc. (IMDX) Earnings Call Transcript & Summary

Hello, and welcome to today's webinar. My name is Sara Riordan. I'm a genetic counselor and the Director of Medical Education at OncoCyte. We are very fortunate today to be joined by leading lung cancer experts to discuss biomarker testing in early-stage non-small cell lung cancer. This webinar is being recorded, and we'll make the recording available after the webinar. First, I'd like to introduce our fantastic panel of speakers. First, we have Dr. David Gandara, Professor of Medicine Emeritus at the University of California Davis. Dr. Gandara is a world renown medical oncologist and recognized thought leader in lung cancer and has authored over 700 articles, book chapters, abstracts and editorials. He is a past President of the IASLC and a prior Board member of ASCO. His research interest focus on developmental therapeutics of new anticancer agents as well as preclinical modeling and clinical research in lung cancer. He is the principal investigator on an early therapeutics award from the National Cancer Institute, where he leads an interdisciplinary team of clinical oncologists, pharmacologists, molecular biologists and statisticians in developing new anticancer agents in a variety of novel drug classes. He also leads a multi-specialty team in the Southwest Oncology Group, an NCI-funded national clinical research organization. Dr. Gandara received his MD from the University of Texas at Galveston and his BA from the University of Texas at Austin. We also have Dr. Johannes Kratz, who is a thoracic surgeon, who directs UCSF's program for advanced minimally invasive and robotic thoracic surgery. Dr. Kratz earned his medical degree at Harvard Medical School. He completed a general surgery residency at Massachusetts General Hospital, followed by a fellowship in cardiothoracic surgery at UCSF. He also has a master's degree in philosophy from Stanford University. Dr. Kratz is a member of the American College of Surgeons, Society of Thoracic Surgeons, Massachusetts Medical Society and American Society of Clinical Oncology. In 2017, he received a UCSF health exceptional physician award. He's the Van Auken Endowed Chair in thoracic oncology at UCSF. Dr. Kratz' research interests include robotic surgery outcomes, lung and esophageal cancers, biomarkers to personalize lung cancer treatment and immunotherapies for thoracic tumors. His current research focuses on understanding the molecular and genetic profiles of high-risk tumors in early stages and developing targeted therapies to treat them. Our third speaker, Padma Sundar, is the Senior Vice President of Commercial at OncoCyte. Ms. Sundar has extensive experience in launching oncology test for global diagnostics companies, including leadership roles at CellMax Life, Guardant Health, Roche Sequencing and Affymetrix. Ms. Sundar received her MBA and her MPH from the University of California Berkeley and her BA in chemistry from the University of Delhi. [Operator Instructions] Welcome to those of you just joining us. We'll begin today with Dr. Gandara, who will be presenting adjuvant and neoadjuvant therapy for early-stage non-small cell lung cancer, the need for predictive biomarkers to personalize therapy. Dr. Gandara take it away.

Okay. Thank you, Sara. I assume you can hear me okay?

Yes, we can.

Okay. Well thanks to all for joining. These are very difficult times for everyone. And I know that there are many, many virtual WebEx and meetings occurring all the time, so I appreciate you joining for what I think will be a very interesting set of presentations for you. And it will be different from a lot of the things that you hear because the focus here, as you can see from my title slide, is on early-stage non-small cell lung cancer, not advanced stage. I'll address what's an unmet need in adjuvant and neoadjuvant therapy for predictive biomarkers so that we can personalize therapy. Can you advance, Sara? And these are my disclosures. I am a consultant for OncoCyte. Next slide. Shown here is the paradox that we have many advances in recent years in advanced stage non-small cell lung cancer toward personalized medicine. The identification now of 8 or 9 oncogene targets, which all need to be tested for. So that's quite daunting because of biomarker-driven targeted therapies and now checkpoint immunotherapy being used in many situations in advanced non-small cell lung cancer in various combinations or as monotherapy. And how do we assess for that? Is it PD-L1? The FDA in the United States last month approved tumor mutational burden, or TMB, and a pan-tumor manner for pembrolizumab. But if you can see for early-stage non-small lung cancer, recent advances have been modest at best. We are continuing to give adjuvant platinum-based chemotherapy based on TMN stage as we have done for over 20 years. So this is just a -- I'm sorry, if you can go back. It's shown here to highlight that the greatest unmet need in personalized therapy in non-small cell lung cancer is actually in early-stage disease after surgery. We know that oncogene targeted therapies are highly effective in stage 4, but they have not improved survival in early-stage, or in some studies have actually caused harm, with the exception of the recent data on the trial called ADAURA, and I'll address that in a few minutes. In a similar fashion, checkpoint immunotherapy is being tested as adjuvant or neoadjuvant therapy but is not proven today. Next slide. This is a slide I put together a little while back about how we transition from empiric therapy to personalized therapy. And by and large, this requires tumor molecular, and now immune profiling, to identify predictive biomarkers. Advance. Almost all of this pertains to stage 4 disease. Next slide. This is from a publication that I coauthored together with Mary Redmond, who is the lead statistician at SWOG and our lung map master protocol, which some of you are available -- or are familiar with. And it shows again a