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PGDx Shares New MSI Data, Provides Update on FDA Bid for Pan-Cancer IVDs

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NEW YORK – Cancer sequencing firm Personal Genome Diagnostics reached a milestone earlier this month with the publication of a study describing the development and initial validation of a method to glean patient microsatellite instability status from liquid biopsy, rather than tissue NGS data.

The results, published in Clinical Cancer Research, come as the company doubles its efforts to gain US Food and Drug Administration approval for what it hopes will be the first comprehensive cancer sequencing IVD kits for both tissue and blood samples, both of which will include MSI assessment.

Historically, MSI was only tested in the context of hereditary colorectal cancer syndromes, but recent evidence has cemented the fact that it also occurs across the landscape of different cancer types. In addition, it has shown itself to be a strong predictor of response to immune checkpoint blockade, culminating in the FDA's 2018 tumor-agnostic approval of pembrolizumab (Merck's Keytruda) for patients with microsatellite unstable disease.

As a result, MSI assessment has emerged as a desirable, if not necessary, component in precision oncology and cancer profiling.

In its early days PGDx offered centralized NGS testing to oncologists through a CLIA lab, but the company shifted in the last few years toward the development of sample-to-answer IVD kits, which it believes will be necessary to broaden access to personalized cancer care.

According to John Simmons, PGDx's vice president of translational medicine, the company is no longer performing any routine patient testing through its CLIA lab — only tests for clinical trials and other research studies — throwing much more of its weight behind its FDA IVD bid.

"Today we are we're talking about 15, 20 percent max, of advanced cancer patients in the US getting genomic profiling done at all," Simmons said. "Several years ago we as a company made [this] transition because we saw what was on the horizon in terms of drug utility and we felt that the evidence had grown to the point that really it was time to start developing these kits as end-to-end solutions that could go out into the marketplace and enable the pathology labs around the globe to provide this testing.".

PGDx received breakthrough device designation from the FDA last year for the kit, which it calls elio plasma resolve, based at least in part on the assay's potential to detect MSI status in plasma as an aid in selecting patients for immunotherapies.

According to Simmons, although the company can't share a timeline for the FDA process, the firm has made "significant progress this year." PGDx also announced CE marking for elio plasma resolve in May, opening up use of the kits to European labs.

"I can't speak to the market uptake but I can say we certainly are engaged with European labs and also very actively engaged with many thought leaders in Europe to build out further clinical evidence and utility for both our tissue and plasma product," Simmons said.

Although the MSI study that appeared this month was conducted using the company's lab-based liquid biopsy test, Simmons said that additional studies with a similar scope have already been conducted and are ongoing with the company's elio IVD product.

"This study really shows in a nice cohort that the [MSI] biomarker in plasma does retain that predictive ability of response. So that was the important piece that we've wanted to highlight here: that detection of MSI in plasma, maintains that predictive response for patients," he said.

In the current study, PGDx — with collaborators at Memorial Sloan Kettering Cancer Center and Johns Hopkins University — described the development of the company's technique for gleaning MSI status from circulating tumor DNA NGS data, which involves barcoding, error correction, and various computational methods to align reads to define microsatellite loci.

More importantly, investigators reported on the performance of the method in a small set of clinical samples from a group of patients treated with pembrolizumab: a cohort that included 19 colorectal, three ampullary, three small intestine, two endometrial, one gastric, and one thyroid cancer.

Overall, 23 of the cases were MSI-high and six were microsatellite-stable based on their tumor tissue. Using its liquid biopsy method, the PGDx team was able to recapitulate expected MSI results for 78 percent (18 out of 23) of the tissue-MSI-high patients and 100 percent (six of six) of the stable patients.

Among five cases that were MSI in tumor tissue but MSS in PGDx's cfDNA analysis, three were patients with colorectal tumors, two of whom had progressive disease on treatment, with the third not evaluable. The two other cases were small intestinal tumors. One of these patients had a partial response and one exhibited progressive disease.

Analyzing outcomes in the whole cohort, investigators reported that by measuring MSI in baseline cfDNA, they could predict progression-free survival on immune checkpoint blockade with a hazard ratio of 0.21.

The test's predictive ability for the full cohort was not statistically significant for overall survival. However, when the group limited its analysis to the 25 cases that had enough ctDNA available for a reliable test, prediction of PFS and overall survival were both statistically significant, with hazard ratios of 0.15 and 0.26 respectively.

Although it focused on MSI, the study wasn't limited to it. Investigators also shared data from a separate analysis of their ability to calculate tumor mutational burden via the PGDx plasma test.

Using whole-exome sequencing data from 8,493 samples from The Cancer Genome Atlas, the researchers determined that a cutoff of five mutations in the PGDx targeted plasma panel corresponded strongly to a much larger whole-exome cutoff, and could be used to identify tumors with exceptionally high TMB at more than 95 percent accuracy.

Interestingly, the authors wrote, all five plasma MSI-high patients in the pembrolizumab study who had exhibited a complete response were also classified as plasma TMB-high by their method. In contrast, six of the seven tissue-based MSI-high patients that had progressive disease were TMB-low according to the liquid biopsy analysis.

"These data suggest that a baseline TMB measurement in plasma may be more accurate than archival tissue, as was the case in this study, because it provides a real-time analysis and corrects for the sampling error that is inherent to tissue sequencing," the team wrote.

PGDx is not alone in recognizing the immediate value of MSI and the emerging potential of TMB. Various tissue NGS tissue tests that report MSI and TMB have now been FDA approved, including assays from Foundation Medicine and Memorial Sloan Kettering.

Foundation also got its own breakthrough device designation in 2018 for blood-based NGS, as did Guardant Health.

Both companies have published on their efforts to validate TMB in blood. And Guardant also published its own study this August, on the accuracy of its blood-based MSI methodology. Also appearing in Clinical Cancer Research, that report concluded that MSI results from Guardant360 were the same as the standard-of-care tissue test in more than 98 percent of a cohort of more than 1,000 patients.

Joining these companies, Memorial Sloan Kettering has also included MSI analysis in its liquid biopsy assay MSK-ACCESS, which received New York State approval this June. Under the FDA's new treatment of NGS tests, it has accredited the New York State Department of Health as a third-party reviewer of IVDs, meaning lab tests that have been approved by NYS DOH do not need to submit a separate 510(k) application to the FDA, but can have their dossier forwarded automatically to the agency for possible clearance.

"I hope we've we passed a point now where everyone really starts to understand that NGS is really a critical component to the management of any advanced cancer patient," Simmons said.

"I think that the field is not just moving at a rapid clip from a technology standpoint ... but it is now moving quite rapidly from an ecosystem standpoint: from the payers, from the regulators, from the oncology community … and beyond just the key opinion leaders and [the] comprehensive cancer centers, we see so much demand from pathologists and oncologists across the spectrum of the institutions who really ... are hungry to have avenues to get that testing for all their advanced cancer patients."