Personalis MRD Assay Predicts Immunotherapy Response Across Solid Tumors in New Study

Original from: genomeweb

Results of a Phase I clinical trial published on Tuesday demonstrate that Personalis' minimal residual disease (MRD) assay, NeXT Personal, accurately predicts immunotherapy response across multiple metastatic solid tumor cancer types. 

NeXT Personal is a whole-genome sequencing-based, tumor-informed, laboratory-developed test performed in Personalis' CAP-accredited, CLIA-certified laboratory.

In the study published in the journal Clinical Cancer Research, a team led by researchers from Spain's Vall d'Hebron Institute of Oncology demonstrated the efficacy of circulating tumor DNA (ctDNA) as a broad biomarker for early treatment response assessment, for survival prediction, and for distinguishing between true disease progression and pseudoprogression.

The investigators analyzed ctDNA in approximately 1,455 longitudinal plasma samples comprising 1,800 tumor-specific mutations across 24 tumor types, drawn from a retrospective cohort of 136 patients and a prospective validation cohort of 66 patients, all with metastatic, stage IV tumors. Patients were treated with immune checkpoint inhibitors (ICIs) alone or in combination with bispecific antibodies or immune cell engagers.

Overall, patients whose ctDNA levels declined by approximately 30 percent between baseline measurements and the time point immediately preceding a patient's second treatment cycle showed significantly better progression-free survival (PFS) and overall survival (OS) than those whose ctDNA levels did not drop. 

Similarly, patients who experienced ctDNA clearance, defined as at least one time point with undetectable ctDNA levels, experienced a median threefold increase in PFS. Patients who remained MRD-negative for at least 180 days showed 100 percent OS. In multiple cases, the authors noted, visible and substantial decreases in tumor size followed this ctDNA clearance. 

The results corroborate those of an earlier study in which Personalis was involved, which determined that baseline ctDNA positivity is itself highly prognostic, suggesting that this measure could help guide treatment decisions. The team wrote that their findings also highlight the "critical importance" of initiating ctDNA monitoring as early as possible. By the conventional assessment time point — immediately prior to the third treatment cycle, for example — nearly half of the patients in the retrospective cohort and 67 percent of those in the validation cohort had already progressed.

In the current study, treatment response prediction further improved when combining ctDNA measurements with other clinical biomarkers such as lactic acid dehydrogenase (LDH), hemoglobin, and the ratio of neutrophils to lymphocytes, suggesting that ctDNA provides information beyond routine clinical data that might be used to better risk-stratify patients.

The investigators argued that combining ctDNA with Response Evaluation Criteria in Solid Tumors (RECIST) measurements provides a better way to identify those patients most likely to benefit from continued immunotherapy, since the unique tumor responses often caused by immunotherapy challenges traditional RECIST measurements. 

For example, by combining ctDNA dynamics with RECIST classifications, the researchers showed that patients with both progressive disease and increasing ctDNA at the pre-second treatment cycle time point may represent the highest-risk patient group, showing significantly poorer OS relative to patients with stable or decreasing ctDNA levels. 

Finally, serial ctDNA monitoring throughout treatment demonstrated high sensitivity and specificity for detecting disease progression and durable clinical benefit and did so faster than standard radiographic imaging. This, the investigators wrote, provides opportunities for earlier revisions of therapeutic plans, as well as a means of evaluating new treatment combinations in an environment in which standard-of-care guidelines have yet to be established.

Although the results support those of previous studies, the researchers noted that the retrospective nature of this study and its small prospective cohort size mean that larger prospective trials are still needed to firmly establish the clinical utility of the NeXT Personal assay, including in other treatment settings.

Personalis is actively working to gather such data and has several other studies to that end underway. Earlier this year, for instance, the Fremont, California-based company began collaborating with the Yale Cancer Center on a clinical trial to evaluate the assay's clinical utility in guiding the treatment of women with hormone receptor-positive HER2-negative breast cancer. The US Centers for Medicare and Medicaid Services began covering the NeXT Personal assay for breast cancer the following month. That announcement helped lift the company's stock price shortly after it lowered its full-year financial guidance due to depressed revenue from other aspects of the firm's business. 

Earlier this month, Personalis published the results of the TRACERx study, in which NeXT Personal was used to assess MRD in individuals with stage I to III non-small cell lung cancer (NSCLC). In that study, published in the journal Cell, Personalis and academic collaborators from the Francis Crick Institute and University College London used the assay to analyze 431 NSCLC patients over a median period of just over five years. 

In that study, NeXT Personal effectively detected residual and recurring cancer across multiple time points, ranging from pre- to post-surgery, during adjuvant treatment, and throughout long-term surveillance monitoring. As with the previous study, the assay detected cancer ahead of standard-of-care imaging and demonstrated that non-clearance of ctDNA correlated with poorer OS and a greater risk of relapse. 

Taken together, the recent studies show "the broad potential impact of ultrasensitive ctDNA testing, both in early and late-stage cancers," Rich Chen, chief medical officer and executive VP of R&D at Personalis, said in a statement.

Source: Personalis MRD Assay Predicts Immunotherapy Response Across Solid Tumors in New Study