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Colin Enderlein: From DeciBio Consulting, I am your host, Colin Enderlein, and this is the DeciBio panel discussion. On today's episode, I will be discussing with a panel of leaders from pharma, clinical testing, and hospital settings how they maximize clinical trial samples, especially to support the growing need for biomarker testing.

Thank you all so much for joining today's panel discussion. As you're aware, the topic we'll be covering is how to maximize clinical trial samples in the increasing needs for biomarker testing. Just to help frame this a little bit, successfully executing clinical trials is a key hurdle to medical innovation today. Especially when we're considering the growing number of data points and biomarkers targeted per sample, success really hinges on the tight coordination between many different stakeholders and industries. What I'm excited about today is really bringing together multiple different perspectives to help explore this topic from a couple of different angles.

As some quick introductions, my name is Colin Enderlein. I'm a principal with DeciBio Consulting, and I'm pleased to introduce our panelists. We have Suso Platero, the Chief Scientific Officer at Discovery Life Sciences, Jack West, Vice President of Network Strategy at Access Hope and a Medical Oncologist at City of Hope, and Omar Perez, Head of Medical Diagnostics, U.S. Medical Affairs Oncology at AstraZeneca. Thank you all for joining today and welcome to the discussion.

Over the next 30 minutes, I'll ask some questions to you individually, as well as raise some of these questions to the group about biomarker testing from clinical trial samples and see if we're able to collect a range of perspectives on these different topics. To kick things off, I want to ask each of you to briefly describe the key reasons for biomarker testing in clinical trials. Starting with Suso, if you could help give us some insights here.

Suso Platero: I think the key attribute is we're trying to find out what's the effect of a given drug in patients. And we make sure that there is some safety, see what the drug does to the patient, and see what the patient tissues do to the drug. And finally, I think we always have the goal in mind of trying to find the right patients that we can add to a specific clinical trial to make sure that the drug is efficacious. So to me, those would be the most important things to do for biomarker testing.

Colin Enderlein: Fantastic. Thanks for that overview. Omar, over to you next.

Omar Perez: I think there's probably at least two important aspects for biomarker testing in clinical trials. One is if you have a biomarker-directed therapy that you're investigating, it's absolutely important to identify that patient up front. So you therefore need that biomarker test in order to select the right patient to understand whether that potential medicine has a good safety and efficacy profile. And then two, importantly, to help advance the science, you need to ensure that you have adequately collected samples to enable biomarker discovery to either further refine your scientific hypothesis, understand disease progression, or maybe even understand mechanisms of resistance. So biomarker testing has multiple applications. And it's clearly important not just for directed treatments, but also to help advance the science for potentially future discoveries as well.

Colin Enderlein: Thank you so much for that. And then, Jack, to round it out with a little bit more of a clinical perspective, it would be great to hear your insights too.

Jack West: Yes, I would really agree with a lot of what's been said, that first of all, several of the trials, certainly in my main field of thoracic oncology, are increasingly directed to a molecularly biomarker-driven subset, whether that is by identifying a driver mutation or high tumor PD-L1 expression. So to enroll on the trial, you'd need to have already pursued the biomarker testing to identify the right trial for the right patient. But beyond that, even for trials that are pretty broad-reaching, we are increasingly interested and see the value in identifying perhaps a subgroup of the patients in a larger study who are the big beneficiaries or potentially a group that does not get a benefit so that we can deselect patients who are unlikely to benefit and only experience the side effects or costs and may be better directed to some alternative approach. I think that we are increasingly becoming more granular.

When I entered this field, we gave chemo doublets to everybody and got pretty lousy results. A huge part of the quantum leap that we've experienced in dramatically improving outcomes for people with advanced lung cancer, and now potentially curable lung cancer, has come from separating out this group and not treating them as some monolithic population, but really identifying subgroups with a lot more granularity.

Colin Enderlein: This is a great framing for the rest of the discussion, thank you all for those intros. The next piece I want to ask about is, what are some of the strategies you employed today to maximize the value of clinical trial samples for biomarker testing? Starting with you, Suso, what's your perspective on this?

