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Data Demonstrates Lucence Liquid Biopsy Test Can Track Treatment-Based ctDNA Changes

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NEW YORK – At the European Society for Medical Oncology Congress this week, precision oncology assay developer Lucence presented data that demonstrated its amplicon-based LiquidHallmark assay could be used to personalize care for people with advanced urothelial carcinoma.

LiquidHallmark is a laboratory-developed test based on the company's AmpliMark next-generation sequencing platform and proprietary SunTzu.AI clinical analytics engine. It detects alterations in approximately 80 cancer-related genes and assesses microsatellite instability, as well as cancer-causing viruses in cell-free DNA samples.

The data presented at ESMO came from a study of 45 patients with metastatic urothelial carcinoma, or mUC, conducted in collaboration with the Dana-Farber Cancer Institute.

In it, 39 participants — all at the Dana-Farber Cancer Institute — underwent immune checkpoint inhibitor, or ICI, therapy while six received cisplatin-based chemotherapy. Investigators collected plasma samples before therapy and about six months afterwards, then correlated changes in circulating tumor DNA with objective response using the LiquidHallmark assay.

The researchers found ctDNA alterations in 96 percent of pre- and post-ICI samples and noted that the high rate suggests that longitudinal ctDNA profiling using a liquid biopsy assay may prove a useful clinical alternative to more invasive biopsies.

"This is somewhat impressive," Guru Sonpavde, a medical oncologist specializing in bladder cancer at Dana-Farber and the study's principal investigator, said in an interview "because in most ctDNA platforms, there is not such a high percentage of patients where you see ctDNA alterations."

Investigators also found that clearance of TP53 alterations during ICI therapy corresponded with treatment response, while the emergence of BRCA1/2 or PIK3CA variants appeared to associate with resistance.

"No responses were seen in patients in whom there was an emergence of a BRCA1/BRCA2 or PIK3CA variant during therapy, while none of the 3 patients with a baseline FGFR2/3 variant responded to ICI," Min-Han Tan, CEO and cofounder of Lucence, said via email. "Our results provide a rationale for possible therapeutic combination of ICI with PARP, CDK4/6 and PIK3CA/Akt inhibition in advanced UC since patients with disease progression on ICI demonstrated frequent emergence of [genomic alterations] in these pathways."

In an interview Tan also pointed out the assay's high sensitivity — approximately 96 percent for a variant allele frequency of 0.1 percent — and ability to detect both known and unknown fusions.

Separately, in an analytical and clinical validation study involving 1,592 clinical samples and currently available as a preprint on MedRxiv, Lucence showed limits of detection of 0.1 percent for single nucleotide variations and indels, and 0.5 percent for fusions. The assay also showed an overall 84 percent concordance from 50 lung cancer samples with the US Food and Drug Administration-approved Cobas EGFR Mutation Test v2 from Roche.

Importantly, the assay appeared to be able to detect novel as well as known gene fusions. The MedRxiv paper describes a 100 percent concordance with orthogonal methods testing for PD-L1 structural rearrangements.

Tan commented that the company's custom primer design approach allows sequencing of both known and unknown fusion partners.

Although the LiquidHallmark panel consists of 80 genes, it can be adapted to other numbers to arrive at specific study goals. Data obtained in the MedRxiv preprint, for instance, comes from 80-gene, 61-gene, and 51-gene panels. Additionally, a "greater number of targeted genes and genomic regions" were included in some cases, which the company points out does not change the underlying molecular principle of the assay.

While the study presented this week focused on urothelial carcinoma, study abstracts presented earlier this year at the 2021 American Society of Clinical Oncology virtual meeting demonstrated LiquidHallmark's utility for detecting lung, breast, and colorectal cancers, particularly for detecting actionable mutations and new structural rearrangements, as well as in interrogating genomic differences between patient populations.

The assay competes in a widening field of ctDNA-based diagnostics, all seeking to identify a broad range of pathogenic nucleic acid sequences in minimally invasive manners, such as Foundation Medicine's FoundationOneLiquid assay, Strata Oncology's StrataNGS test, and Guardant Health's Guardant360 CDx pan-cancer assay.

"Comprehensive genomic profiling tests can investigate hundreds of genes from a single sample, as opposed to sequential testing for single biomarkers or use of limited molecular diagnostic panels, which may quickly exhaust the sample," Geoff Oxnard, vice president and head of clinical development at Roche's Foundation Medicine, said in an email.

"As more targeted therapy options become available for a wider range of biomarkers," he added, "having a test that can look for more common disease-specific mutations, as well as rare but actionable mutations like NTRK, is of heightened value."

Foundation's own FoundationOneLiquid assay analyzes over 300 genes and detects variants such as MET exon 14 splice site mutations and ALK fusions. The FDA approved it as a companion diagnostic test last year.

Meanwhile, Lucence, which has locations in Singapore and Palo Alto, California, is actively exploring newer companion diagnostic research collaborations with academic and industry partners, and it plans to begin enrolling participants in a study utilizing LiquidHallmark for lung cancer in an early detection setting, although it did not say when that would begin.

"Lucence is currently investigating liquid biopsy applications for determining immunotherapy outcomes," Tan said, "such as AmpliMark-enabled T-cell receptor profiling in blood to sensitively determine clonal diversity."

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