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Regulatory Documents for Newly Approved Liquid Biopsy NGS Panels Detail Diverse Test Claims, Methods

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NEW YORK – Recently posted regulatory documents on Guardant Health and Foundation Medicine's liquid biopsy tests reveal important differences, including the handling of germline cancer risk variants, that may affect oncologists' management of patients. 

This summer, the US Food and Drug Administration approved the first two pan-cancer multi-gene liquid biopsy tests: Guardant's Guardant360 CDx assay in early August and Foundation's FoundationOne Liquid CDx later that month.

The agency's documents summarizing the safety and effectiveness data for the two assays, which were recently posted online (see here and here), have provided new details on how the tests diverge not only in their companion diagnostic indications but more broadly in their design, scope, and reporting methods.

Differences in how the two tests deal with germline variants — inherited alterations that appear across the body's cell populations, rather than acquired somatic mutations that occur only in cancer cells — are of particular relevance as experts are increasingly calling for universal germline testing of cancer patients, given the importance of such information to understanding cancer risk for not only for patients themselves but also for their families.

In one study of nearly 3,000 cancer patients, presented last week at the American Society of Human Genetics' virtual conference, germline genetic testing uncovered pathogenic cancer risk mutations in 13 percent of tested patients, nearly half of whom would have been missed based on existing guidelines. The same germline genetic testing results led to a change in treatment for more than a quarter of patients. Based on these results, the authors, which included researchers from the Mayo Clinic and the genetic testing firm Invitae, called for universal germline testing of cancer patients. 

Guardant360 CDx is approved to report germline variants in a limited but important set of genes associated with inherited cancer risk. Other germline findings are filtered out before results are reported. FoundationOne Liquid CDx, meanwhile, reports all variants it identifies without distinguishing whether they are somatic or germline. However, according to the company, the lab report indicates that follow-on germline testing may be needed for detected variants suspected to be germline.

Liquid biopsy next-generation sequencing assays like Guardant's and Foundation Medicine's detect both somatic mutations and germline alterations in the overall pool of circulating cell-free DNA. Whether the detected variants are germline or somatic can be distinguished relatively accurately based on their allele frequency, since DNA fragments representing germline alterations tend to appear at much higher volume due to their relative ubiquity in the body compared to somatic variants.

In interviews last week, representatives from both Guardant and Foundation advocated for the benefits of their approaches to germline variants.

"If we see a variant that is suspicious for germline, we make it clear, as per the FDA [labelling for these tests], that this does not replace germline testing and that actual germline testing is indicated when appropriate. And we try to aspire to help clinicians know when that is," said Geoffrey Oxnard, who joined Foundation in June as the VP and global medical lead for the firm's liquid biopsy portfolio.

Foundation's policies in this regard are evolving, Oxnard added. "At a minimum, in the report, in the section that describes each gene variant, we say, 'This is known to be a pathogenic variant in ClinVar and it might be necessary for germline testing.' And we are even now in the process of refreshing that reporting to be as forthright as possible regarding when that's important for patients."

To add to this, the firm is also looking into ways to help patients actually get this follow-on testing, he added.

In contrast, Guardant has determined that it can best serve patients by focusing mainly on somatic mutations but also reporting a limited slate of incidental germline findings that "could have clinical relevance for treating the patient," according to President and CEO AmirAli Talasaz.

"Based on what we are hearing from the majority of our clients, sometimes less information is better, [as long as it is] inclusive of all clinically relevant mutations and complete in terms of NCCN guidelines," he said.

CDx claims

Notable differences between the two tests' tumor profiling and companion diagnostic indications represent another consideration for oncologists encountering or considering these newly FDA-approved assays for the first time.

Foundation's ctDNA test was initially approved as a CDx in two settings: for identifying non-small cell lung cancer patients with EGFR exon 19 deletions and exon 21 L858R alterations who are eligible for AstraZeneca's gefitinib (Iressa) and osimertinib (Tagrisso), or erlotinib (Genentech's Tarceva); and advanced prostate cancer patients with BRCA1/2 alterations who can receive rucaparib (Clovis Oncology's Rubraca).

This week, the company announced that the FDA had approved three more CDx claims for the test — for identifying PIK3CA-mutated advanced breast cancer patients considering alpelisib (Novartis' Piqray); BRCA1/2-mutated ovarian cancer patients eligible for rucaparib; and ALK-positive NSCLC patients receiving alectinib (Genetech's Alecensa).

In contrast, although Guardant has announced various companion diagnostic partnerships that are ongoing, Guardant360 CDx was approved with a single CDx claim, for detecting EGFR exon 19 deletions, L858R, and T790M in NSCLC patients eligible for osimertinib. Guardant prioritized this CDx indication, according to Talasaz, because EGFR testing in lung cancer is one of the top areas where not only its test, but genomic medicine as a whole, is being used.

The two companies' regulatory strategies with regard to these CDx indications also illustrate the multiple paths other labs might take to achieve such a designation in the future.

In Guardant's case the company was able to support its CDx claim for osimertinib by performing two bridging studies that demonstrated the safety and effectiveness of its assay in identifying patients eligible for the EGFR-directed treatment.

Foundation used a similar bridging approach to garner its BRCA1/2 CDx indication in prostate cancer but established its EGFR test claims in a different way — by proving its test was non-inferior to the FDA-approved Roche Cobas EGFR Mutation Test v2.

At least one of Foundation's newly announced CDx claims, however, was based on clinical trial data in which the liquid biopsy test was directly used to guide treatment, Oxnard said. In the study used to support the alectinib CDx claim, researchers used the Foundation test to directly assign patients to treatment.