Suso Platero: Yeah, I think that's probably one of the keys and Jack specifically mentioned lung cancer. I've done a lot of clinical trials in lung cancer. The key here is to try to maximize the value of the sample that you have by using the minimum amount that you can to perform those experiments. And sometimes even using the same type of tissue to do different types of experiments. For example, using formaldehyde paraffin-embedded tissues to do both immunohistochemistry and next-generation sequencing. Sometimes the ability to use those tissues to do different types of technologies helps you quite a bit to get a lot of information from those things. And other things like, for example, using blood to use also liquid NGS, also at the same time that you look for specific proteins. Again, another example of using the same type of sample for different applications. And I think that's something that we're always trying to figure out and working out when we help our clients with clinical trials is - how to get the maximum amount of information out of the samples that you have.

Colin Enderlein: Great context. I actually want to raise the same question to Omar, just from the pharmaceutical side of things. How do you really maximize that value of clinical trial samples during biomarker testing?

Omar Perez: Yeah, sure. I think having participated in the development and the writing up of numbers in clinical trial protocols, there's always marrying both the intent and the outcome of the value of the biomarker testing. I think first and foremost is really having a clear biomarker strategy for that particular indication and trial. Like, what is the end intent to ensure that you address the questions being asked in that R&D effort? But also importantly, providing enough education to the multidisciplinary care team who ends up actually executing on that trial to make them aware of what's the importance of collecting that tissue specimen? Why is it that you need 20 to 25 tissue slides to go execute on this strategy? And then ultimately, I think very clearly articulating this need and value and consenting for it with the patient. Because oftentimes, you try to maximize a particular sample for many different outputs, but technology and science evolves, and trials can last multiple years. Therefore, you need to sort of forecast the next three, five, seven plus years in some cases, and you may not know what that may be. You really have to think strategically as to: what do I need to collect that's allowable within medical practice? How is that information going to be generated to help advance that particular trial? And then, Will we have the option to sort of grow from that in the event we do have materials to evaluate newer technologies?. Then, I'll go back to this and maybe some of my panelists can comment, something that is very important is consenting and letting the patient know how this information is going to be used.

I think we've really learned a lot in the last 15-20 years of putting biomarker-driven trials forward, developing the science. It's super exciting to see precision medicine efforts now bringing medicines in a three to four, five-year time frame, where 20 years ago, it used to be 15 years just to get one product out- that tells you the advances in pushing forward. Ultimately, the value proposition of how much information can you get from a particular tissue is important. Every single tissue specimen goes through a process. Biopsies are enduring for a patient, so for those on the R&D side, maximizing the opportunity you get and what you do with the information is important.

Colin Enderlein: Absolutely. This actually sort of narrows down a little bit closer towards the forefront of individuals actually executing some of this testing. Jack, asking you, what are some of the assays or tests, or what's the ideal suite, I should say, of assays and tests that support clinical trials today? And what are some of the strategies you employ to cover all or most of these? So obviously, this is a multidisciplinary approach. You'll be collaborating with the care team, with the pharmaceutical companies, in many cases service providers. So, what is that ideal range of technologies you have at your disposal?

Jack West: Well, I would actually say that I think that what is important is trying to be as comprehensive and forward-thinking as you can, but also working within the confines of what's actually feasible. Because, you know, the reality is that when we look at issues like repeat biopsies in the setting of acquired resistance for, say, EGFR inhibitors, what's been reported, even by investigators at illustrious centers hugely committed to clinical trials work and obtaining repeat biopsies, and having patients who are far more motivated than the typical patient getting treated at a VA or community-based site, they have only been able to get about 40 percent of the intended desired repeat biopsies. I think we need to acknowledge and look at, okay, what are the wants and what are the needs? It is possible to do multiple blood-based tests to look at circulating tumor DNA, particularly in advanced settings, as we have the sensitivity. We just need more data to look at the utility of that. But I think that you certainly want to get tissue at the beginning to be able to submit that, but you need to be as judicious as you can possibly be about repeat biopsies because our track record is that reality intervenes. We really need to be thoughtful and judicious about what is actually possible when we're talking about invasive procedures in the real world and especially how extrapolatable those are beyond the most motivated patients at the handful of centers and how is it going to play in the broader world.

