The Blood Test That Could Change Cancer Treatment Forever | Eric Matthews - General Manager, Biopharma, Natera

Ira Pastor: Sam. Mhm. Um, Welcome to another episode of progress, potential and possibilities discussions with fascinating people designing a better tomorrow for all of us. I'm your host Ira Pastor. Welcome back everybody again to another episode of the show with another really awesome guest for you today. Uh, on the show today we are joined by Eric Matthews who's the General Manager Biopharma at Natera. They are a leader in personalized molecular diagnostics, uh, and the company behind Signatera which is the first FDA approved molecular residual disease companion diagnostic. Uh and over the last 25 years Eric has been involved in bringing over nine medicines to market across 19 different indication launches. Uh, building a career really at the exciting forefront of oncology, precision medicine, biopharma innovation. Before joining uh Natera, Eric served the Chief Business Officer Charis Life Sciences focusing on diagnostic data and drug discovery partnerships. Prior to that as Chief commercial officer at Arcus. BioScience is helping forge their strategic collaborations including their partnership with Gilead and before that held previous leadership roles including a VP of Global Marketing for Immuno Oncology, AstraZeneca. He was commercial leadership positions as well as Genentech and Roche working on some of the most influential cancer therapies of the modern era including Avestin and Tecentrc. Eric holds an MBA in health sector management, master's in Health policy as well, uh, in economics and did dual bachelor degrees in molecular bio and economics at Duke. And today we're going to be discussing a range of things including the future of molecular residual disease testing, ultimately how these personalized blood based diagnostics are changing cancer care entirely. The recent FDA approval is the first molecular uh, residual companion diagnostic and uh, ultimately what's next for the next decade of individualized oncology? Uh, a lot to get into a lot of really exciting topics. Um, Eric Matthews, welcome to our show.

Eric Matthews: Thanks Aaron, great introduction, very kind, appreciate it. I'm excited to be here. Hopefully we can uh, address any questions that you know are kind of pressing for the, the audience and a very dynamic time. There's a lot going on.

Ira Pastor: Absolutely, absolutely. There's been a lot going on the last couple months. I'm excited to jump into all of it. Um, before we touch on any of it. I mean I would love just to you know, to, to hear a little bit more about you as you, I mentioned linear bio. You know you started off sort of fast and furious getting into pharma. I, I overlapped with you actually for about a year at looking sort of far back. But um, just say a couple more words about yourself and why pharma sort of excited you from the beginning of your career?

Eric Matthews: I mean, going back to the beginning, I guess I've always been fascinated by this intersection of societal value from therapeutics and actually in the spirit of the World Cup, I grew up playing soccer, but I was also someone who suffered from asthma. So my doctor really helped me through, you know, the early stages of figuring out how to compete in sports and uh, still, you know, manage, uh, you know, asthma as a chronic disease. So that's really kind of what started my journey here actually. And you know, now I'm, uh, really focused on cancer care and helping people get back to normal lives. So, um, it has been that arc of personal story into, uh, kind of today.

Ira Pastor: Absolutely. And let's start off with, you know, you know, basically, um, you know, exposing our audience to this principle of molecular residual disease, which is, you know, sort of broadly this presence of these microscopic traces of cancer that hang around the body, you know, during and after treatment. Uh, introduce the audience to the concept a little bit of, you know, why it's so crucial. We hear a lot about imaging, but imaging is not enough. And there's a lot of reasons why we need to go earlier and deeper, uh, talk a little about this because it's a topic we haven't gotten into yet on the show.

Eric Matthews: Sure, yeah. This is really all the technology behind blood based testing for these tiny fragments of DNA, um, is really bringing a new opportunity to understand which patients are at risk of, uh, progression, where their cancer may come back, versus patients who really should be able to know if they're more cancer free and can go on to live more normal lives. Um, by the time a scan picks up the tiniest speck of a 2 millimeter lesion on a CT that actually represents millions of cancer cells. Um, uh, I think for any patient, we'd rather not wait for there to be millions of cancer cells to have an option for an intervention that is really this treat. On molecular residual disease, which we call tomer paradigm shift, which is for patients who have gone through the upheaval, uh, of a cancer diagnosis, then through the, the surgery or the radiation or the chemotherapy, and are then hopefully in a curative state. We really want to be able to monitor those patients and give them more of a clean slate. There is no detectable cancer or through serial monitoring where on every three to six month basis there is, uh, uh, a repeat blood test that can tell a patient you're still in the clear, or maybe there's a hint of cancer DNA that needs to be checked out. Let's do a full workup and assess the options. That's really the whole shift now that's happening versus waiting for um, the disease to show up on a scan. And that's that whole new frontier that we're trying to figure out the best way to treat patients as well as give them the most peace of mind.