paradox between the clinical application of predictive biomarkers and the potential for cure. So obviously, the potential for cure or long-term survival is greatest in early-stage disease, like stage 1. But the lowest clinical application in predictive biomarkers is in early stage. So we need a lot of work here. This is an unmet need. Next slide. This -- and I won't go through it in detail, but it is a time line since 2003 to present for adjuvant therapy postoperative in non-small cell lung cancer early stage. This is just the Phase III trials. And if you can -- Sara, just advance slowly -- these trials are primarily based on cisplatin-based therapy, the CALGB trial, the only one that used carboplatin approved in the long run to not be still positive for overall survival. We have had several attempts at targeted therapies. As you can see from the slides here, including EGFR-TKIs, bevacizumab, using an approach toward BRCA-mutated cancers. And then I show one that's kind of in an odd color here, the adjuvant trial from China, from Yi-Long Wu. Because although it met its primary point of disease-free survival, we'll come back to what was just reported at ASCO last month, and that is failure to achieve overall survival. None of this shows the ADAURA data because that is the new elephant in the room. Next slide. And if you can advance, there you go. So these are the NCCN guidelines. And as you can see, even for Stage 1a peripheral tumor, no lymphadenopathy. You can see in the red box there that NCCN still says, well wait a minute, see adjuvant treatment, even for these very early stage patients. Next slide. And as you can see here, it is because of recognition that despite this being the earliest stage of lung cancer that there is, not everyone does well. And in fact, in many series, a surprisingly high proportion of patients relapse and subsequently die of metastatic disease. So NCCN defines what they call high-risk categories for Stage 1 post an R0 complete resection. And you can see they are shown here. So these are these high-risk patients where it suggests consider chemotherapy. And the problem with these risk factors, which I'm sure many of you know about and you may use them in your tumor boards to decide who in Stage 1 should get adjuvant chemotherapy, these are all prognostic. That means the patient is likely to do worse compared to other patients within that stage. They are not predictive of benefit from chemotherapy. So this is a real issue. And in fact, in our tumor Board at UC Davis, our thoracic tumor Board, we really don't use much of this to decide who should get adjuvant chemotherapy. A patient getting wedge resection doesn't necessarily mean that, that patient needs adjuvant chemotherapy. A patient with unknown lymph node status means that there wasn't standard of care lymph node sampling done, for example. Next slide. And this discrepancy about benefit of adjuvant chemotherapy in various stages is shown in this very nice slide that I got from Dr. Escalante. This shows some of the major adjuvant trials. And in red, it means the trial was negative in that stage. In green, it was positive; and gray means not tested. So you can see, in the 2 trials that included Stage 1a and in the trials that included 1b, they did not show any benefit in survival in any of those studies. Now you can see the CALGB trial is kind of a purplish or mauve color. That means, initially, it was reported to be positive and subsequently lost that survival benefit. So you can see the survival benefit is really in Stage 2 and 3. Next slide, and next slide. Metanalyses, and there are several of them, have shown this quite clearly. As you can see from the hazard ratios here, Stage 2, Stage 3, clearly benefits patients in terms of survival. If you put all the studies together, you can see for Stage 1b that it's really equivocal. And for Stage 1a, even a suggestion that there could be harm. Next slide, and next slide. And neoadjuvant therapy doesn't fare any better. This is a nice comparison metanalysis of neoadjuvant, in other words, prior to surgery versus adjuvant after surgery. And as you can see, the data are very similar between neoadjuvant and adjuvant trials, and you can see the hazard ratios are identical. So we do have some modest benefit here, but the issues are, who are we benefiting? Next slide. So shown here is an algorithm by which we could look at who benefits from adjuvant therapy and which are the prognostic factors versus predictive factors. And you can see this has 3 categories that has patients with residual micrometastasis who are resistant to adjuvant therapy. It has a large proportion of patients who are actually already cured with surgery alone. And if you can advance, it is this group in the middle when we use therapy empirically. These are the patients who benefit from therapy and potentially are cured by the use of adjuvant chemotherapy. Next slide -- or I'm sorry, just advance. The group below, here's where prognostic biomarkers could help us; and the group above, predictive biomarkers. How can we increase that group in the middle who are benefited by adjuvant chemotherapy? Next slide. And I'll just show you an example of the dilemma that we all face in our clinics. This is a patient with about a 4 centimeter -- you can see it's 4.1 centimeter mass in the right upper lobe. It's an adenocarcinoma. There is no evidence of distant metastasis. The patient has a vast right upper lobe lobectomy with mediastinal bisection, and the tumor is about the same size pathologically. All the lymph node sampling, hilar and mediastinal is negative. This patient is Stage 1b by the seventh staging system, which is actually derived, some of you know, from the ISLC, for which I'm past president. So I'm very proud that we lead this staging effort time after time. But this patient, if you can just click once, this very same patient is Stage 2a by the eighth system. And if you go back to the time when all the adjuvant trials were