Colin Enderlein: This is actually a great segue to a highly related question, what do you see as some of the top pain points when it comes to biomarker testing today? And Jack, since you've been – you sort of started skirting around on this, let's start with you. Obviously, what's feasible and what's realistic, it sounds like that's something that's top of mind, but if you're thinking about what are the pain points that are potentially limiting you from being able to conduct all the biomarker testing you want to, what might those be?

Jack West: Yeah, and I spend an incredible amount of my time thinking about these things because, you know, I think that one of the real challenges we have in the concept of precision oncology molecular medicine is the – what we know, versus, what's actually done in practice or not done in practice. And the challenges are that testing is not done as often as we would like, that we know that it's pretty regional and that probably has to do with the kind of patients that you see.

You know, I work in a place where there are a lot of never smokers, a significant Asian population and we see a lot of patients with EGFR mutations, ALK rearrangements and other drivers. So, many – not just the academic oncologists, but many of the community-based oncologists see so many relevant results from molecular testing that they're all in on this. However, if you're practicing in Kentucky or Alabama or something and you see a large proportion of smokers and squamous histology, you're not going to see that same proportion and I would say that commitment isn't always there and there's potentially a knowledge gap of the folks in the broader community not knowing about the latest new driver mutation that isn't very common. Beyond that, there is often a shortage of tissue. There's never enough tissue and we had a couple of decades of trying to get by with the least amount of tissue to make the diagnosis of non-small cell. You'd use maybe cytology and people got good at making a diagnosis based on incredibly little tissue and now we've tried to unlearn that– when you ask “how much tissue do you need”, well how much can you get? I want all of it. I want everything you can get – because it's never enough and there's also the challenge of the turnaround time. We are increasingly doing studies looking very broadly for a wide range of doing NGS and that may take two, three or sometimes more weeks and patients and physicians are eager to get going and so that can be a challenge.

Another area that I think is a major bottleneck and that we don't acknowledge enough is, the interpretation. The report has to get to the doc too often its sent and it's put on a fax, taken off a fax machine and uploaded into the Epic Media tab never to be seen by human eyes again.  But beyond that, it's very complex. These reports are often 40, 50, 80 pages and incredibly difficult and most oncologists were not trained with that level of sophistication to identify- you can identify an Exon 21 or an Exon 19 EGFR mutation, but some of these other ones, the notation is different in one report versus another and people are prone to miss a potentially relevant RET fusion or HER2 mutation and what's that versus amplification. It is truly complex and I think that there's a major bottleneck, a gap there. We see that even when patients have a mutation or a driver, too often they aren't getting the optimal treatment for it, maybe because it's just not recognized. We really need to address that gap.

Colin Enderlein: You touched on a lot of different areas here, tissue being a limiting factor and the education component are factors that resonate with the other attending members. Suso, I'd love to hear your perspective on this. What would you go deeper on and potentially add to?

Suso Platero: I think that hit all of them. I will add just one more: logistics. Sometimes, during a clinical trial, samples get sent to the wrong address, and having control of that- it takes so long to rectify. Having tight logistics and making sure that things get moved from the hospital to the testing lab in a good timeframe is key to having that fast turnaround that is needed, especially when the patient is waiting. You want to get that testing done as soon as possible and report back. And then, obviously, the sample. Sometimes we get samples with no tumor on it, so you have to make sure that the sample is collected the right way and at the right time. To me, those two factors are also important.

Colin Enderlein: Fantastic. Omar, anything else to add on this topic? Otherwise, I have a question for you right after.

