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Julia Kirkland: From DeciBio Consulting, I’m your host, Julia Kirkland, and this is The DeciBiome…

Whether we are keeping you up-to-date about the latest news in the life science industry, or providing you with compelling debates, we have got you covered.

Today we have a particularly interesting debut episode as we recap trends and activity in 2022 and discuss 2023 projections and predictions in the liquid biopsy space with real takes from clinicians and biopharma stakeholders across the industry! Super exciting episode here today, (Alex), I’ll let you take it away

Alex Amram: Liquid biopsy is a rapidly growing area in the field of precision medicine. As a pulmonologist we spoke to defines it: Liquid biopsy refers to the analysis of tumor-derived circulating genetic material in the serum or other body fluid.

Popular analytes of interest include known oncogenic or tumor suppressor gene mutations on freely circulating tumor DNA (ctDNA) that sheds from the contents of dying cancer cells, epigenetic modifications or methylation, and fragmentomics of the tumor DNA (deoxyribonucleic acid) in genes of interest, multi-omics which is the combination of multiple analyte analysis in a single test, and even the analysis of whole circulating tumor cells (CTCs) that have metastasized or at the site of interest.

While tissue biopsies have long reigned as the gold standard, liquid biopsies offer a noninvasive, faster approach with increasingly comparable diagnostic efficacy measured primarily by metrics such as percent test sensitivity and specificity in detecting cancers, and their adoption is quickly growing, marked by new investments and developments in the space seen monthly.

To overview current liquid biopsy use in oncology, the field fits predominantly into three main application areas: 1. Early cancer detection (EDx), 2. therapy or patient selection (Tx), 3a. and MRD or 3b. monitoring, MRD referring to minimal residual disease.

Early cancer detection aims to shift cancer care by catching patients at earlier stages in cancer development, therapy and patient selection focuses on targeting therapies to patients who are most likely to benefit from them, and MRD and monitoring consists of multiple use cases at the end of the patient journey looking for signs of minimal residual disease in the blood that might indicate recurrence, therapy responsiveness, and even also guiding therapy selection.

But where is liquid biopsy moving? And how fast are these developments approaching? Well, to hear the thoughts and hopes of stakeholders, we spoke to a few oncologists and pathologists to understand what they think will be the most interesting liquid biopsy developments to happen in 2023.

First up, a pathologist at a hospital network we spoke to expects early cancer detection to be the most impactful development for liquid biopsy

Pathologist, Hospital Network: Instead of continuously chasing after new treatments, which eventually ends in death, the potential for catching cancer early on in the disease process, I think will be quite a game changer.

Amal Thommil: Thanks for that intro Alex. As the pathologist mentioned, interest is gathering around NGS-based (next-generation sequencing) early cancer detection and the potential shifts in patient care it can create as cancers are caught at earlier stages.

Early cancer detection can include targeted, single-cancer approaches, such as Guardant SHIELD, intended for detecting early signs of colorectal cancer (CRC) in average-risk adults, which announced availability in the US in 2022; or broad multi-cancer approaches, such as GRAIL’s Galleri, which is currently undergoing large clinical trials to showcase its utility as a broad population screener.

While current early cancer approaches, such as mammograms for breast cancer and colonoscopies for colorectal cancer, are expected to take a long time to phase out, stakeholders expect single cancer early detection, especially for large incidence or high shedding cancers, to be more feasible in the short term as complementary assays, while multi-cancer approaches collect more data that will take more time to establish clinical utility.

The pathologist also mentioned that while early detection may be the biggest game changer, they still think MRD and monitoring - and even its use for therapy selection - are very significant development

Pathologist, Hospital Network: Also, the detection of minimal residual disease is significant though not nearly as much as cancer detection. However, I think when you can catch relapses early, it will be very impactful for the patient especially when there is potential to try new treatments, stronger doses or second and third line treatment options.

MRD has a myriad of potential use cases from determining the need for adjuvant therapy post-surgical resection, evaluating responses to a therapy, to monitoring for any signs of relapse. Stakeholders note their confidence in MRD’s clinical utility and impact on patient care is also increasing with clinical trial readouts. In 2022, we saw Guardant Reveal’s coverage approval for CRC and Natera’s Signatera test expanding coverage from CRC to include muscle invasive bladder cancer (MIBC) as a Medicare reimbursable indication.