Ira Pastor: And can you say a couple words also about, you know, how the current. Because I know there's, there's the core test and we're going to be going in both directions of, you know, the, the initial products which you develop this prognostic and then where we're going in terms of the companion, ah, use with certain pharmaceuticals and biologics. But talk a little bit because you're looking for the circulating tumor, uh, DNA fragments, other sort of cellular biomarkers. Just walk us through a little bit of how the core signetera. Personalized test is currently designed today. I know you take the patient's tumor and there's different assays and all that. Uh, walk us through a little bit of what happens today and a little bit of what the current product. So the early product, let's say the prognostic, because I know you developed that for a range of cancers so far and I want the audience to hear about that first before we go into some of the new stuff that's happening.

Eric Matthews: Sure, yeah. I mean at its core, Signatera is, is a tumor informed blood test based on the sample of a tumor that gets sent into our labs. We analyze the entire exome or genome and look for, um, the DNA abnormalities that are most likely to predict for recurrence based on running now within the tens of thousands to millions plus tests, we have a lot of information on which fragments of DNA are the most dangerous, essentially. And so from the standpoint of specializing a personalized assay, looking for the variants specific to that, uh, patient's tumor that we need to monitor the blood for. We can provide that personalized assay so that on every blood draw subsequent to that initial baseline, we're looking for that specific signature of DNA variants that we saw in that original tumor. And so from that standpoint, um, we have established through publishing data in solid tumors and hematologic malignancies, we now know that this approach of a tumor informed test is the most sensitive. We're the least likely to miss, uh, a cancer recurrence by doing a bespoke tumor informed assay.

Ira Pastor: And while that's obviously a major part of the company and that story, you know, you've been Developing that there now for a few years in atera. The bigger story is what's happening now in terms of sort of the progression of the technology from, you know, purely prognostic into this ability to predict, to guide certain treatments. And sort of this is, you know, what's behind sort of the recent historic FDA approval. Before we get into what went to that approval, let's talk a little bit about this first use case which is bladder cancer. And we did an episode on this actually a couple weeks ago talking about the problem here in the sense, okay, we have ah, a fairly large population of patients in the United States. Um, we learned about sort of muscle invasive disease, carcinoma in situ, that here we have a unique condition where very difficult to see on the scans. Patients don't want the major, you know, the radical cystectomy and the removal of the bladder. And so we have a large part of patients we know are going to recur, but we've been sort of going blind. And in this particular case, um, you know, you basically developed the test to say, hey, uh, we can look a lot earlier and we can also pair that up with a uh, biologic. Talk about why, first of all, why bladder cancer was decided as the first use case here. I know, you know, you worked with Eccentric and Genetect previously, but talk a little bit about that and what led up to this collaboration because it's very, it's a very important synergy and I'd like you to walk, walk us through that.

Eric Matthews: Yeah, no, and I just, I'll say this is in the, in the setting of after cystectomy, but we are really focused on the next stage of hopefully bladder sparing approaches. So just um, to kind of put that out there. I think by leveraging the sensitivity of signature, that's like the next wave of studies is actually getting into functional preservation in areas where we can avoid um, uh, a bladder, uh, surgery. But in this case to just go into the history quickly, um, there was a study called Invigor UH010, the original Genentech study. That was an all comer adjuvant study and it was negative. But when it was then analyzed by MRD positivity. So just looking at the patients who are MRD positive after surgery or subsequently, we saw a really profound treatment effect of about 0.6 for survival as well as for um, disease free, uh, survival. So we kind of had a heads up that we knew that the approach for Invigor 011 which led to the recent FDA approval would work. We did take that data to the FDA and they said, well this looks very interesting, but you have to do the prospective study. So that's where it's really a credit to the people at Genentech working with us to fund a new study. This is the Invigor 011 that only enrolled patients who were positive for um, uh, ctdna, um, either right after their cystectomy or in a one year observation period where, uh, over that one year observation, if a patient became uh, MRD positive, they could enroll into the study. That was the whole shift in what is now what we call the Tomer approach for treating on MRD M positive either right after definitive therapy, yet you can still find cancer in the blood, but you cannot find it on imaging or over an observation period where we are able to find a cancer recurrence months, sometimes years ahead of actual, um, uh, definitive evidence on a scan. So now, I mean, what I think the fact that we have this prospective phase three evidence tells us is that this approach works, we now know in a randomized prospective way. Treating on MRD M positive leads to a survival benefit, in this case, uh, a 0.5 hazard ratio. So a 50% improvement in, in survival for the patients who were treated when they became positive in that setting. I think that's just extremely profound because you can do all the post hoc analyses you want, but if you haven't taken the risk in the years of clinical development to show that prospectively there will always be that doubt. We've now completely shown, at least in this one setting of ah, bladder cancer post hystectomy, um, a really exciting result, which is those patients who are otherwise destined to become metastatic could be treated and given another chance at cure.