done, this patient goes back to Stage 2b, I mean, to 1b. So when I presented this case in a blinded fashion to oncologist medical meetings, and we have audience response where you vote: would you give adjuvant chemotherapy or not. If I show this patient as a Stage 1b, then over half the audience says, "No, I wouldn't treat this patient." But if I present the patient as Stage 2a by the eighth system, then the overwhelming majority say, "Yes, this patient deserves adjuvant chemotherapy." The reason I emphasize this is it's the same patient. And we are influenced by the fact that staging, and it's appropriate, that the bigger the T, the worst the prognosis, but not necessarily the benefit from chemotherapy. Next slide. And this just shows how the staging evolution occurs. You can see stage T2b in the eighth system translates to -- and if you can click, Stage 2a in the eighth system. And then click again. And as you can see in the ISLC analysis of a -- over 100,000 cases, you can see the 5-year survival for this sort of patient, 60%. So obviously, lots of patients relapse. And next slide. Well here are the modalities we have in advanced stage disease. We have chemotherapy. We have targeted agents. We have immunotherapy. So the questions for early-stage disease are, are there new predictive biomarkers for chemotherapy, what are the trials? For targeted therapies, the same thing. And again, here, I will discuss ADAURA, which just occurred. And for immunotherapy, all ongoing trials. Next slide. Well in the next presentation, you will hear about a new predictive biomarker developed by my colleagues at the University of California for San Francisco for molecular profiling to define who's at highest risk at the earliest stage, and do they benefit from adjuvant chemotherapy. And this is just one of the publications to come out of this group by Dr. Kratz. And the next publication will tell you all about this. But this is a test, for the first time, I think, ever, which has potential to show us how we should manage these early-stage patients. Next slide. Well moving out of chemotherapy then to what else is happening in terms of adjuvant therapy. This is the NCI Alchemist master protocol. It aims to do genomic sequencing on 6,000 to 8,000 patients total. It's been in existence for a little over 5 years. And you can see it uses the seventh system, so Stage 1b, greater than 4 centimeters, and Stage 2 and Stage 3 completely resected. And in those patients with an EGFR mutation detected, they can be randomized to erlotinib or placebo for 2 years. The same thing for ALK, randomization to crizotinib or placebo. And then initially, without a molecular alteration, the patients were followed. But subsequently, a nonmatched trial called ANVIL was added, Phase III of nivolumab versus placebo for 1 year after all other adjuvant therapy since any of these patients could receive chemotherapy as well. Well we don't have the results from any of these trials yet, but this is what's ongoing with International Cancer Institute. Okay. Well here is the elephant in the room, as I called it. This is a press release, which occurred a couple of months ago saying that the ADAURA Phase III trial and surgically resected early-stage disease of adjuvant osimertinib versus placebo was closed early because it had achieved a high bar in terms of benefit. This was by press release. And so for a month, there was considerable debate. What did this mean? Next slide. So we heard the details at ASCO in the plenary session in this presentation from Roy Herbst. These are the details of the ADAURA adjuvant trial. All of the patients had EGFR-mutated disease. One of the 2 major types of EGFR mutation either exon 19 deletion or L858R, they had complete surgical resection. They could give chemotherapy adjuvantly at the investigator's discretion because, remember, this had some patients as 1b by the seventh system for this study. And then they were randomized to osimertinib or placebo. And the primary endpoint was disease-free survival. Very importantly, the duration of therapy here was 3 years, where all the previous trials, it's only been 2 years. And this trial was closed early by the Data Safety Monitoring Committee because the magnitude of benefit for disease-free survival was so great. So this is an early presentation of the data and, of course, it doesn't have as many patients as originally projected because it was closed early for ethical reasons. I think most of you in this audience have seen these data. On the left, you see the disease-free survival in Stage 2 and 3a because that was the primary end point, it was DFS in Stage 2 and 3a. I'll come back to Stage 1 and show you those data in a moment. You can see it is quite impressive. You can see the hazard ratio, something we rarely see in oncology, 0.17. And you can see at 36 months the great discrepancy in disease-free survival, but you can also see the maturity is low. And in fact, a lot of the patients are still receiving osimertinib who run that arm of the study. On the right, you can see that osimertinib benefited patients in every one of these categories, including the type of EGFR mutation, the stage, though you can see the least benefit was in Stage 1b, the hazard ratio still is 0.5, and whether or not they received adjuvant therapy. Next slide. Shown here, again, is the fact that the greatest improvement in disease-free survival was for Stage 2 and especially Stage 3a. But there was benefit, as I mentioned, for Stage 1b as well. Next slide. Well what about survival? And I probably would not have shown this slide, and the reason is it is so immature that it really doesn't help us. This is overall survival in Stage 2 and 3a. It is very immature. You can see there is some separation of the curves but really nothing we can take away. So this, I think, in my opinion, and this is highly controversial around the world, ADAURA met its primary end point, and I believe that it will be approved by the