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Collaborators Publish Data on Resolution Bio Liquid Biopsy Test as Company Turns to CDx Effort

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NEW YORK (GenomeWeb) – Researchers from Dana Farber Cancer Institute and Resolution Bioscience have published a full report on the development and early validation of a panel covering targetable oncogenic mutations and resistance mechanisms in 11 genes with relevance to treatment of non-small cell lung cancer patients.

The results, which appeared online last week ahead of print in Clinical Cancer Research, are some of the first published in full since the company launched demonstrating the validity of its bias-corrected sequencing approach.

Resolution, which entered the liquid biopsy market earlier this year, is planning to develop kits for labs to purchase and perform its novel methods in-house, as a tool for detecting panels of actionable mutations in the blood of cancer patients.

This summer, Resolution had begun discussions with potential early-access testers for an RUO version of these kits. Resolution CEO Mark Li told GenomeWeb this week that he could not yet provide details about how this list is shaping up, but said that there are more interested parties — contract research companies and academic institutions — than Resolution will likely end up partnering with for this initial controlled launch.

As it builds its RUO kit program, Resolution also plans to validate panels for specific tumor types, like the NSCLC panel, and pursue US Food and Drug Administration approval of these assays for clinical use. In addition to NSCLC, Resolution has said it is looking into collaborations around bladder, prostate, ovarian, breast, and head and neck cancers.

Li said the company hopes to begin getting kits to early testers in 2016, but that some of the company's focus has shifted to another front, gearing up for participation in a global clinical trial of an unnamed cancer drug.

Though he declined to provide details on the drug or pharmaceutical company involved, Li said that as part of this effort Resolution is also in discussions to develop a companion diagnostic for the drug.

Regardless of the indication, this will be a milestone, he said, for a sequencing-based panel, let alone one focused on circulating cell-free DNA rather than tissue.

"We have been extremely impressed in that this company is willing to sort of blaze the trail in looking at a blood-based panel companion diagnostic," Li said.

"Obviously with the amount of money involved in these programs, you need to be more conservative," he said, "But I think on the pharma side they are coming to a realization that with blood-based testing they are not just going to save money and be safer for the patient, but because of tumor heterogeneity, this potentially helps keep you from missing a lot of [eligible] patients."

Meanwhile, in the study published last week, researchers from Dana Farber led by Geoffrey Oxnard evaluated a Resolution Bio test using a panel of mutations in 11 genes associated with NSCLC.

In its study, the Dana Farber team first validated Resolution's testing method on cell lines, showing that the NGS approach could identify mutations present in DNA dilutions down to 0.4 percent allelic frequency with 100 percent sensitivity and specificity.

Then the group sent a set of clinical samples for Resolution to analyze from 48 patients with advanced progressive disease that had been tested already using conventional approaches. Resolution was blinded to the known genomic status of these patients, and reported back to the team its own results for each.

The investigators also assessed blood samples from patients using a droplet-based PCR approach that the Dana Farber group has been developing in house.

According to the study authors, Resolution's plasma sequencing panel detected a full range of mutations and other alterations, including ALK, ROS1, and RET rearrangements, HER2 insertions, and MET amplification with 100 percent specificity and about 77 percent sensitivity compared to the known features for each patient.

In samples that also had positive droplet PCR results, the sensitivity of the Resolution test was similar to that of the more focused PCR testing.

"This cohort was highly enriched for interesting mutations" Li explained. "[They] sort of reached into their private select cellar and threw all sorts of curveballs at us."

Some samples had extremely low DNA amounts. This reflects the fact that the samples Resolution tested were made up of already extracted DNA, Lee Lim, Resolution's chief technology officer, told GenomeWeb.

In clinical practice the company performs its own extraction as a rule, to be able to maintain a higher sensitivity than the 77 percent reported in the study.

"We've done extensive work with healthy people to figure out what we should expect when we accession a sample clinically and we never see anything at that low a level," Li said.

"We have guidelines set up around extraction to make sure we are collecting more DNA and running at a higher level … so we have control over making sure the sensitivity of the assay is upwards of 90 [or] 95 percent to ensure the best chance of getting a signal," Tera Newman-Eerkes, Resolution's vice president of strategy and clinical operations, further explained.

As the company looks toward adapting its approach to a kit format next year, being able to maintain these standards will be a crucial part of working with early-access users, Li said.

"We have put together our own internal [standards] on extraction as well as the assay itself, so with this list of CROs and research institutions that want to be part of our early-access program, we'll be working with them intensely to make sure they can successfully run the assay," Li said.

Importantly, Li and Lim said, the Dana Farber study clearly shows that Resolution's methods allow the company to detect a range of genomic alterations, not just point mutations, something other sequencing-based liquid biopsy companies have not shared extensive data on.

"If you want to do precision medicine in lung cancer, you'd better be able to detect ALK, RET, and ROS," Lim explained. "Our technique was developed specifically to provide a method for that."

Another distinguisher of Resolution's approach is that the company's bias-correction method allows it to run its panels on the Illumina MiSeq, rather than the HiSeq.

"In light of the reimbursement troubles a lot of people in this field face, not even in blood, but just with NGS genotyping … the economics of running this on a HiSeq don't make sense. Consumables costs from Illumina are going to be more than you can hope for in reimbursement," Li said.

"Our assay system is different than the standard oligo pull-down methods, and it greatly increases our on-target efficiency so that 90 percent of the reads we pull down are on target. That allows us to run four patient samples on a MiSeq as opposed to one on a HiSeq," Lim explained.

Using the MiSeq also reduces the turnaround time compared to other liquid biopsy sequencing approaches, according to Resolution.

Interestingly, in the Dana Farber study, researchers included two patients for whom standard tissue testing had not revealed any substantive results. In both of these patients, Resolution's test was able to detect an alteration with relevance for treatment. For each case turnaround time was six business days, the authors reported. 

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