Omar Perez: I completely agree with the barriers highlighted. A lot of the implementation aspect is happening at the local level, and there are so many different paths in which you get a test ordering to a tissue sample to a new report. Understanding that institutional practice and what is a barrier for that practice and how we can overcome it is really important. The U.S. health system is very fragmented, and biomarker testing varies from academic centers to community centers to big IDNs.

In addition to understanding which biomarkers to order testing for and which ones are guideline-concordant and if you have processes built into your EMR to actually do that, the interpretation of the reports and the time to get those reports to the appropriate molecular tumor boards and multidisciplinary team all add time. Unfortunately, there's a patient at the end of that timeline. The entire supply chain of getting the test to report needs to be optimized. We often hear from ad boards and insight-gathering mechanisms that reimbursement and patient out-of-pocket costs are still a fear, and providers are very well aware of this, particularly as we move to comprehensive genomic profiling and, in some cases, concurrent NGS tissue and liquid biopsy. The thoracic space has been advanced in this regard, but other tumor types such as breast, prostate, and ovarian are following steps. Community oncologists are new to the molecular testing space, so getting that education out there in real-time. It is a struggle for all of us. The barriers highlighted are continuous, but with collective input, we can hopefully overcome them.

Colin Enderlein: That makes a lot of sense. Let's think more solutions-oriented. For some of these top barriers, especially from the education and actionability standpoint, what are some of the optimal solutions you can think of that would help start to address these issues?

Omar Perez: From the educational perspective, we appreciate, at least in my organization, that education needs to reach out to the provider wherever they may be, and we may need to tailor education specifically to specialty. It's not just the medical oncologist; it's also education for the entire multidisciplinary team, whether it might be the thoracic surgeon, pulmonologist, gynecologist, or urologist. We need to reach these individuals where they get their information, which may not be at an annual oncology conference, but more at a regional and local level. Looking for innovative ways to do that, whether it's on the ground and doing face-to-face or through digital innovation approaches, we have been exploring a number of those aspects. Equally, as such, we believe that education should also happen at the patient level. We work with external patient advocacy groups to educate and inform about the value of biomarker testing. We are also recognizing that our payer society needs to appreciate the value of precision medicine. I think education has multiple components and we are taking a comprehensive look as to how to move that needle. There are a variety of different projects and initiatives with collaborations that we've done to help demonstrate that.

Colin Enderlein: I'll pose the same question to Suso and Jack. What are some of the key solutions you can imagine that would help address some of these issues we've been outlining?

Suso Platero: I think one solution is having a tight turnaround time for testing and keeping to that specific turnaround time. Providing the information back to the treating physician as soon as possible is important so that they can work with the patient to decide the best treatment for that specific patient. By shortening that timeline, we're able to speed up the treatment process for that specific patient.

Jack West: We need to change the expectations to normalize always getting broad molecular testing in the majority of these patients. Pathologists understand that you don't have a breast cancer case completed until you know the hormonal status and HER2 status, etc. We need to make that as mandatory in lung cancer, that you haven't done your job unless you have reported the PD-L1 and the key molecular markers. Some of them may not be actionable and maybe we do not have to have 60-200 markers, but if you have not reported on EGFR, ALC, ROS etc and everything that has a paired therapy then you have not done the requisite work and you should be held accountable for that.

At the same time, we need to make the systems easier and not rely on individualized decisions and interpretation by every doctor. That means having more reflex processes and less decision-making points.

It would be valuable for NGS reports to come with an impression, like a brain MRI. If I order a brain MRI, I do not get the raw images back with the expectation that I will review and interpret that it is meningeal carcinomatosis. That is remarkably difficult to do and there are specialists who do that and I am not one of them. It is almost ridiculous that we would expect, out of all the oncologists in the country, to have the requisite knowledge of the fine points of NTRK , but that is not realistic. We should have a set of dedicated specialists interpreting reports and offering clear recommendations of what to do with the results. Just like I have a neuroradiologist interpret the brain MRI. Or, this could be a good use of artificial intelligence, as we don't have enough major expert molecular oncologists and pathologists to offer commentary on every report. We need to look better at the implementation science and not just the theoretical utility of these things.

