NEW YORK – As the diagnostics space trends more toward liquid biopsy, companies are shifting focus from using the technology to detect advanced stage disease to trying to discover earlier stage disease.
Foundation Medicine, a Roche subsidiary, took a step in that direction with its acquisition of Lexent Bio earlier this month, a decision that stemmed from "a desire to have more of a multiomic approach to our diagnostic portfolio," said Foundation's Chief Scientific Officer Priti Hegde.
Foundation has been active in the next-generation sequencing space and looking at somatic mutations to inform treatment decisions, Hegde said, but as the firm continues to understand the role of liquid biopsy, it needed an orthogonal tool to sequencing. Chief Medical Officer Brian Alexander also emphasized that Foundation is always searching for "more ways that we can get information that's usable by people" to make clinical decisions about treatment – "not just what treatment, but when." Liquid biopsy, he continued, offers options for patients and clinicians to get the necessary genomic data to make those decisions.
In addition to advanced cancer monitoring that Foundation is already doing with liquid biopsy, early-disease detection is an area the Cambridge, Massachusetts-based company is moving into. Methylation "provides a sensitive tool to identify disease" early when there are potentially restrictions on the number of tumor-specific DNA molecules available, Hegde said, adding that it provides them a method to look not just at tumor-specific signals, but also to get a sense of the tissue of origin.
Stephane Budel, a partner at DeciBio Consulting who monitors the liquid biopsy space, said that methylation is a "must-have" for early cancer detection and said there is "no doubt in my mind the market will continue" toward early detection.
Many of the decisions made for patients with early cancer are based on a physician's prediction about what the patient's chance of having a recurrence is and when it will happen, Alexander said. The nodal status and other different characteristics of the tumor help clinicians make those predictions but knowing whether there is tumor DNA in the blood would help with that decision, he added.
To emphasize the importance of knowing whether tumor DNA is in a patient's blood, Alexander cited an abstract presented at the 2019 San Antonio Breast Cancer Symposium which found that detection of circulating tumor DNA in early-stage triple-negative breast cancer after patients undergo neoadjuvant chemotherapy is an independent predictor of disease recurrence. The mutated DNA was detected using the FoundationOne Liquid assay.
Lexent's technology, which combines whole-genome sequencing, fragmentomics, and DNA methylation, is a key component of Foundation's steps into the early-disease space. The company is working on two different fronts: One product would provide comprehensive monitoring for advanced stage disease, quickly using the blood to make accurate assessments of response for patients undergoing therapy, and one would offer insight into minimal residual disease, said Haluk Tezcan, Lexent's former chief medical officer and now the VP of clinical development at Foundation. Lexent's products are still in relatively early stages of development, he added.
The company's technique uses initial pre-treatment whole-genome sequencing of a patient's cell-free DNA and application of algorithmic methods to quantify genomic changes over time. "Instead of a snapshot in time of the cancer, we are now providing a movie-like picture of the tumor, which I think will only enhance the current database of genomics and patient information," Tezcan said.
In contrast to a company like Grail, which looks for the presence or absence of a signal to identify early-stage disease, Tezcan said Lexent's minimal residual disease product is trying to go below where there is no evidence of disease present, just microscopic disease presence.
In a poster presented at SABCS last year, Lexent found that analyzing whole-genome, cell-free DNA early in the course of a new therapy "holds promise to identify patients with disease progression faster than traditional methods."
Lexent's Confera Dx assay is currently being used in the metastatic segment for monitoring disease over time, and Hegde said Foundation is interested in the application of its tools for continuing this monitoring. The company is also using its technology in the early-disease setting, although that application is less mature than the metastatic application, she said. According to data released by Lexent, sensitivity for the assay in identifying clinical progression was 54 percent and specificity was 100 percent.
Tezcan emphasized the importance of sensitivity for the assay's application in minimal residual disease and said that by combining the different signals from DNA sequencing and methylation, Lexent is trying to reach that higher sensitivity. One of the benefits of Lexent's technology is that the test they have developed is blood-based only, which Tezcan said made it easier for patients, since they only have to get blood drawn for it.
Last year, Lexent announced a non-exclusive partnership with Illumina to develop its Confera Dx assay to run on Illumina's NextSeq 550Dx system.
Foundation already has tools with "great applicability in the metastatic setting to inform treatment decisions for patients," such as the FoundationOne CDx test, which has been approved by the US Food and Drug Administration alongside more than 20 cancer drugs, or FoundationOne Liquid, Hegde said. But "as the oncology landscape is moving into the early-disease setting," Lexent had the specific technology Foundation was looking to develop and filled the gap in Foundation's offerings, she added. Foundation is still working on generating its own data in the early-disease space, but the acquisition proved to be "a lot more productive in the long run" for research and development than creating their own early-disease tools from scratch, Hegde said.
Budel said acquiring Lexent instead of developing its own technology will also allow Foundation to become entrenched in the early detection space early on, beating out other major liquid biopsy firms to stake their claim.
For Lexent, the appeal of Foundation was in its similar mindset about the importance of monitoring disease in both early-stage and metastatic settings, Tezcan said. They also "have the expertise and the background to be able to help us in trying to get our products … into the hands of clinicians and patients," he continued. Lexent will be fully under the Foundation umbrella, but will be able to work in a unit, Tezcan said.
Benefits for Lexent also include the name recognition of Foundation and Roche, which will offer Lexent credibility and awareness, Budel said. Foundation also has the robust sales force needed to promote Lexent's technology to oncologists who may not be familiar with the product, he added. Lexent's methods also have the potential to be expanded for use on healthy people to screen for cancer, Budel said, and Foundation's resources could help with those additional indications.
FoundationOne Liquid has applicability in the early-disease setting, Hegde noted, but was limited by the number of tumor DNA molecules that can be surveyed in plasma. Methylation provides a tool to build on sensitivity and specificity in early disease, and because Foundation has minimal experience in the methylation space from a diagnostic perspective, they needed a team with more expertise.
It is not just about the development of the diagnostic assay, however. The bioinformatics pipeline and algorithm to interpret data from the test was also important to Foundation as it considered applications in the early-disease space, and Hegde said despite Lexent's small size, they "have done a remarkable job of not just developing a diagnostic assay, but also having a very mature pipeline that allows you to interpret the data," allowing Foundation to "leapfrog from where we are today."
Lexent also has a rich biobank of clinical samples for both early disease and metastatic settings, which Foundation felt would complement its portfolio, Hegde said.
Foundation's broader plans around liquid biopsy involve its FoundationOne Liquid assay, which is currently being reviewed by the FDA for regulatory approval after submission late last year. The company has the FDA-approved FoundationOne CDx tissue assay, and Alexander said they wanted a liquid biopsy assay to generate data, as well. Hegde noted that liquid biopsy is a relatively new space, and that "a lot of the things that we're doing here are things that we're doing for the first time, so we're sort of collectively defining a path here for liquid biopsy that has regulatory approval."
Hegde said it was too early in Lexent's research and development stage to discuss what cancers would be prioritized, but said the company is interested in pan-cancer tumors. Foundation is interested in developing a toolbox for cancer, irrespective of whether the tool is tissue-based or plasma. "We're just really interested in developing tools that inform patients on their treatment journey," Hegde said.