Amal Thommil: While developments in MRD testing and adoption are on a more indication-by-indication basis due to different cancers having distinct testing and treatment paradigms and varied shedding of circulating tumor DNA into the blood, an oncologist we spoke to from an academic medical center (AMC) describes an interesting use case across indications that he sees in the short term

Oncologist, Academic Medical Center: The most interesting liquid biopsy development I see happening in the near term is the integration of serial monitoring for identifying tumor progression and treatment response. I think that this is being explored across a number of products and particularly in the disease of lung cancer. I see a use case for comparing the detectable ctDNA levels over time as compared to CT scan imaging.

Amal Thommil: Another oncologist from an academic medical center outlines some interesting trials using ctDNA analysis that are set to read out in 2023

Oncologist, Academic Medical Center: In a prospective study of breast cancer patients undergoing regional nodal irradiation, investigators are evaluating changes in ctDNA and their correlation at several time points subsequently to invasive recurrence free survival (RFS). An interesting part of this study, the investigators will also evaluate changes in T cell immunological phenotype during and after radiation.

In another study in breast cancer, investigators are aiming to identify breast cancer subtype specific tumor signatures through whole genome sequencing (WGS) of ctDNA. This study may identify, through comparison with healthy volunteers, a set of loci across the genome most informative of cancer contribution and cell free DNA (cfDNA) among patients with resectable melanoma, who received neoadjuvant, checkpoint blockade or BRAF targeted therapies.

Another study hopes to correlate changes in ctDNA concentration during neoadjuvant therapy with pathologic complete response. This will be particularly important in identifying the subset of patients who are not responding as expected to new adjuvant therapy and may benefit from treatment escalation or surgery at an earlier time point in their treatment trajectory.

Gastrointestinal malignancies are arguably the area with the most robust evidence to date. An interesting study from MD Anderson is evaluating the impact of lifestyle changes combined with aspirin and vitamin D among patients with colorectal cancer, treated with definitive therapy, who have detectable ctDNA. The study hopes to determine the clearance rate after three months of optimal lifestyle intervention. I find this study interesting because as an athlete myself, it will be fascinating to see what impacts diet and physical activity can have on ctDNA.

Through these liquid biopsy developments and more, this year will bring us closer to further individualizing therapy for patients with solid tumors.

Amal Thommil: As novel therapies arise and therapy paradigms shift, therapy selection will remain crucial in the patient journey within oncology. A medical oncologist from a community hospital expresses their thoughts on where liquid biopsy will be in 2023.

Medical Oncologist, Community Hospital: “I believe the use of liquid biopsies will become much more commonplace in the curative setting. Currently, in diseases such as lung cancer and colorectal cancer, we have different new ways of using therapies that both involve either chemotherapy and or immunotherapy. In a curative setting for patients with early stage disease at a time when there's no tumor that we can see on scans. However, we know that treating in this setting will prolong survival.”

Amal Thommil: Coming back full circle to the pulmonologist who defined liquid biopsy for us, they leave us with some of their hopes for the evolution of the liquid biopsy landscape

Pulmonologist, Community Hospital: “There's no current liquid biopsies approved to my knowledge that assess PD-L1 status. So, it's certainly an evolving treatment landscape. I certainly look forward to upcoming trials and new available products that will help in the early detection of these issues and also improve the sensitivity of testing. It certainly currently does have its place in the treatment landscape, but I'm sure as the technology evolves, and we have more randomized control studies, that this will become a more important part of the lung cancer, diagnosis, screening, and treatment landscape.”

As the stakeholders we speak to note, applications across liquid biopsy hold great potential in impacting the standard of care for patients, but at different points and timelines. Early cancer detection can shift cancer detection to earlier stages and be a game changer for a patient compared to a new therapy, but multi cancer early detection (MCED) is still a distance from wide clinical use and single cancer early detection (SCED) is the likeliest in the near term.

MRD or monitoring allows noninvasive frequent touch points for patient response surveillance to therapy or signs of relapse before imaging detection could potentially inform therapy escalation or deescalation or earlier action against recurrence.

Therapy selection remains a core point in the diagnostic workflow of a patient and there is potential for liquid biopsy to be more commonplace, or include new biomarkers, to help patients receive effective, targeted therapy.