Colin Enderlein: Starting with you Omar, I'd love to hear how you might expect biomarker testing to evolve in the next three to five years. This can also include how you hope it will evolve and what technologies or sample types you're excited about.

Omar Perez: Following up on the prior comment, theirs is a really exciting program that we're piloting with the Association for Community Cancer Centers. It's called the Precision Medicine Steward Program, where we're actually piloting implementing placement of skilled individuals within the multi-disciplinary team to help navigate that tissue to report process and to work with your oncology care team to really do triage and to connect those dots, to see if that can actually help improve. To Dr. West's point, we can't expect every single oncologist out there to be on top of every single guideline update. They're happening way too fast, and the technology is happening fast as well. We're piloting this Precision Medicine Steward Program as a potential nurse navigator type of role that can hopefully help some of these centers.

In terms of the future of biomarker testing, I think we'll see a continued evolution of technologies, such as liquid biopsies, which can provide a less invasive way to obtain samples. As we've seen technology advance, clearly liquid biopsies have played a significant role. The lung cancer space has greatly evolved as well. There's approved products out there for liquid biopsies. We're seeing that trickle through to the other cancer types. We're excited for imaging-based approaches as well to sort of predict when or not somebody might have a relapse, whether it's a molecular relapse or whether it's an imaging-based relapse. The science is still evolving, but the entire goal is to be able to predict who may relapse and where you may need to intervene much earlier. And we're equally as excited as the potential for early cancer detection technologies, blood-based methodologies that can hopefully identify patients, not just when they're symptomatic, but when they're asymptomatic, to then triage before something happens and to essentially identify earlier stages of cancer where we know we have the most intent for a cure. The clinical utility and the evidence is still forthcoming, but they're very exciting, and we hopefully will see them one day as routine practice.

Colin Enderlein: Fantastic. Suso, I'd actually love to ask you the same question, sort of at the middle between the pharmaceutical as well as the clinician perspectives. How do you see things changing in the next three to five years?

Suso Platero: I think we're sitting in a time where we're going to see an explosion of more data coming to us. And the reason for that is because we're having all these technologies that are multiplexing. So, for example, in immunohistochemistry, you can do multiplex, six, seven, eight markers that something together with fluorescence. We're doing now, for example, flow cytometry with the Cytek Aurora. You can do spatial spectral flow cytometry. Now you can do 35, 40 different markers and follow them. And then obviously liquid NGS. You can look at thousands of SNPs and thousands of different genes that you can follow up. and we're going to see this explosion of data coming at us. All of these technologies, we have them at Discovery Life Sciences. I think it's important for us to be at the forefront of technology, to be able to agglomerate all this data and then put it in a way, as Jack mentioned earlier, that is easily readable for the doctor that is treating the patient. But what gets me really excited is that all these different technologies are advancing so fast and that we're going to be able to do so much more. So much so, that I think the samples that are needed for testing are going to diminish. And the turnaround time is going to decrease remarkably to be able to give that patient the data that the doctor needs to treat him.

Colin Enderlein: It makes a lot of sense. The last question I'm going to ask, and this is going to be posed to each of you from a slightly different angle, as we have representation from the pharmaceutical side of things, the commercial reference lab side of things, and of course the physician side- is how can these other stakeholder groups help set you up for success in generating more value from clinical trials? So starting with you, Jack, looking around the other stakeholders that make up the ecosystem, how could you receive help in order to optimize what you're doing?

Jack West: Well, I would say that the reality is that just about all of the interesting work that we do in my field is ultimately funded by pharma. I think it's important that we have, we work with our pharmaceutical partners to ask the right questions. I think ideally we all resonate and have concordant goals. I would really underscore that I think that liquid biopsy work is something that I would love to see integrated into more and more of what we do as a surrogate endpoint. This has the potential to be as transformative as PET scans in how we operate. We just need to clarify that it is as useful a tool and prognostic as we expect and I think that's really easy to do. I think the harder part is going to be to clarify that we can use it to change the trajectory and do something differently and smarter. And that would be to clarify who needs intensification early on, like using a liquid biopsy just weeks into the start of therapy before you get a scan to get some quick feedback about whether this is likely to work, whether you should adjust the timing of your scans earlier and potentially later because you're very confident it's working.