FDA, this regimen, and that it will be used. It is unique in giving the EGFR-TKI for 3 years. Not everyone got adjuvant chemotherapy, but that's based on stage. So although some people could criticize it for that, I think that's the only way to have done this study. Next slide. Well if you only knew about ADAURA, then maybe your mind would be made up one way or the other. But at the same ASCO meeting, we had an update on this important study. It's called adjuvant from Yi-long Wu in China. This is a different design. This is a trial that randomized surgically resected patients to gefitinib or to platinum-based adjuvant therapy after surgical resection. So it's one or the other. All the patients have the same common EGFR mutations. This shows that the majority of patients in this trial had Stage 3a disease. So this is in a more advanced stage population than the previous trial. Next slide. On the right, you can see the disease-free survival still remained positive, although you can see at the end of the curve, it seems to come back together and shown as the comparison with the hazard ratio of ADAURA for the same event. So disease-free survival, there's a loss of benefit about a year after stopping the adjuvant therapy. Remember, it was given for 2 years; ADAURA, for 3. And you can see, disappointingly, no improvement in overall survival. So of course, the question is, what will happen with ADAURA longer follow-up. Will it translate to improved overall survival or not? And is that important? And there's, again, controversy, debate about this. Next slide. What's going on in the adjuvant space for checkpoint immunotherapy? There are multiple trials. This shows some, but not all, of the Phase III trials. As you can see, they typically will randomize to a checkpoint inhibitor versus placebo. Patients cannot received adjuvant chemotherapy. You can see it says as indicated, so same design as ADAURA. You can see different drugs. You can see the end points for primarily disease-free survival in the NCI trial called ANVIL. You can see their co-primary end point with overall survival. We have data on none of these studies yet. So in my opinion, adjuvant checkpoint immunotherapy remains investigational. Next slide. Neoadjuvant therapy. There's certainly biologic rationale for giving treatment before surgery to see if we can modify the course of the disease. This publication in the New England Journal, now 2 years ago, raised a lot of excitement because a patient has got 2 doses of a checkpoint inhibitor, nivolumab, prior to surgical resection. And then they had surgical resection, and the authors were able to look at the pathologic response. The first thing, as you can see in this diagram, these images, is that there was a poor correlation of radiographic response and major pathologic response. A major pathologic response, that is, reduction of the tumor, viable tumor cells, to less than 10% occurred in almost half the patients, whereas only 2 patients, 10%, had a radiographic response prior to surgery. So this showed us that even a brief exposure, 2 doses of an inhibitor, can induce major biologic effects. Next slide. But as commonly happens, when other studies try to duplicate these results, the results were not so optimistic. These are 2 of those trials, LCMC3 and NEOSTAR. You can see that the major pathologic response was very low by comparison. And in the LCMC3 trial, patients were also subtracted out of the denominator if they didn't make it to surgery. You can see the resist response was also low. And you can see a proportion of patients from 10% to 20% were actually lost to surgery, probably lost their chance at surgical cure. So this gives us pause. Again, my opinion, this remains investigational. Next slide. Now some would argue that if you give a neoadjuvant checkpoint inhibitor together with chemotherapy, it's better. And these data suggest that, that is so. This is one of several studies using this combination approach in a neoadjuvant fashion. This is primarily, again, Stage 3a disease. It is a very small study. You can see the number of patients is only 30. Nevertheless, there's a high major pathologic response and complete response rate and radiographic response. Does that mean we should be doing this outside of the clinical trial? In my opinion, no. Next slide. There are definitive studies being done in this space, and this is one of those. This is the EMPOWER 030 trial that we are participating in, and I helped develop. And you can see, in this case, this is a randomization, as per the previous study, to either include checkpoint immunotherapy, in this case, it's [ palivizumab ], together with platinum chemotherapy, or just get the platinum chemotherapy preoperatively. The primary end points, co-end points, are major pathologic response and event-free survival, basically, disease-free survival. So this is the sort of trial, again, that could help make neoadjuvant therapy with a checkpoint inhibitor standard of care if it is positive. Next slide. So in summary, adjuvant cisplatin-based chemotherapy remains the standard of care in Stage 2 and 3a. Whether it should be given in Stage 1 disease is controversial. You'll hear more about this in the next presentation. New predictive biomarker panels for chemotherapy, and here, I refer to the assay developed at UCSF that you will hear about, have shown preliminary predictive value and are under Phase III study. Otherwise, everything else in my mind that you see here is investigational. #7, better methods to detect micrometastasis, such as circulating tumor DNA or under development. And if there are questions about this, we can talk about this in the Q&A session at the end. So thank you very much.

Thank you very much, Dr. Gandara, for that wonderful presentation. I'll now be handing it over to Dr. Kratz, who will be presenting the importance of accurately assessing recurrence risk in early-stage lung cancer and the data behind the DetermaRx test. Dr. Kratz, go ahead.

