Personalized Estimation of Motality Risk – Digital Age Makes it a Reality

Rory McCann:
I'm Rory McCann with Cambridge Healthtech Institute. I'm joined today by Dr. Mark Stewart, who is the Vice President of Science Policy at Friends of Cancer. He's been invited by SeraCare, a longtime premier sponsor and partner of Molecular Medicine Tri-Conference, to speak during the Companion Diagnostics and Clinical Biomarkers program in San Francisco next month. Mark, thank you for joining me today.

Mark Stewart:
Thanks for having me. I'm really looking forward to this.

Rory McCann:
Would you start by sharing a little bit of a background on tumor mutation burden and its role as a biomarker to guide cancer immunotherapy in clinical trials and patient care?

Mark Stewart:
I guess, in its simplest terms, tumor mutational burden is simply the total number of somatic mutations that are counted within a tumor genome, and this can vary according to tumor type as well as among patients. There's evidence that's emerging that shows association of tumor mutational burden with neoantigen load.

Neoantigens are, in effect, these novel self-service epitopes that help our body recognize it as a foreign substance. In fact, it leads to increased T cell reactivity and, therefore, leading to a antitumor immune response, which is the way that these immune checkpoint inhibitors actually function.

In the simplest form, I think tumor mutational burden simply measures the quantity of mutations found in a tumor. Its use as a biomarker is being heavily investigated now in order to evaluate whether it may help predict the likelihood of a patient that has cancer to respond to immune checkpoint inhibitors.

We actually recently published a paper that just came out last week, and the number of trials that are being currently conducted investigating tumor mutational burden is significantly increasing and, in fact, just in 2018 alone, there were 54 trials that were identified in clinicaltrials.gov with an estimated enrollment of over 11,000 patients. So, it's clearly an emerging biomarker that a lot of people I think are excited at its possible potential.

Rory McCann:
Could you share a little bit about who Friends of Cancer is and what is their role in the TMB harmonization efforts?

Mark Stewart:
There are probably many people that might not be aware of Friends of Cancer Research, but I suspect they are quite aware of some of the outcomes of many of our efforts. Friends of Cancer Research is an advocacy organization based in Washington, DC. We were actually founded in 1996 and, as our name might suggest, our first efforts really focused on increasing public awareness and support for cancer research. We did this by hosting a number of town halls across the U.S. with a goal of really trying to identify and create new champions for biomedical research.

We're also looking at running our software and our platform within other health solutions, including ones that might be used in workplace wellness solutions. So we're basically building the science base, the proof points that this can be done, and it has the potential to add tremendous value in the form of health impact, and then picking the right place from a business perspective to get started with scaling.

It was over the past decade where our focus really transitioned into looking more at regulatory processes and how there was this void where patients really didn't quite understand or weren't quite as involved in the regulatory aspects of drug development. So, we started working closely with Congress and federal agencies, and I think since that time to now, we've really become a leading advocacy organization that's having a great partnership with FDA, and drug sponsors and academia has really helped the lifesaving innovations to patients.

You know, I do think people look at our previous efforts in drug and diagnostic development and recognize our ability to get the right people together and really work towards consensus recommendations, particularly trying to get people in a room together that may not necessarily always work together, work well together. I think that puts us in a unique position, particularly around this whole tumor mutational burden harmonization effort that we have underway.

We also have the ability to really integrate the patient voice into this. That's really what the driving factor for this whole harmonization effort is. The use of immunotherapy has really taken off in recent years, and it's exciting to see that there are some cancer patients that have experienced incredible responses to these new therapies, but unfortunately, that benefit's only been seen in a minority of cancer patients. So, there's certainly a need to be able to better identify the patients that are likely to respond, and that's where tumor mutational burden really comes into play here. I think recent clinical studies have certainly associated high TMB with improved patient response rate, and it's clearly emerging as a biomarker response for these immunotherapy agents.

Rory McCann:
What are some of the barriers to harmonization at this point? The need is great for harmonization. What are some of the challenges you're currently experiencing in your efforts?

Mark Stewart:
Recent clinical studies have associated high TMB with improved patient response rates and survival from immune checkpoint inhibitors, and as a result of TMB, it is emerging as a biomarker response for these therapies. But if you look at the various diagnostic tests that are available and methods, you'll notice that there's quite a bit of variability in terms of how TMB estimation and reporting is currently taking place. I think that in itself certainly demonstrates a need for standardization and harmonization of TMB assessment across assays and sensors.