Ira Pastor: And just again for the audience, so, you know, for decades finding cancer, treating it, wait for recurrence, now, you know, insert the molecular diagnostic in there. And again, the trial that uh, Eric's talking about, the Invigor 011 study and this phase three study, 41% reduction, risk of death, 36% reduction in risk of disease recurrence. Um, and again these, these are major numbers that again speaks to the um, the amazing potential for um, adrenaline, sort of, you know, lost cases, let's say, um, that we might not have focused on in the past. So um, I think it's, you know, this is exciting, not just, you know, from the science and sort of the patient impact, but sort of the bigger vision. You know, you're really creating um, a whole new paradigm here and thinking how this is all done um, being said, you know, talk about the bigger vision because you mentioned okay, in particular bladder cancer. You're going to move from okay, you know, after cystectomy, sort of earlier stage disease. I see a lot of other press releases, a lot of other collaborations going on and of course you've got the experience for years now with these various other cancers. So what comes next here? Um, a lot more bladder cancer work. I saw some melanoma stuff happening. Walk uh, us down the path, Eric, of what, what else you see on the, on the horizon for this particular approach?

Eric Matthews: Sure, yeah. As you know, I mean Signatera is approved and reimbursed in a number of solid tumor settings as well as um, ah, lymphoma. Um, uh, you know we have. I um, guess in one sense there's a lot of different places to go. It's really a partnership with the therapeutic companies to really understand that. That sort of uh, therapeutic option. And is that mechanism uh, really well suited for the adjuvant setting? That's always like the first, is it safe enough? Is there established uh, activity in the metastatic setting before bringing it into the, into the curative intent space? All that said, I think the pharma companies, the biotechs are really looking at the curative intent space differently now because to be able to bring a uh, uh, therapeutic into that space just provides an entire halo to the program that you're able to sort of achieve these really remarkable outcomes now based on um, early signals in the metastatic space. So we're hoping to help pharmas bring their therapeutics into the adjuvant space more quickly. And I think to your question about where would you go, is it colorectal, lung, breast? There's um, really the entire spectrum in this setting that we have seen many pharmas coming to us looking for um, scoping out a trial approach. So it's definitely an exciting time where um, it's hard to think of where you couldn't go relative to where you could go.

Ira Pastor: And again thinking about the overall picture clearly, um, oncology, well, immuno oncology. Now this is a major portion, portion of uh, uh, of this space. I mean it's a huge area in terms of hundreds of billions of dollars products now. And at the same time, you know, there's always that sort of pharmacoeconomic question hanging over the head of healthcare payers and systems and all that. Clearly uh, with what you're doing here, I mean you talked about reimbursement but you know, the ability to decide here, okay, yeah. Ah, these therapies, uh, are, you know, may work in this population, not in that population. Obviously, there's some very profound, uh, economic, you know, benefits here for the healthcare system. Say a couple words about that as well. I think it's kind of important.

Eric Matthews: Yeah, I think. No, thank you for that. It's a really. In our press release on the Invigor study as well, that patients who are MRD M negative, you know, had a, like, 100% survival rate after a year, 97% after, uh, two years. So there. There's both a de escalation as well as an escalation opportunity with MRD So on the de escalation side, you know, sparing patients from therapy that is unnecessary is a huge savings to the system, but it's obviously at the patient level, very profound. Um, the other aspect of de escalation is when, you know, a monotherapy might be more appropriate than a combination therapy. Um, and so there's. There's a number of steps, uh, around de escalation where you can either delay therapy to when it's necessary or, uh, provide really meaningful information to a clinician on where can they deploy a safer or less toxic therapy and hold the combination therapies for a more serious, uh, uh, diagnostic setting. Uh, I think that's that part of, um, the, uh, equation where it goes both ways. Where can you de escalate and then where might escalation be needed?

Ira Pastor: And, you know, I was wondering, Eric, because again, reading about, you know, obviously the work in bladder cancer, again, uh, collaborations, colorectal melanoma, a lot of stuff going on. Um, what's the potential for what you're doing there in Natera, sort of at the opposite end. I mean, because what we're talking about here is molecular residual disease. But it seems like, uh, you know, all the excitement now in terms of early detection, this principle of immuno interception that potentially happens could happen a lot earlier in some of these approaches. Um, so does it seem to me the sort of the early tumor development. I'm not, you know, especially oncogenesis, but similar, you know, concepts here could work sort of at the earlier stages in the big prevention side of things. Um, how do you think about that area as a company nowadays?