Thank you so much, Sara. I appreciate it. So if you could advance a slide. First of all, thank you so much to Dr. Gandara, for that excellent -- setting the stage. I think you really get a sense of the difficulties we face in how we treat our early-stage patients. And I'm going to talk, as he alluded to, a little bit about the asset that was developed to help meet some of these challenges. I am a consultant, as is Dr. Gandara, for OncoCyte. And then Razor Genomics was the original company that was started that commercialized the assay in a CLIA laboratory. Next slide, please. So you heard a lot about sort of a global overview of what's happening to patients and how we're treating patients as a group. And I'd actually like to start at the opposite end of the spectrum because the stage has already been set by Dr. Gandara. And I'll talk about a patient that I treated. And this patient is representative of this very problem that we face that he so aptly described. So this is Mrs. Elle. She's 53-year-old lady. She presented to me with cough and elevated CEA of 15.7, and she was actually undergoing sort of a general health exam in Asia. And as part of that health exam, they did screen her blood, found that elevated CEA level. And with the cough, they were worried. And so they did a full-body CT on her. And they didn't find anything in her colon, but they did find a 3-centimeter left upper lobe mass, which you can see on the CT scan here on the right of your screen. This was in 2017. She was otherwise fairly healthy. She was never a smoker, as you can see. And she underwent, what most people would consider, the gold standard treatment of early-stage lung cancer. That included a surgical mediastinoscopy, which interrogated her lymph nodes. Those were all negative inter-mediastinal. And then shortly thereafter, I performed a robotic left upper lobectomy with a full mediastinal lymph node dissection, again, gold standard care for early-stage lung cancer. She turned out to have a 3.2-centimeter lung adenocarcinoma, no NCCN high-risk features, which have already been described by Dr. Gandara, and no positive lymph nodes. So many levels were interrogated. They were all negative. And so her ultimate-stage biopathology was T2aN0, or Stage 1b non-small cell lung cancer. Next slide, please. Now unfortunately, you know how this story goes for more patients than we'd like to admit. She returned to Asia. And then 6 months later, this was her interval CT scan. And unfortunately, as you can see on this slide, she did have a another recurrence that was seen in her mediastinum. So she was an example of treatment failure despite sort of gold standard workup, gold standard treatments for early-stage lung cancer. Next slide. And this is really the problem that we face. So we hear a lot about lung cancer in general, but if we focus on non-squamous non-small cell lung cancer, there's over 40,000 patients annually who are diagnosed in the U.S. Now although, as a surgeon, I like to think that I offer them the best chance to cure, unfortunately, I see that 30% to 50% of the time, these patients who are treated then go on to recur after surgery despite their diagnosis of "early stage disease". And this current recurrence we really think is a big problem because it's due to hidden or occult metastasis. And so by definition, those metastases that are present at the time of surgery, but neither me or anybody else knows about them at the time we decided to take these patients to surgery. And so far, we have not found better modalities, until now, to detect the presence of micrometastasis in these patients prior to surgery. Next slide, please. Now her story is not an uncommon one. Unfortunately, both the timing that she recurred and also the location that she recurred was fairly common. So if you look at this study that looks at when patients recur, she recurred at about 6 months, and that is the peak recurrence, on the left, for patients that recur after surgical resection with non-small cell lung cancer. Also in terms of location, this graph basically divides things up between new primary, which is rare, but does happen; local recurrence, which is really around the surgical staple line or within the same lobe; and then distant recurrence, which includes regional in this study, recurrence, so that would be her lymph nodes, her mediastinal lymph nodes, which is what Ms. Elle unfortunately experienced or just a metastasis, which is elsewhere extrathoracic. So putting these things together -- again, this is more evidence that supports that idea that when patients recur after surgery, it's not because we left some disease behind or the margins were positive or we're not taking out lobes. It's really reinforcing the idea that, unfortunately, these patients already have undetectable micrometastasis at the time of surgery, which then later blossom 6 months later typically and blossom away from your surgical side of resection. Next slide, please. Now Dr. Gandara already sort of alluded to this data, but just as a reminder, there were a lot of trials to basically determine whether adjuvant therapy for these patients who are Stage 1 and early-stage patients is a benefit. And particularly in Stage 1 patients, if we focus on that, we don't have evidence that adjuvant therapy benefits those patients. In the very earliest stages, actually, we have evidence that chemotherapy in the adjuvant setting may, in fact, be harmful to this patient population. So again, this is the best risk stratification that we had up to this point. We could just loop -- I mean, excuse me, group all of these patients who had Stage 1 disease, for example, together. Know that a large percentage of those patients recurred despite being Stage 1 patients and also know that giving adjuvant chemotherapy to everybody didn't help in this setting. Next slide, please. So again, there's something unique happening in lung cancer here that's not happening in other solid tumors, right? A large percentage of even the earliest stage patients are recurring, and adjuvant chemotherapy doesn't help in those settings. And that's why you already heard about these NCCN criteria that exist to try to pick out just by group and expert consensus, okay, what are those risk factors that might show a different prognostic category for these patients despite us cramming them into these preexisting categories of Stage 1a by size and lymph node status Stage 1b, et cetera. There needs to be better risk stratification, right? And the NCCN has realized this for years and years. And the best that they've been able to come up with is that just group consensus. So what sort of makes sense, although there's very little evidence that these are true prognostic factors and even weaker evidence actually that -- or no evidence, as Dr. Gandara would say actually, that these are predictive biomarkers where giving these patients adjuvant chemotherapy would improve their outcomes. Yet, they're