We also have more and more of these therapies, immunotherapy, targeted therapies that are being applied for early stage potentially curative disease. And we don't know the endpoints of when to stop or who needs it. We know that a subset of patients are cured with surgery alone, but we still right now are now starting to treat lots of these patients with years of pill-based therapy that costs tens of thousands of dollars a month, which may be required. But some of these patients, they're already cured and it's just alligator repellent doing nothing and that's a very expensive treatment with lots of side effects. We're going to start probably doing this kind of thing for stage three after chemoradiation. We have immunotherapy being applied for a year or more for patients with surgery. I think we can use tools like liquid biopsies, ctDNA, to identify who really needs more and who can stop so that we get to a point kind of like where we are with CML right now, where we have long-term molecular remissions that we can identify. People can come off of treatment and then if we see that that's changed, they can go back on. But it's really tailored to the needs rather than essentially treating blind and over-treating people with expensive treatments that have side effects. I think that that's something I would love to see and I think we will see in the next few years. We just need to see that we can use this information to hone our treatments and do better.

Colin Enderlein: Well said, Jack. Thank you. Omar, same question to you, but with the different perspectives of collaborating with your clinical counterparts as well as your reference lab partners on how to maximize and get the most value from clinical trials.

Omar Perez: Yeah, I mean, I think it's critically important for us, particularly in the pharmaceutical development area, to really pressure test our scientific hypothesis with the medical oncology community. We are very engaging with our medical oncology advisories, individuals and committees, and to really help us redefine what may be the next future for the next three to five or ten years plus. And so getting that input to really understand patient journeys at a level where our medicines today that we're planning for, which will not, if successful, be out for another five plus years, are really going to have a major impact. So that oncologist perspective is absolutely critical for us. I think equally so with our CRO partners who help us execute on the clinical trials, the execution and implementation science is also critical. In order to maximize the development opportunities, we need to actually identify these patients and make sure they actually enroll in our trials. We work very effectively with our CRO partners to help us activate the appropriate clinical trial sites, to help us with our enrollment targets. A big effort for AstraZeneca is to diversify clinical trial representation to make sure that we're actually reflecting the US patient population. It's an ecosystem, and we know we can't do it alone so we actively collaborate with both our medical oncology community, our CRO partners, and others to really help advance the science.

Colin Enderlein: And then, Suso, as another critical vertex on this ecosystem, what's your perspective on this?

Suso Platero: Yeah. I think at the core, we all have the patient in mind, right? We all want to help this patient through the treatment and to be able to have the best outcome possible for it. And I looked at this as a partnership between the oncology, between the pharma company, between the service providers-that we all need to come together in a partnership to be able to do this in a fast, efficacious, and high-quality way in order to obtain the best result for the patient. I think to me, communication is going to be key for we're able to have this partnership and at the end, we all need to want the same thing, which is to move these medications as fast as possible and to make sure that the patients that need them receive them as fast as possible.

Colin Enderlein: Fantastic. Well, that concludes all the questions that we have for today. Thank you all so much for taking the time to join this panel discussion on maximizing clinical trial samples, especially to support the growing need for biomarker testing. We hope to catch you next time on the DeciBio podcast.

**Some of the text / quotes are edited for conciseness and readability.

Thank you to our guests:

Suso Platero, Ph.D. Chief Scientific Officer, Discovery life Sciences

Omar Perez, Ph.D. Head of Medical Diagnostics, U.S. Medical Affairs in Oncology, AstraZeneca

Jack West, MD Medical Oncologist; Vice President of Network Strategy, City of Hope; Access Hope

Colin Enderlein, Principal, DeciBio Consulting