One is for the relatively small number of genes that we understand well enough to screen for with deep coverage in sequencing, probably in the range somewhere of 59 to 150 genes or so, those need to probably be screened for in everybody, and it's now reaching a price point where it's possible to do that, and the results of that is people have new opportunities to protect their health by better understanding their risk, particular disease that are associated with variance of those genes.

Practically speaking, these different ways in which labs are presenting TMB can ultimately lead to confusion for oncologists and patients. So, recognizing this, we've convened a working group involving cancer institutions, diagnostic partners, drug sponsors, the FDA. It's truly been a collaborative effort, and I think without key partners like the National Cancer Institute and SeraCare really coming to the plate, I think we'd be in a much different position than we are now, so we're very fortunate to have all of these key players involved in this project.

Rory McCann:
Who are these market leaders for the TMB assays? Who are the key players in this effort?

Mark Stewart:
While no test has been approved for use in the clinical setting, there's certainly a number of diagnostic companies and academic centers that clearly recognize the importance of TMB and are developing assays. There are two assays that I'm aware of, one being the FoundationOne Companion Diagnostic, and then the Memorial Sloan Kettering MSK-IMPACT test, that have received approval and authorization respectively. There are several targeted gene panel assays from a number of other companies and organizations currently being developed and validated, including some that are looking at TMB assessment in the blood.

Rory McCann:
What are the global considerations that we should keep in mind going forward? You're working with these great U.S. organizations, but are there any global considerations we should keep in mind as you go forward in your research?

Mark Stewart:
The scenario that you're seeing playing out in the United States certainly isn't unique, and the same concerns and considerations around the need for harmonization for measuring and reports in TMB is a global concern. We've actually had the fortunate opportunity to connect with a variety of other efforts that are taking place in other countries and continents. We've actually had the fortunate opportunity to partner with a few other organizations in other countries and continents.

One of those is the organization called QuIP in Germany, which stands for the Quality Assurance Initiative Pathology. We've had a successful partnership, I think, because we've had some shared pharmaceutical organizations and diagnostic companies involved in our efforts. When we first came together a little over a year ago, we both kind of laid out our strategy for harmonizing TMB.

As a result, we were pleasantly surprised to see that, in fact, we were adopting kind of complimentary and multidisciplinary approaches towards the same goal, which I think added some confidence that we were likely headed in the right direction. As data from our different efforts have been generated, we've been fairly open in terms of discussing kind of the implications and recommendations that we're able to draw from them. At the end of the day, we want to ensure that the recommendations that we do put forth are implementable, not just within the United States but can impact and have positive effect for patients globally.

Rory McCann:
Thank you for being part of the Molecular Medicine Tri-Conference and its Companion Diagnostics and Clinical Biomarkers program. We are looking forward to meeting you in San Francisco. What are you planning to accomplish by attending and presenting at the meeting?

Mark Stewart
Sure. I'm really excited to be at this meeting. I have to admit, it's my first time going to it. After looking at the website and the speakers that are going to be there, it's just an incredible opportunity, I think, to be able to interact with all the experts in the field that are gathered at this meeting.

For us as an organization, it's exciting to hear about what are some of the current efforts currently taking place within the field of companion diagnostics and biomarkers, but more importantly, it's exciting to see what's on the horizon. As an organization that's really looking at ensuring regulatory pathways, and developmental pathways really speak to the market, it's important for us to really know what scientific innovations are currently taking place so we can better prepare for them.

Generally speaking, there's a lot of activity around the use of liquid biopsies. It's of particular interest for our organization, as we're undertaking a new pilot project here in 2019 around the clinical application of liquid biopsies, so I really look forward to seeing some of the talks and meeting some of the speakers to learn more about it.

Rory McCann
Well, we are looking forward to having you there as well and hearing your talk, and hearing what Friends of Cancer Research is doing this year and what you're looking forward to in years to come. Mark, thank you so much for joining us, and we look forward to seeing you in San Francisco.

Mark Strong
Thank you. I look forward to it too, and hopefully the weather's a little warmer there than it is in DC right now.

Rory McCann
You can hear more from Mark and SeraCare on Tuesday, March 12. You can check out www.triconference.com, that's triconference.com, for more information. We hope you'll join us in San Francisco.