still commonly discussed. They are sort of guidelines that everybody uses and follows. Although in the real-world setting, I do have to agree with Dr. Gandara, that our tumor Board really doesn't pay a lot of weight to these "high-risk features" for these patients because a lot of them truly are not helpful. Again, wedge resection, really not in this era; an unknown lymph node status, I think we can probably do better than that. And we should be able to have a little bit more sophisticated view about the biology of the tumor and whether that is really, truly a prognostic factor for recurrence and whether adjuvant chemotherapy would help that kind of patients. Next slide, please. So all of this that we've been discussing with Dr. Gandara, again, so aptly laid out, and what I've been talking about really cries for the need for better risk stratification, right? So the current staging system that we have in lung cancer, unfortunately, simply isn't robust enough to really differentiate those patients who are unlikely to recur from those who are likely to recur. And because of that, we really can't target our chemotherapy and our adjuvant therapy in very sensible ways. We know that recurrence in these early-stage patients is a big problem. If we are able to better risk stratify these patients and really truly take out those patients who are high risk for recurrence, they are the patients that are most likely to benefit from adjuvant chemotherapy. So not adjuvant chemotherapy, for example, for all Stage 1 patients but adjuvant chemotherapy for very high-risk Stage 1 patients who are likely to recur. If we can do that, we may be able to not only present -- prevent a lot of mortality, which is the most important thing, but also, it may be of a tremendous benefit by preventing late-stage treatment of disease, which is, of course, very costly and often ineffective. Next slide, please. So that's exactly why we came up with this test. So it was our group at UCSF. And, again, I'm a surgeon, but this is our patient population, right? We're treating these patients with surgery, and we're offering them a chance of cure, yet, we were seeing over and over again that, unfortunately, a lot of these patients were not cured through surgery. So the first sort of part of this was, okay, can we start to identify patients who are truly at high risk based on their tumor biology of recurring and harboring micrometastasis at the time of surgical resection. So this whole test is designed around that biological notion that some tumors have more aggressive biology, and they're more likely to harbor micrometastasis than others. And the test can be applied to any patient who undergoes surgery for Stage 1 to 2a, non-squamous, non-small cell lung cancer. And basically, when you get the results of the test back, it will risk stratify those patients into either a low, intermediate or high risk of recurrence. And it's up to the provider, of course, to determine how they use the results of this assay. But at least in UCSF, we are referring those patients who have intermediate and high risk of recurrence to our oncology group for a discussion of chemotherapy. And since 2012, we've been sort of leading the way in giving chemotherapy to our patients with intermediate and high-risk disease. The low-risk patients, of course, don't get any chemotherapy recommended to them after surgery. Next slide, please. So here are the bones of our test. And this is all actually fully transparent. So I'll briefly describe it here, but if you want to learn more, actually, nothing about the test is super fancy. Nothing about it is not disclosed. In our original Lancet article, we described the entire process. Not even the algorithm is actually proprietary. That's all out in the open and published. And we did this for a very simple reason. Again, we're surgeons. We're simple. We're pretty direct. We like to choose things that are reliable and have been around for a long time. And so we started with a resected paraffin-embedded specimen. So those are widely available, tissue blocks available at any pathology setting around the world. Those specimens are not stored, and they're not frozen. They're stored at room temperature. And so nothing fancy. Those blocks can get sent in. Shavings of those blocks or slides can get sent in that are unstained, and RNA can be extracted. And through simple PCR, so again, nothing fancy, a technology that's been around for 50 some years, we're measuring gene expression of 11 target-related genes and 3 reference genes. And through that algorithm, again, it's not a secret, it's open, and it's published, we are able to risk stratify our patients into either high, intermediate or low risk of recurrence after surgical resection. Next slide. So other groups had done this up to that point, but I think that the reason that our test sort of received the most attention now has persisted, whereas no other test in early-stage lung cancer exists, is that we were able to validate this test on 2 large international cohorts in a blinded fashion. So we developed this test in a large group of patients at UCSF, over 350, with all stages of non-squamous, non-small cell lung cancer. And then we were able to validate this test in 2 large international cohorts, one of over 400 patients with Stage 1 disease at Kaiser Northern California; and again, in an international cohort of over 1,000 patients with Stage 1 through 3 disease in China. And again, this was a blinded validation, the most rigorous kind of validation than any sort of prognostic test can undergo, at least in this setting. And in both of these cohorts, we were able to reliably identify those patients who are at the highest risk of recurrence after surgical resection. This is just an example of a Kaiser validation cohort. Next slide, please. Now you may think again that this idea that stage may be good enough or, okay, well what about like very, very tiny tumors? Maybe there's a limit or a certain subset of tumors for which this can be applied for. Well it turns out that it's not true. So even if we look at our tiniest tumors, so at the time this study was released, we were looking at T1A tumors, which was -- which were defined as tumors 2 centimeters or less. So these were tiny tumors that, by our staging system at that time, were the smallest category with no negative disease. And those tumors are by no means safe. So again, tumor biology, aggressive tumor biology is aggressive tumor biology no matter how big or small the tumor is. And this was a follow-up paper that was published in JAMA that showed that despite having tiny tumors, you could still identify patients at high risk of recurrence, 50% chance of recurrence in 5 years, with this assay. Next slide, please. So we've talked a lot about the prognostic power of this test. And so now I think it's -- most people would accept that this test does a pretty good job. It's been retrospectively validated and in a