There have been three oncology drug approvals by the U.S. FDA over the last few years that were based solely on a genetic biomarker, rather than the location in the body where the tumor originated. But to make that tissue-agnostic approach a reality for oncology patients, detecting those genetic biomarkers will have to become increasingly easy and standardized.

Personal Genome Diagnostics Inc. (PGDx) has developed a liquid biopsy test to assess microsatellite instability (MSI) based on cell-free DNA (cfDNA) in plasma. MSI is the first pan-cancer biomarker used in a tissue-agnostic approval by the FDA; it indicates use of Kenilworth, N.J.-based Merck & Co.'s immune checkpoint inhibitor, Keytruda (pembrolizumab). In May 2017, the FDA gave its nod to Keytruda for patients with unresectable or metastatic tumors that tested high for MSI or mismatch repair deficiency, marking the agency's first site-agnostic drug approval.

Tissue biopsy is the standard means of assessing MSI. However, in roughly one-fifth of newly diagnosed cancer patients, it's difficult to obtain a sample sufficient for various tests or even to excise one at all. There are some indications – such as advanced lung cancer – for which a tissue biopsy isn't feasible because the patient is simply too ill.

A recent small study, published in the Sept. 10, 2019, issue of Clinical Cancer Research, found that the PGDx liquid biopsy test agreed with tissue biopsy 78% of the time in the detection of high MSI. The study was based on a lab-developed version of the assay.

Plasma-based NGS

"PGDx has been working on this for quite a while. We ran the first prospectively enrolled study based on MSI status with Keytruda, which featured one of our founders, and the samples from that trial were evaluated with this manuscript," John Simmons, vice president of translational medicine at PGDx, told BioWorld.

"We really wanted to show with the assay that we developed that you could identify patients who are high MSI by plasma," he added.

There is already an in vitro diagnostic test that includes that MSI panel – among others – known as PGDx elio plasma resolve. It received a CE mark in March and is the first kitted plasma-based, next-generation sequencing oncology test to receive European certification.

In July 2018, the PGDx elio plasma resolve received a breakthrough device designation from the FDA. The qualitative IVD test uses targeted high-throughput, parallel sequencing technology to detect single nucleotide variants, small insertion/deletions, amplifications, rearrangements and MSI in a broad multigene panel in circulating cfDNA isolated from plasma samples. It is designed to include several clinically actionable variants across tumor types, enabling more informed oncology treatment decisions.

Baltimore-based PGDx is a spinout of Johns Hopkins University. Early last year, it reported that it had secured a $75 million series B round that was led by Bristol-Myers Squibb and New Enterprise Associates to develop tissue and plasma in vitro diagnostics for late-stage oncology applications, including initial treatment determination and monitoring of residual disease. The expectation is that the products will help to improve clinical insight, the speed of test and treatment results and the health care economics for hospitals and payers.

Measuring MSI

MSI occurs when the number of repeats of short, repeated sequences of DNA, or microsatellites, are different from the number of repeats from the original DNA. It is thought to indicate a defect in the ability to repair mistakes made when DNA is copied in the cell. MSI can be detected by measuring the length of altered microsatellite sequences in tumor DNA, as compared with normal DNA.

In the study, a 98 kb pan-cancer 58-gene panel was used to identify MSI frameshift alleles in cfDNA. The researchers identified certain sequence data for error correction and used an algorithm that determined the instability of the loci, which are the position that a particular gene occupies on a chromosome. If 20% or more of the loci were found to have MSI, samples were classified as MSI-high. The study included 61 advanced cancer patients and 163 plasma samples from healthy individuals.

That produced a sensitivity of 78% and a specificity of more than 99%. The liquid biopsy also assessed tumor mutational burden (TMB), which measures the number of mutations found in a tumor. Patients who are both high-MSI and high-TMB respond particularly well to checkpoint inhibition. The TMB test resulted in 67% sensitivity and 99% specificity.

The study also looked specifically at 29 metastatic patients, who can have their own complex issues around tissue biopsy, given the number of tumor sites within the body. With those, the liquid biopsy identified 18 of the 23 MSI-high patients.

"Our data also demonstrate that liquid biopsy analysis of MSI and TMB may be more predictive of immunotherapy response than archival tissue, given that it is both a real-time and global measurement and resolves the inherent sampling bias of tissue biopsy," commented Andrew Georgiadis, senior scientist at PGDx.

Tissue-agnostic gets real

The difficulty of the tissue-agnostic oncology drugs is that, conceivably, every newly diagnosed cancer patient should be tested for the underlying genetic biomarkers. But that isn't currently the case. Simmons noted that only about 20% of cancer patients are having any next-generation sequencing testing at all. So, making those sorts of tests more accessible to physicians, who remain largely oriented around tissue-centered treatment and diagnostic practices and treatments, is crucial.

MSI is particularly important for a large portion of patients in a handful of cancer types, according to a recent study across 39 tumor types. Overall, high MSI occurred in only 3.8% of cancer patients. But in patients with uterine and endometrial carcinoma, colon adenocarcinoma and stomach adenocarcinoma, the rates were significantly higher at 31.4%, 19.7% and 19.1%, respectively. Those are the indications that are the clearest fit for MSI testing, although it can more rarely play a role in other cancer types.

"A majority of patients with advanced incurable cancers who have an MSI-high tumor should be given the option to be treated with immunotherapy," summed up Dung Le, a study author and an associate professor of oncology at the Sidney Kimmel Cancer Center at Johns Hopkins. "If the tests become more accessible, less expensive, and require fewer resources such as tissue acquisition and pathology resources, more patients could be tested."

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