Amal Thommil: Now here’s Andrew, a partner at DeciBio who leads our efforts in liquid biopsy, with some of his thoughts and predictions for LBx in the near term:

Andrew Aijian: 2023 is going to be a big year for liquid biopsies. We've known for quite some time and there's been a lot of talk about how the MRD and monitoring and early detection markets are going to be huge market opportunities. There's been a lot of investment and development efforts in these areas and we saw a little bit in 2022 of the potential with tests like Signatera from Natera seeing pretty high uptake and adoption in the early years. We began to see the potential of these markets

I think 2023 will definitely be the year where we'll be able to see more clearly what the market opportunity is now that we have multiple MRD and monitoring tests commercially available. We're expecting to see some developments with respect to inclusion in guidelines, reimbursement, and FDA approval. We also see multiple early cancer detection tests that are now commercially available. I will be tracking very closely the rate of adoption of these new assays and see, are they trending and are they projected to be as accessible as many sort of industry observers have anticipated?

These are still fairly young markets, but you know, based off of some of the the early trajectory, we expect that within the next couple of years MRD and monitoring, as well as early detection; the volumes in these applications are going to significantly surpass volumes from therapy selection testing. It will just be interesting to see when that happens if this is in the next one or two years, or closer to the next three or four years.

The other thing I'm looking at in 2023 is what I call these next-generation liquid biopsies. These are tests like the Guardant Infinity, Caris Assure, or Personalis’ NEXT Personal liquid biopsy assay, which are all much more comprehensive in terms of the size of the panels as well as different types of analytes that are being incorporated into liquid biopsy assays. I'll be interested to see what the adoption and uptake of these assays looks like. These are all being targeted towards pharma research. They're much too big for routine clinical use, but the expectation is that there's an opportunity within pharma for much more comprehensive blood based profiling. And so, I will be interested in understanding what the adoption looks like within pharma and the extent to which these new assays can be incorporated into research programs at a price that pharma is willing to accept, because we've already been hearing that the pricing for some of these research assays is not sustainable and this is not even accounting for the next-gen. assays. Even for the current generation of assays, pricing is already perceived as being too high even by pharma standards. Pharma has expressed that they're not able to incorporate these assays into large-scale research programs because the present costs are too high. That being said, pharma does have an appetite for more and more information, so how are they going to balance that appetite for more and more information while also keeping an eye on the cost and the spend on these assays?

It'll definitely be interesting to see which of these assays gains more traction? What are the types of research insights that pharma gains from all this additional molecular information? And to what extent can they actually implement them at scale in their research programs given the supposedly higher costs of these assays will have to be justified by all the additional analysis?

Amal Thommil: Thanks Andrew, and something I want to understand more is your expectations on decentralization of testing. Blood samples are easier to biopsy or collect, but when do you see a shift from centralized testing?

Andrew Aijian: One of my other hypotheses for 2023 is that we'll begin to see more decentralization of liquid biopsy testing for therapy selection, particularly in the US. I think there's increasing acceptance of the clinical utility of liquid biopsy and volumes are getting high enough to the point where certain labs are going to be able to better justify bringing that testing in-house. This market, to date, has been largely centralized to specialty reference labs. But we think that just the increasing volume of liquid biopsy tests for therapy selection, and potentially some of the monitoring applications, is going to drive interest in bringing this testing in house.

There are some kits available that will enable labs to do this. I think MRD and monitoring as a whole will likely remain centralized in the near term, partly just due to some of the availability of the assays that are out there. Also, there's at least a sense among stakeholders that the MRD application, the post-surgery application, requires pretty exquisite sensitivity, which many people believe favors the tumor-informed approach. I don't anticipate that that tumor-informed approach is going to be decentralized. Broadly, that's an approach that is likely going to be better executed from a centralized perspective. However, some of the surveillance and late stage monitoring applications, especially when in the late stage where exquisite sensitivity isn't really as important; that can certainly be decentralized. I expect at some point, maybe not in 2023, but we do expect to see that late-stage monitoring picks up the opportunity for some decentralization of that type of testing.

Julia Kirkland: If you’re as excited as us to see where liquid biopsy goes from here and to keep up with the interesting developments mentioned, check out our monthly LBx Newsletter on LinkedIn or on our website where we gather important clinical and commercial news.

Thank you to Amal, Alex, and Andrew from DeciBio Consulting for their commentary and production help. Thanks to all of the stakeholders who participated and gave their insights. And Thank you Cameron Braverman for the beat on this podcast. And lastly, thank you to our listeners for tuning in. Hope to catch you next time on The DeciBiome.