blinded fashion of basically demonstrating through tumor biology who is most likely to recur. Well we also have some prospective data, and this is our first 100 patients. These are just consecutive patients that underwent the tests. And we needed to wait a little bit, of course, for our -- for those patients to develop enough follow-up time. But the results of a prospective cohort after this test was validated and CLIA approved and so forth were released in clinical lung cancer in 2018. And there's sort of 2 takeaway messages from the first 100 patients who underwent this kind of test. And the first was that in a prospective setting that, again, we showed significant risk stratification and the ability for this test to really pick out those patients at highest risk of recurrence. So that's shown by this solid red line. And you can see those patients that are high risk without chemotherapy really do poorly in terms of their disease-free survival within 5 years, whereas the low-risk group has a very low chance of recurrence, actually. So this current separation between high- and low-risk patients in Stage 1 and 2a is much better than the current separation that we're seeing with our traditional staging systems. That's the one thing that this test truly is adding prognostic power to our current staging system. But perhaps more importantly, everybody wants to know whether this test is also predictive. Again, the whole reason behind testing people is not only to determine what their prognosis is and do we need to scan them more frequently, do we need to be sort of on more of a lookout for recurrence. But of course, we would like to improve their outcomes by giving them adjuvant chemotherapy. And again, I mentioned before that since 2012, we've been giving our high-risk patients chemotherapy after a discussion with oncologists. And some of the patients will elect to enroll in chemotherapy, and some of them won't. But if we follow the patients who are high risk with chemotherapy, you can see a significant difference in their outcomes. In fact, their overall survival started to approach this overall survival of the low-risk group in those patients who are targeted patients now who are giving chemotherapy. This data is from our first 100 patients, but data from the first 200 patients has now been extracted. And that's been submitted for presentation at the upcoming ISLC. Next slide, please. Now again, just going back briefly to these NCCN criteria. And this is sort of based on group consensus, and we can see that these criteria really break down in terms of really being able to even provide a prognostic benefit to patients or prognostic power to risk-stratifying patients, much less predictive power. So again, no evidence at all that these criteria are predictive. I will say with the slight caveat that tumors greater than 4 centimeters, which is an NCCN high criteria, there was sub post-hoc analysis that was performed, the CALGB 9633 trial that showed those patients may benefit from adjuvant chemotherapy. But the other criteria really have no evidence behind them. And again, in a prognostic sense, if you were in the high-risk group here for the NCCN criteria, all you needed to be in this high-risk group was one of their positive criteria. And you can see that there's some initial survival curve separation, but the ability of the NCCN criteria to really risk-discriminate between those patients who are low and high risk, the criteria breaks down over time with the nonsignificant p-value. Whereas, again, this test that focuses on tumor biology really stands the test of time, and you're really able to risk-discriminate those patients over time. Next slide, please. Now one last sort of piece of information, is it truly the case -- of course, we believe in this test at UCSF because we developed it, and we've been using it. Is it truly the case that other physicians around the country are influencing their treatment decisions based on the results of this test? And it turns out that they are. So this was just a survey of physicians who have used the test in treating over 120 patients. And a quick survey of those oncologists, thoracic surgeons and other providers determined that 30% of the time, the treatment recommendation was changed after getting the results of this test back. And that usually meant that high-risk patients now were much more likely to go -- undergo a treatment or a recommendation change of some sort. Again, that can span the gamut between needs more frequent monitoring. We need more frequency CT scans. We need a higher level of surveillance. We need further staging, for example. Sometimes you didn't get a lymph node assessment, et cetera. And that can range all the way from that to adjuvant chemotherapy in that setting. Last slide, please. So back to Ms. Elle. So we presented her story a little bit. We talked about how she had received this gold standard workup, and she had still recurred. Unfortunately, that's not the whole story. And so next slide, I want to fill in sort of the back story was that she underwent her resection at UCSF. And she did get this DetermaRx test, and it came back as high risk. She was referred to our oncologists who recommended adjuvant chemotherapy. However, since she had returned to Asia, she conferred with her oncologists, who didn't agree with that recommendation, just recommended observation. And as a result, she didn't really get the full benefit of the discussion and full benefit or chance to receive adjuvant chemotherapy for her high-risk disease. And again, as you know, unfortunately, she recurred 6 months later. Next slide. So in sum, I think Dr. Gandara already told us how adjuvant treatments has an impact on survival, can have an impact on survival, but the early -- the earlier we can apply adjuvant chemotherapy in this setting, so the earlier we can get patients with advanced disease or micrometastasis, the better we have a chance at curing these patients and achieving long-term survival of these patients. You've already heard that a natural correlator to that is we need a better way, above and beyond stage, of risk-discriminating these patients and truly identifying early stage patients who have aggressive tumor biology and high risk of harboring micrometastasis. Those patients then go on to under -- to experience recurrence, unfortunately, many years after their surgical resection. So now we have that kind of assay. So this assay, again, was developed at UCSF and now is in a CLIA setting marketed as DetermaRx. And we have multiple validation studies to provide this improved risk discrimination. And again, you saw the last couple of slides. We now have evidence that shows in a prospective setting that patients who are labeled as high risk from this assay also benefit from adjuvant chemotherapy in this setting. So I think I'll stop there. Thank you again for this opportunity to present, and happy to answer any questions at this time.

