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Promega Maintains Microsatellite Instability IVD Plans Amid Evolving Cancer Test Landscape

NEW YORK – Molecular testing firm Promega achieved a new milestone this month in its plans to furnish the cancer oncology market with approved in vitro diagnostic kits for microsatellite instability testing, receiving a CE mark for its OncoMate MSI assay and reiterating its plans to follow that up with regulatory clearances in the US and Asia.

Promega's intentions for its MSI IVDs include indications for both Lynch syndrome — where testing is recommended for patients with colorectal and endometrial cancers as an initial screen — and immunotherapy companion diagnostic testing, which emerged in 2017 as a new use-case with the US Food and Drug Administration's approval of pembrolizumab (Merck's Keytruda) for patients with MSI-high or DNA mismatch repair deficient tumors, regardless of their location or tissue type.

Unlike other precision oncology drug-diagnostic companion examples, the FDA did not approve a specific test when it gave its nod to pembrolizumab in MSI-high cancers, instead directing Merck and potential diagnostic partners to work post-hoc on developing tests and bringing them through regulatory review while the field relied on existing laboratory-developed assays.

Promega first announced it would pursue FDA and other regulatory pathways for its PCR-based MSI platform as a companion diagnostic soon after the pembrolizumab approval, but after several years, the US oncology community still remains without an official FDA-recognized MSI CDx. This week, a second tissue-agnostic pembrolizumab biomarker, tumor mutational burden, jumped ahead of MSI with the accelerated approval of the drug for TMB-high patients identified with Foundation Medicine's NGS-based companion test.

Despite this leapfrogging by TMB, Promega is holding firm in its plans, which it reported for the first time soon after the 2017 MSI approval of pembrolizumab and then reiterated last fall, announcing its own official CDx partnership with Merck.

Heather Tomlinson, Promega's director of clinical diagnostics, said that the company expects to garner FDA clearance for an IVD version of its OncoMate MSI assay for Lynch syndrome first, while it completes additional studies for the pembrolizumab CDx indication.

"It's been a really busy three years as we have continued to develop our MSI technology … as an in vitro diagnostic product," Tomlinson said. In terms of working with the FDA, she added, Promega has already completed extensive studies to support Lynch syndrome testing, comparing OncoMate with a predicate assay, the Ventana MMR immunohistochemistry panel.

"We have determined the overall percent positive agreement and negative percent agreement as part of that process, as well as conducted extensive analytical studies to demonstrate assay performance," she said.

For guiding immunotherapy, the firm also needs to add patient outcome data to this dossier. "There will be an additional clinical trial period that we will work through and the timeline on that we're still finalizing currently," Tomlinson added.

The lack of an official CDx platform for MSI testing has not prevented growing implementation of the biomarker following the initial pan-cancer pembrolizumab approval, with labs implementing various available technologies, including Promega's research-use MSI PCR platform, immunohistochemistry assay for DNA mismatch repair markers, and other PCR tests from firms like Biocartis, which is also pursuing FDA IVD clearance for its own PCR-based Idylla MSI kit, expecting to achieve it this year.

In parallel, with the growth of next-gen sequencing in advance cancer patients, various NGS platforms have also incorporated calculation of MSI status into their comprehensive genomic profiling approaches.

Several NGS tests have also already been approved by FDA. Although many of these assays include MSI loci and report out MSI status, FDA doesn't currently recognize any as having a specific companion diagnostic claim for pembrolizumab. Rather, the tests are approved for a more general tumor profiling indication. That could soon change, however. Foundation Medicine said initially, for example, that it would pursue MSI as well as TMB approval through its own CDx collaboration with Merck.

Tomlinson argued that there remain concerns about gleaning MSI from NGS data that ensures a continuing market for PCR-based tests. These include assay variability and the lack of comprehensive data defining clinically actionable cutoff points across different cancer types.

Various NGS MSI strategies that have emerged rely on their own individual panels of genomic loci, with variation from panel to panel and usually many more targets included than the seven that makeup the more extensively validated Promega PCR kit.

Promega's method includes five nearly monomorphic mononucleotide repeat markers (BAT-25, BAT-26, MONO-27, NR-21 and NR-24) and two highly polymorphic pentanucleotide repeat markers (Penta C and Penta D), which serve as a quality control for sample authentication of matched normal and tumor.

The test methodology involves comparing allelic profiles of the five markers generated by PCR amplification from matching pairs of test samples. The presence of alleles in the abnormal sample that are not found in a corresponding normal sample indicates MSI.

NGS also costs more, often requires more tissue, and because of this, can fail more frequently when samples are limited or of low quality, Tomlinson also suggested.

"Also, turnaround time is a big concern, especially when you're thinking about immunotherapy. NGS typically take days to weeks compared with hours to days for OncoMate MSI, meaning that important results can get to the physician to help guide patient treatment more efficiently," she said.

Another differentiator, she added, is that whereas technologies like NGS focus on the presence or absence of mutations, Promega's PCR approach "actually measures the function of the proteins as they process the DNA strand."

Gleaning MSI from the NGS panel certainly has its own sample conservation and efficiency value, she admitted, especially for labs that are developing and employing their own comprehensive profiling assays. But in practice, she argued that Promega often sees customers running the company's PCR assay in parallel with NGS panels.

"We do [have] labs who have extensive NGS panels also running MSI by PCR in order to get the results faster to support patients who might be candidates for immunotherapy … but also as an insurance policy against [a relatively] high failure rate."

The diversity of available MSI and mismatch repair test options is something professional oncology and pathology organizations are now trying to get a better handle on, with the implementation of a collaboration to develop clinical guidelines spearheaded by the College of American Pathologists (CAP), the American Society of Clinical Oncology (ASCO), the Association for Molecular Pathology (AMP), and Fight Colorectal Cancer (Fight CRC).

In February, the groups opened a public comment period, asking relevant stakeholders for their views on a set of draft guidelines entitled "MMR and MSI Testing in Patients Being Considered for Checkpoint Inhibitor Therapy."

Among the draft recommendations, the societies strongly recommended using MMR IHC and/or MSI by PCR over NGS methods for various specific cancer types, like colorectal cancer, endometrial cancer, and gastroesophageal tumors.

"It really goes back to the recognition that NGS ... is not yet recognized as an effective strategy because of the high failure rate and potential for exposure to unnecessary cost," Tomlinson said of the draft recommendations.

"I think another factor there is that immunotherapy trials are being generally enrolled locally, typically using MSI by PCR or IHC, as that's what is available at most of the local enrollment sites. So I think there is just an acknowledgement that these technologies are entrenched and moving away from them is going to be a product that takes a long time and likely requires more evidence," she added.

Tomlinson also said Promega submitted its own perspectives during the comment period on the draft recommendations, as did various clinicians that the company maintains relationships with.

As the field moves forward, liquid biopsy has also drawn attention, with NGS firms like PGDx and Guardant Health collecting data on blood-based sequencing methods that measure MSI among various other cancer biomarkers.

In some ways, liquid biopsy could solve some of the issues that make NGS challenging, including obviating any issues around tissue sample requirements.

Tomlinson said Promega is engaged in its own liquid biopsy efforts, hoping to be able to translate its technology for use on blood samples, so that researchers, and potentially clinicians, could test MSI at multiple timepoints during a patient's course of therapy.

The company has not released any data in this vein yet, she said, but it is currently supporting an active clinical trial at the University of Southern California.