According to Talasaz, additional CDx claims for Guardant360 may also be based on data from this type of interventional study but could also be from retrospective analyses where the company evaluates its test using baseline blood samples collected as part of already completed clinical trials.

"We have prioritized [pursuing CDx indications] for new and upcoming drugs," he said, adding that the firm expects to announce news regarding some of these pharma partnerships in the near future.

Assay scope

As more oncologists encounter these tests in their new FDA-approved form, an important consideration may also be differences in the overall breadth of genes gauged and depth of sequencing.

Debate over larger versus smaller NGS panels in cancer precision medicine is ongoing, with prominent companies and academic labs taking positions on both sides. Greater coverage of the genome obviously opens the possibility of detecting more cancer-associated variants, some of which could be informative for care. But the likelihood of finding useful variants outside of the most commonly mutated cancer genes is low enough to raise questions about whether the benefit is worth the potential risk of confusing or overwhelming ordering oncologists.

Beyond their specific CDx claims, both Guardant360 and FoundationOne Liquid are approved by FDA with a more general tumor profiling indication.

When these tests detect genetic variants that fall outside of the FDA-approved CDx settings, the agency notes that neither test is approved to guide treatment with specific drugs based on those results. That said, the breadth of the tumor profiling information an oncologist can access via the two tests varies significantly.

Before its FDA-approved liquid biopsy CDx test, Foundation had created two prior versions, both of which covered just 60 or 70 genes. The FDA-approved panel more than triples this at more than 300 genes, mimicking  its tissue-based NGS panel.

"We think there's something to keeping it simple. When we realized there was an opportunity to have two assays, liquid and tissue, covering the same genes … that was the elegant solution that meets the needs of cancer care today and where cancer care is going," said Oxnard.

The liquid biopsy test gauges variants across its full gene panel, but then bolsters this for approximately 75 clinically important genes, where variants can occur at much lower levels. "The compromise of depth in some regions makes the assay cost efficient and more scalable, so we can get a lot out of an assay that comes at a reasonable cost," he noted.

A complementary feature, Oxnard highlighted, is that FoundationOne Liquid CDx results are now reported with an estimation of tumor fraction that the company calculates based on a measure of genome-wide aneuploidy. This way, ordering oncologists know if a test result is based on a richer or more scant sample in terms of tumor DNA content.

Guardant's approval has taken a different path. The reportable range for the FDA-approved version of its laboratory-developed test covers only 55 genes, a reduction compared to the 74-gene non-FDA approved version it has been marketing now for several years.

Talasaz explained that the change reflects Guardant's desire to tune its FDA-approved offering so that it could report variants down to lower frequencies without losing sensitivity due to the presence of clonal hematopoiesis of indeterminate potential, or CHiP — a biologic phenomenon whereby blood cells accumulate somatic, but not necessarily cancer-associated mutations. CHiP has emerged as a significant confounding variable for comprehensive liquid biopsy panels.

"The sensitivity of the test was very important for us, and we wanted to make sure we keep our limits of detection still low and our cutoff for reporting clinical actionable mutations low," Talasaz said. "There are some genes where we find more mutations in them impacted by CHiP, which typically show up at low allelic frequency in blood. … So, we decided to go this route of reducing the reportable range to 55 genes on the IVD report."

This preserves Guardant's ability to report very low frequency mutations in the remaining genes of the panel.

Interestingly, ATM and CDK12 are not in the list of 55 reportable genes for somatic mutations due to their propensity to harbor CHiP mutations, but variants in these genes can still show up in the test report if they are determined to be germline.

Growing adoption

With FDA approval, both the Guardant and Foundation tests are now covered under the Center for Medicare and Medicaid Services' national coverage determination (NCD) for comprehensive genomic profiling assays in advanced solid tumors. And commercial payors may follow Medicare's lead. "We've learned from our tissue NGS assay [that] commercial payors rapidly come on board to support a test that has regulatory approval," Oxnard said. "And we're seeing that now with liquid."

Discussing its expectations around the FDA approval earlier this year, Guardant said that the NCD wouldn't make much of an immediate difference for Guaradant360's commercial progress, since the non-FDA approved version of the test already had local coverage from Medicare Administrative Contractor Palmetto GBA.

That said, the firm also believes that there is plenty of opportunity for broadening access to genomic medicine.

"A lot of early adopters remain adopters and are using our liquid biopsy product, but still, there are over 300,000 advanced cancer patients that we believe would benefit from our test," Talasaz said. "When you look at the whole comprehensive genomic testing field, tissue or liquid, you see that the numbers are increasing, but still, many patients are not getting genotyped properly."

Although the use of liquid biopsy testing has grown in recent years, the uptake has been greater within academic and large cancer centers than in the community setting, as is the case generally with precision oncology interventions. Now that two tests have FDA approval, it may sway more oncologists to evaluate firsthand the advantages of non-invasive testing.

"We believe liquid biopsy, with its fast turnaround time and ease of use in terms of logistics, could really increase the compliance to comprehensive genomic testing and the benefits for patients in [facilitating] access to the right treatment," Talasaz said. "This FDA approval is going to have an impact on oncologists who were staying on the sidelines."

Oxnard echoed this sentiment, highlighting Foundation's rapid expansion of CDx indications for the liquid biopsy test. "It feels like suddenly we are making liquid biopsy relevant to so many cancer patients who just six months ago were not sure if this is relevant for them," he said.