Great. Thank you, Dr. Kratz. And I think we're going to just -- before we get to questions, we're just going to have Padma Sundar speak for a few minutes about some updates about DetermaRx adoption, and then we'll get to those questions.

Thank you so much, Dr. Gandara and Dr. Kratz. That was a very insightful presentation. So just wanted to give you a brief glimpse into what's happening with the test in the real clinical world setting. OncoCyte had the privilege of making this test available to clinicians worldwide starting end of January. And just in the United States, we are very happy to announce that this test has been actually adopted at -- right now, it's actually 47 health systems throughout the United States, and that number is growing literally every day. And you can see that there's been significant adoption across multiple states in California, Washington, Nevada and so on and so forth, including some very large community health systems, such as Florida Cancer Specialists. So very happy that doctors have recognized the utility of this test. Next slide. So what have we seen so far in the first 100 cases analyzed? We're actually -- we've done well over 100 cases. But we wanted to take a look at what we are observing in terms of how doctors are using this test. So we've observed that across the first 100 cases, physicians are utilizing DetermaRx even in the earlier stages of lung cancer where risk stratification is most useful for chemotherapy decisions. The majority of cases that we've seen are actually Stage 1a. And in terms of the results, about 38% of the patients have had high- or intermediate-risk results. And these would obviously be very actionable because doctors have told us that they would want to keep a closer watch on these patients, including utilizing adjuvant chemotherapy for these patients. In terms of where these samples are coming from, 42% of these patients are being seen in a major academic center, but we are getting 58% of these cases in the community setting, which we're very pleased with because we realize that, that's where a majority of early stage lung cancer is treated. Next slide. So one question that we do get is around the cost of the test. Because of the compelling dossier that we submitted to Medicare on the clinical validation and the clinical utility of the test, Medicare did decide to cover this test. So it is covered at no cost for your Medicare patients. And we've observed that about 70% of the patients do have Medicare coverage. So this is available at no cost to them. We are already getting reimbursement from commercial payers as well including Blue Cross and Blue Shield of California. And we also have a very generous patient assistance program, which is in place with us with the cost of the test. One exciting study that we don't have the time to get into but we presented at the ASCO annual meeting is the health economic data of this test -- impact of this test. Because this test enables the timely treatment with low-cost adjuvant chemotherapy, which, in turn, leads to a reduction in the number of late recurrences, which would unfortunately require aggressive treatment and end-of-life costs, we did a health economic analysis and determined that this test saves about $11,000 per patient. And when you add up the health savings across the 40,000 patients who will be eligible for that test, that amounts to a $450 million savings to the U.S. health systems, which is significant in cost savings. So that's all we have, and please do look for the abstract that we will submit on the expanded predictive data. That should be available in October and will be presented at the North American Lung Cancer ISA conference.

Wonderful. Thank you, Padma. We have some time to take questions now. [Operator Instructions] And I'm going to start by asking some questions that have already come in during the presentation. The first one, Dr. Kratz, I'm hoping you can address this. For the nonmedical audience that's on this webinar, hoping that you can give a very -- a high-level description of the DetermaRx test and how this is different than some of the other molecular tests that we hear about in lung cancer.

Yes. Thank you very much. That's a great question. So I think there's 2 ways to think about molecular tests in lung cancer, and the first is the tests that determine what causes lung cancer. And these are really the tests that you hear about where you're hearing about driver mutations. And so these are tests that test for mutations and genes that cause lung cancer, so EGFR, ALK, KRAS, p53, et cetera. And those are mutation-based tests, which again, give us an idea of what causes lung cancer. Now this test is different because regardless of the cause of lung cancer, lung cancers can take on different phenotypes or characteristics in terms of how aggressive those lung cancers are. So for example, you may have an EGFR mutation that causes lung cancer, but -- or you may have 3 different ones, and each one of those can have a different outcome for that patient. So some of those lung cancers can be very benign. Other lung cancers that are EGFR-driven can be very aggressive. So where our test really fits in is determining not what causes those lung cancers but how aggressive it makes those lung cancers once somebody develops them.

Wonderful. Thank you, Dr. Kratz. Let's see. We have a question. This is from Bonnie Adario. I think this is for you, Dr. Gandara. She asked, "How can we get more physicians to pay more attention to stage? It is very important to receiving therapy."