Eric Matthews: Yeah, no, I think, you know, early cancer detection is a big focus of the company and something we talk a lot about in our quarterly, uh, earnings calls. As there's a lot of focus on this area, we think we are optimally suited to this space because we have such experience understanding specific, uh, variants that we pick up um, in the setting of monitoring. Being able to apply that to early cancer detection is a natural place for us to go. Um, we have those uh, trials underway. We've enrolled thousands and thousands of patients in those trials and we're excited to bring those results uh, very soon.

Ira Pastor: Awesome, awesome. Um, while we have you um, tell us what else is happening that we should know about that sort of public facing. I did notice that only recently, the last couple days there's been some press releases about sort of, you're diversifying into sort of organ rejection and sort of the whole transplant area. And it seems there's some interesting sort of biomarker related stuff uh, there that obviously fits in very well with what you're good at. Um, what else is happening at the company that we should know about while we have you today? Other public facing initiatives, uh, on the calendar and then any. Anything else that I missed while we have you, please.

Eric Matthews: Yeah. The area of transplant is another really exciting application for cell free DNA where uh, being able to detect cell free DNA in the blood can give us a heads up on risk of rejection. So uh, we just announced today actually a strategic partnership with a company called Eladon where um, our technology will be used to look at kidney cancer rejection and uh, monitoring a new therapy that can prolong and preserve uh, uh, the new organ and avoid risk of rejection.

Ira Pastor: That's awesome. And again it speaks to uh, not just the uh, diversity of the potential of your technology but that is having worked there myself, that is another huge segment. So that's again very impressive for the company but a great collaboration.

Eric Matthews: Really excited to be coming up to the ESMO meeting this fall. We have a portfolio of products in cancer that uh, are coming to the European Society of Medical Oncology. So uh, we've got um, a lot of real world data now where we're able to help uh, the pharma companies essentially de risk their trial designs by providing the best comparator for a specific population based on now the clinical footprint of Signatera, which is in tens, hundreds of thousands of patients. I think that is a really unique thing that Natera uh, is bringing to um, clinical development is helping to really fix the system. It's really hard to understand how best to bring a therapy into the adjuvant setting. But between uh, our ability to match patients based on our clinical testing footprint into a trial and then scope that trial to read out in the fastest possible timeframe is this tomer approach that I hope we're starting to see the groundswell of trials come to us where if companies want to take that risk. Um, I think what we've seen now, we've been announcing these over the last six months is that companies are doing this more and more in a way where they see this opportunity become more and more uh, of an attractive place for them to do clinical development. Uh, of course the tried and true late line metastatic settings, um, are kind of a must do. Um, but now that there's four companies with PD1, VEGF, bispecific antibodies, I think they're trying to also differentiate their programs by looking for where can they go that's different and unique. That's certainly where this trinomolecular result, uh, opportunity, uh, becomes attractive. And that's really a data informed approach. You need to know where the patients are. And fortunately because we've expanded the signatera footprint to so many thousands of patients, we can provide that information in terms of how many patients are available for a trial, how can we get them on trial. We're doing a lot of work to help connect those patients who need an option to the trial, um, that can be deployed for them.

Ira Pastor: Mhm.

Eric Matthews: Awesome.

Ira Pastor: Awesome. Yeah, I love the way you put it. Sort of this drift from scan guided to molecular guided. And um, yeah, uh, it's definitely uh, an exciting time for the company. I'm excited for you and sort of being right at the center of this pretty radical shift in the way things have been done for decades now, but uh, clearly benefiting patients, uh, especially with these severe unmet needs in the oncology space and beyond that too. So um, I'm excited for you, um, again, uh, for everybody out there that uh, is going to be listening to this episode, uh, across the various podcast networks or uh, who will be watching on the YouTube channel, uh, you've been listening to Eric Matthews, general manager of Biopharma at Natera, doing really amazing work at the intersections of oncology, precision medicine, biopharma innovation. Uh, Eric, again I want to thank you for taking the time out of your schedule to come talk to us to update us on what's been happening at the company. Uh, thank you for everything you do there, for patience and if you like to say you're on our show, thanks for putting Create a Better Tomorrow for People. It's a great story and I look forward to helping share it.

Eric Matthews: Thanks Ira.

Ira Pastor: Really great having you.

Eric Matthews: Yeah, great to be here.