NEW YORK – Liquid biopsy assays of increasing breadth have begun to proliferate and push into the clinic as US companies seek to differentiate themselves in a crowding market.
Although innovators diverge in their ambitions and timelines for clinical implementation, they generally agree that broader panels comprising hundreds or potentially thousands of genes are valuable to patients and represent the future of precision oncology. And while these panels are being implemented in pharma research and in a limited clinical capacity, their immediate benefit to patients is still under debate.
Recent launches include a new 523-gene panel, xF+ from Tempus, which the company highlighted this summer as the largest clinically available liquid biopsy panel.
Caris Life Sciences also announced a new whole-exome liquid biopsy product in June, called Caris Assure. Both firms began with limited initial launches with plans to expand to a wider market during the latter part of this year.
The new assays join several other broad sequencing panels developed in recent years, most of which have been primarily oriented toward research, including Personalis' exome-sequencing assay NeXT Liquid Biopsy, Guardant Health's OMNI assay, which is similar in size to Tempus' new xF+, and Personal Genome Diagnostics' PGDx Elio plasma complete kit.
"By expanding broadly in tissue, we have been finding more," said Caris President and Chief Scientific Officer David Spetzler. "It's not driven by one gene at a time … so when we started to look at liquid, it was already from this mindset of understanding that whole-exome and whole-transcriptome sequencing will be superior."
"We didn't want to start small and miss the opportunity to generate this data because at the end of the day, what's going to accelerate the science and the medicine is collecting the data and getting to work on it," Spetzler added.
The utility question
According to liquid biopsy pioneer and Memorial Sloan Kettering oncologist Luis Diaz, the conversation around utility of broad liquid biopsy testing shifts depending on who is participating.
"You have three different constituencies that have very different interests," Diaz said. "Pharmaceutical companies are trying to mine all these exomes and genomes for targets for their trials, and they're like, 'Great, this is going to help us.' I think pharma in general would be content as long as the price point doesn't break CMS's or payors' banks."
Similarly, for researchers doing discovery and translational work, more data is, of course, exciting. "[It] doesn't always lead to more things, but every so often we'll find something novel," Diaz said.
That said, there remains skepticism about the actual benefit to patients, he added. "One of the things I've been waiting for to happen but hasn't happened is … blowback from the clinical community, saying 'Listen, we're doing all these huge panels, but in most cases, we're not finding anything that is going to save the patient's life,'" Diaz said.
Tempus Executive VP of Oncology Mike Yasiejko said that his firm's decision to broaden to over 500 genes but not a whole exome reflects an intention to be forward-looking in terms of emerging utility, but also practical in terms of the current costs of sequencing and limited added value considering currently available therapies.
"Given what our model is, we really want to try to lean in on not only thinking about the assays that are necessary immediately, but the ones that will allow for the support of emerging therapies and … will make it so that the workflow for the practicing clinician is as easy and simple as possible, while exposing as much potentially relevant information for the care of that patient as is possible," Yasiejko said.
Tempus has been marketing a 105-gene liquid biopsy for several years. "I want to say in 2020 we began talking about what an expanded panel begins to look like — what are the things that we think we need to build … so that we could create flexibility, as we knew there was going to be a lot of innovation happening in the drug development space," Yasiejko said.
The company decided on 500+ genes as a sweet spot to maximize efficiency and immediate clinical value, while simultaneously supporting research without the need for separate assays to be performed.
"If you look in [databases] or think about cancer biology, there's a sliding scale in terms of which genes are involved," said Nike Beaubier, Tempus' senior VP of life science pathology. "KRAS and p53 probably get you 80 percent of cancer patients. And then it's probably really about 600 genes or so that are involved in cancer on some level. And that's kind of the area that we're hitting now."
But different players in the space apparently view the value of farther reaches of the genome differently.
For example, Caris' Spetzler cited a very different number than Tempus' estimate of 600 genes regarding the amount of the genome involved in the generation and perpetuation of malignancies. "If you do a literature search, you'll find that over 87 percent of all genes are showing up in publications as being associated with cancer," he said.
"Fundamentally, I think what we've been suffering from is kind of the looking for your lost keys under the lamppost scenario," he added. "If you're only looking for BRCA, you are only going to find BRCA."
Personalis CEO John West echoed this sentiment. "I have to admit, I kind of look at it after all these years … the fact that we're in 2022 and people would still be saying, well, we're going to look at half the genes, or 40 percent … [its surprising considering that] the sequencing has become so much less expensive," he said.
Personalis has kept its blood-based exome sequencing focused on the research space for the most part thus far. West suggested that the path forward is indeed into the clinic, but the company isn't pushing for that until a case can be made for clinical utility above and beyond targeted panels.
He made a case for letting academia drive the generation of clinical utility evidence. "When Foundation Medicine came out in 2009, most of the clinical utility for what they had done was already established by other people. In general, the diagnostic industry has not necessarily led the way in terms of establishing clinical utility," West said.
Caris, in contrast, sees itself a crucial driver of this innovation.
"You can't wait and assume that somehow the data is going to magically appear. We have to generate the data," Spetzler said. In that vein, the company has been collecting clinical outcome data on what he called "the vast majority" of its clinically tested patients "to generate the data to show that size matters, that bigger is in fact better."
Spetzler also argued that there are already clinically established genomic features that benefit from broader sequencing, such as loss of heterozygosity to guide the use of PARP inhibitors. "As we start to increase our understanding of the complexity of molecular aberrations that drive cancer, we get better and better about guiding particular patients to the right therapy," he said.
Caris, Tempus, and Personalis all mentioned tumor mutational burden, a recently instituted but complicated and controversial immunotherapy biomarker, as a primary driver for implementing broader liquid biopsy panels.
