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In New TRACERx Data, Personalis MRD Test Shows Improved Sensitivity With Potential Clinical Impact


NEW YORK – A novel assay being commercialized by Personalis has performed better than other circulating tumor DNA assays in tracking patterns of response and tumor evolution in early-stage non-small cell lung cancer patients in the UK-led TRACERx study.

The Menlo Park, California-based firm's NeXT Personal is a tumor-informed minimal residual disease (MRD) platform that uses whole-genome sequencing, rather than the exome or targeted sequencing featured in most competing tests, to develop blood-based panels personalized for each NSCLC patient. As a result, the company is able to create much larger panels — comprising up to 1,800 targets per patient — which, coupled with noise suppression, allows limits of detection much lower than other assays, according to Personalis.

In a presentation over the weekend at the European Society for Medical Oncology Congress, James Black, a TRACERx investigator from the Francis Crick Institute, reported initial findings from the recent adoption of the Personalis test into the trial.

Black, who is a postdoctoral clinical fellow in the lab of TRACERx principal investigator Charles Swanton, said the results indicated that NeXT Personal can detect pre-treatment ctDNA in significantly more cancer patients than technologies used previously in the cohort, especially among patients with adenocarcinoma.

The goal of MRD testing in early-stage NSCLC is to assess patients' risk of recurrence after surgery in order to inform treatment decisions. High-risk patients may explore even more intense therapy than is typically given, while ctDNA-negative individuals might consider avoiding adjuvant chemotherapy all together.

In a discussion of the data at ESMO, Federica Di Nicolantonio, an associate professor at the University of Turin School of Medicine, estimated there are as many as 13 different MRD assays utilizing a tumor-informed strategy that oncologists can use. As Personalis begins offering NeXT Personal in the clinic for the first time, it is pushing for a competitive advantage over other tests on the market by highlighting improved sensitivity. According to Personalis CEO Chris Hall, the firm hopes to make its test available clinically by year-end.

In their study, Black and colleagues used NeXT Personal to identify and track MRD in over 170 patients from the TRACERx cohort. Compared to previous TRACERx publications involving other commercial MRD assays — Natera's Signatera and Invitae's Personalized Cancer Monitoring panels — NeXT Personal appeared to yield significantly higher ctDNA detection rates, especially among adenocarcinoma patients.

In his presentation, Black cited one of the team's most recent publications, a study published earlier this year in Nature Medicine using the Invitae technology, which confirmed that the preoperative presence of ctDNA was predictive of poor clinical outcomes in lung adenocarcinoma. "However, ctDNA negativity as defined by that assay [was] not by any means a perfect biomarker of low-risk disease," he said.

The question the team hoped to answer with its adoption of the Personalis technology was whether, and to what extent, clinical sensitivity for predicting low-risk cancers is limited by assay sensitivity.

Black said the 170-patient cohort used for the latest study was "slightly different" than those featured in previous publications using the Natera and Invitae assays. As such, the data don't reflect a true head-to-head comparison. Nevertheless, the team was able to compare NeXT Personal's ctDNA detection rates in non-adenocarcinomas and adenocarcinomas against what had been reported in two prior publications — the Invitae study published earlier this year and a prior report featuring Signatera from 2017.

Detection of ctDNA in non-adenocarcinomas was relatively high for both prior assays at 92 percent. NeXT Personal detected ctDNA in 100 percent. The difference in adenocarcinomas was more striking with an overall ctDNA detection rate of 81 percent for Personalis compared to 42 percent and 19 percent in the studies involving Invitae's and Natera's assays, respectively.

Similar patterns appeared when investigators divided patients by stage. NeXT Personal detected a cancer signal in 52 percent of stage I cases, 88 percent of stage II cases, and 100 percent of stage III tumors.

According to Black, the key clinical question at this point was whether this boost in sensitivity provides additional clinical information. To explore this, the team restricted the cohort to adenocarcinomas with ctDNA detected at a level that was below the 95 percent limit of detection for the previously used Invitae test. "What you can see is a really striking difference in outcomes between those patients with ctDNA detected at low levels versus those in which we're not detecting it at all … with this NeXT Personal assay [who have] a remarkably favorable prognosis," Black said.

These pre-surgery ctDNA-negative individuals had a 100 percent five-year overall survival rate and 94 percent relapse-free survival rate. In comparison, patients who were ctDNA-positive prior to surgery had a high risk of cancer recurrence over five years. Notably, based on the limit of detection restriction criteria, these high-risk individuals would not have been called as ctDNA-positive using other MRD tests.

"If you weren't able to detect those patients, if they were misclassified, that would dramatically change how they'd be perceived and potentially treated," said Personalis Chief Medical Officer and executive VP of R&D Richard Chen.

Di Nicolantonio agreed that the study data do support that NeXT Personal's limit of detection is "well below what has been reported for other assays."

While she said the sensitivity for stage I tumors still seems to suffer relative to stage II and III cancers, the overall MRD performance certainly merits prospective use of the assay in other cohorts, and in interventional studies that explore de-escalating therapy when tests are negative or intensifying therapy when they are positive after surgery.

"We are really looking forward to Phase II adaptive trials in the early-stage setting that are similar to what has been done in advanced disease," she said.

Hall said that when Personalis launches its test in the clinic, its use will be more escalation-oriented and aimed at "getting patients the therapies they need out of the gate in the right way."

That said, one of the promising things about the results at ESMO was that the ctDNA-negative patients had such good survival after five years. "If that holds up, the hope is that maybe you could start to identify patients [in whom] you could take a less invasive approach," he said. "About 95 percent of early-stage lung cancer patients get no benefit from chemotherapy, but we don't know which ones. … We are getting very positive receptivity about the de-escalation story, but it's going to take some studies and some time to stitch together."

TRACERx has an ongoing collaboration with Personalis, in which researchers are tracking 350 tumor-specific mutations in each of approximately 450 patients and evaluating whether there is also a clinical impact associated with NeXT Personal's ultra-sensitivity in the post-surgery and longitudinal monitoring setting.

In preliminary data from a subset of the cohort, Black said the assays' sensitivity for predicting disease relapse was 54 percent at a landmark time point between 10 and 120 days post-surgery, with longitudinal sensitivity rising to 85 percent with 96 percent specificity. The lead time in detecting relapse compared to detection by standard clinical surveillance was 173 days.

In responses to questions from ESMO attendees, Black said that combining NeXT Personal with other MRD methods could potentially lead to even lower limits of detection, but it's not clear that such improvements would be clinically meaningful.

"Preoperatively, in terms of disease stratification, from the data we were showing [and] with the limit of detection that we're able to get, we had a really meaningful separation" of risk groups, he said. "There are probably outstanding questions about the post-resection setting because ctDNA fraction could go potentially quite a lot lower, so for that even more sensitivity could be important," he said.

According to Hall, Personalis has ongoing studies with several other major academic medical institutions, with a lot of work in breast cancer as well as in immuno-oncology therapy monitoring, a growing area of focus for companies with MRD tests. "We expect data to be coming out through all of 2024, and our aim is to be submitting for coverage in breast cancer, lung cancer, and immuno-oncology therapy monitoring as the year goes on," Hall said.