"TMB is one of the main drivers of creating bigger panels," Beaubier said. "A hundred genes or so is not enough to do it accurately because driver genes are overrepresented. You really need at least 300 or 400 genes to do TMB at all, and the more the better."
Personalis' West and Caris' Spetzler argued that even several hundred genes are not enough for deriving TMB.
"As we start to think about tumor mutational burden, we know that the very best way of measuring that is this whole exome. Anything less than that is an estimate," Spetzler said.
West went even further, arguing that even exome-scale mutation data may not be enough to properly tune and optimize mutational burden as a biomarker of response. Personalis, he said, is working on an approach that couples exome-scale sequencing with gene expression analysis, to determine not only how mutated a cancer is but also how antigenic it has become as a result.
This, he argued, may be the feature that definitively makes the case for clinical utility of exome-wide liquid biopsy, persuading payors to cover it at rates that match the cost of sequencing.
"We can create a biomarker that looks at this … and we have better and better versions of that; it's becoming more and more accurate now, but it will still take time," West said. "To get that to the clinic would require clinical utility studies that would show the efficacy of that and make it clear what are the exact clinical decisions that would be informed."
He also pointed out, however, that "we know that that in many kinds of cancer, only maybe 20 or 30 percent of patients respond to checkpoint inhibitors like Keytruda." While many patients are given these drugs, and the hope is that something will happen, "people don't really know," West added.
According to Diaz, the optimization of current biomarkers and the generation of better ones are lesser problems than the need for new, better therapies. "The real limitation is that we need more drugs … that work," Diaz said.
He added that he applauds the engineering required to develop increasingly comprehensive panels and even whole exomes for liquid biopsy, but the ultimate benefit is still more of a hypothesis.
But Caris' Spetzler argued that this too can only be accelerated if more exomes and transcriptomes are sequenced in clinical practice and linked to clinical data. Research use won't cut it.
To that end, Caris' initial launch has made the Assure assay available to a limited number of customers, including members of its Precision Oncology Alliance, a group of about 70 institutions that pledge to collaborate on research utilising the firm's growing clinical and genomic database.
"One of the things that's super important first and foremost, is that this is a clinical assay meant to help patients. We have to have fast turnaround, so we are starting slow so that we can make sure that we are delivering on time and then we can scale it up," Spetzler said.
Tempus said much the same of its plans for xF+. "It's important that we gather feedback and we listen to that feedback … so that we can make adjustments and tweaks as we think about that broader rollout," Yasiejko said.
He added that feedback thus far has been "very positive."
"We've seen a lot of uptake in the academic medical centers thus far, but increasingly in community practices as well, and we do want to make sure that we're getting feedback from community oncologists, because we obviously know that majority of patients are being treated there."
Broad liquid biopsy tests benefit from the example set by their tissue-based predecessors, with streamlined reporting systems that highlight the most relevant findings for physicians now ubiquitous in the field.
Tempus' clinical report highlights therapy matches upfront with clear information about trial matching. "You don't want to give [physicians] a 50-page report that they have to spend an hour trying to read. So, although it's a big panel, we make the report very user friendly and approachable," Beaubier said.
"There is art and science to what's happening behind the scenes," added Yasiejko. "The broader panel is effectively your choice set, and then based on that individual case, there are different things that are highlighted or not highlighted, with the net result being the simplest report possible that provides the relevant associations to therapies and trials based on that individual case," he said.
Data on all the genes is still available, Beaubier said. "If they want to look at gene number 514, 515, we give them that data. … They can go to the files … and write papers, generate hypotheses, what have you. And that's really part of our mission, to push the field forward, but at the same time, those mutations aren't going to be front and center in the report by any means."
A similar approach also works for Caris, though the long tail of additional findings can be much larger with exome-scale sequencing. Interestingly, the company only highlights a conservative list of about 200 genes in its clinical report, Spetzler said, though this is "constantly expanding as new evidence is published." Meanwhile, cost remains another point of contention, with Tempus' Beaubier expressing skepticism on the financial feasibility of whole-exome liquid biopsy sequencing.
"I can tell you, just a 523-gene panel is very expensive to run, because you have to sequence so deeply … around 5,000X deep," she said.
Spetzler said that while assessing mutations across the whole exome and transcriptome is anything but easy and isn't cost-effective with current reimbursement and sequencing costs, the company still believes it is worth it in the long run.
"It's an investment that we're making because we believe this is the future," he said.
In the meantime, because Caris has such a large-scale operation, the company can achieve economies of scale that make it "more reasonable for us than it would be for anyone else," Spetzler argued. "We're already running 400 exomes and transcriptomes a day so adding in more at higher depths isn't too terrible," he said.
Furthermore, Spetzler said, its test is reimbursed the same as any liquid biopsy sequencing assay, which means that it falls under the standard rate established by Medicare and thus is actually cheaper than certain small panel tests that draw higher reimbursement due to ADLT status.
"There's no difference in cost between ordering everything from us versus something smaller from somebody else," Spetzler said.
Spetzler added that Caris believes the tipping point is imminent for making a clinical utility case for exome-scale liquid biopsy over small panel tests.
"We're now approaching a couple 100,000 patients where we have full transcriptome data, 160,000 patients where we also have full exome data, and we've been doing that for a couple of years in tissue," he said. "We have to wait long enough to see how the patients did, what drugs they got, [and] what happened to them. And once we have that mature dataset, we can start to go in and find these patterns, [but] we've been doing this long enough that the cohort is large and we're hitting that point where we can actually start to analyze the data."
"That's when … the utility of exome and transcriptome becomes truly revealed, and that's going to cause, I think, a pretty significant shift," he said.