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Multicenter Study
. 2025 Jun:9:e2500181.
doi: 10.1200/PO-25-00181. Epub 2025 Jun 26.

Prospective Multicenter Study Evaluating a Combined Circulating Tumor DNA and Circulating Tumor RNA Liquid Biopsy in Metastatic Non-Small Cell Lung Cancer (LIQUIK)

Jens Samol  1   2   3 , David Ng  1 , Jonathan Poh  4 , Min-Han Tan  5 , Richa Dawar  6 , Jennifer Carney  7 , James Orsini Jr  8 , Katherine Scilla  9 , Yew Oo Tan  10 , Tan Min Chin  11 , Chee Keong Toh  12 , Boon Cher Goh  13 , Gilberto Lopes  6
Affiliations
Multicenter Study

Prospective Multicenter Study Evaluating a Combined Circulating Tumor DNA and Circulating Tumor RNA Liquid Biopsy in Metastatic Non-Small Cell Lung Cancer (LIQUIK)

Jens Samol et al. JCO Precis Oncol. 2025 Jun.

Abstract

Purpose: To evaluate the performance of a circulating tumor DNA (ctDNA) and circulating tumor RNA (ctRNA) liquid biopsy, LiquidHALLMARK (LHM), compared with tissue next-generation sequencing (NGS) and Guardant360 CDx (G360 ctDNA) liquid biopsy for biomarker detection in metastatic nonsquamous non-small cell lung cancer.

Patients and methods: This multicenter, prospective study (ClinicalTrials.gov identifier: NCT04703153) enrolled patients across the United States and Singapore. Patients were tested with tissue NGS, LHM, and G360 ctDNA. The primary objective was noninferiority of LHM ctDNA to tissue NGS and G360 ctDNA. Secondary analyses included turnaround time (TAT), overall response rate (ORR), and progression-free survival (PFS), with exploratory analysis of the clinical utility of ctRNA.

Results: LHM ctDNA (48.2%) detected 11.4% fewer biomarker-positive patients than tissue NGS (59.6%) and did not meet noninferiority criteria. Compared with tissue NGS, LHM ctDNA and G360 ctDNA were concordant in 72.1% and 66.1% of patients, establishing noninferiority of LHM ctDNA to G360 ctDNA (P = .002). TAT was shorter for LHM ctDNA than for tissue NGS (mean 9.7 v 21.7 days; P < .001). ORR/PFS was similar in patients receiving targeted therapy based on all three assays. Addition of ctRNA increased the diagnostic yield of tissue NGS-confirmed gene rearrangements by 28.6% relative to LHM ctDNA and all actionable biomarkers by 15.6% relative to G360 ctDNA. LHM ctDNA and ctRNA (51/68) detected 8.8% more biomarker-positive patients than G360 ctDNA (45/68), demonstrating superiority of LHM ctDNA and ctRNA (P = .001).

Conclusion: LHM ctDNA is noninferior to G360 ctDNA, but not tissue NGS. Treatment outcomes based on liquid biopsy are comparable with those based on tissue NGS. Incorporation of ctRNA into LHM ctDNA improves the diagnostic yield of actionable, tissue NGS-confirmed gene rearrangements.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Chee Keong Toh

Stock and Other Ownership Interests: Johnson & Johnson/Janssen

Consulting or Advisory Role: Merck, Bristol Myers Squibb/Celgene, Astellas Pharma, MSD Oncology, Roche, dksh

Travel, Accommodations, Expenses: Daiichi Sankyo/AstraZeneca

No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
STARD diagram of the LIQUIK study population and the biomarker detection rates of each assay. ctDNA, circulating tumor DNA; G360 ctDNA, Guardant360 CDx; LHM ctDNA, LiquidHALLMARK ctDNA; neg, negative; NGS, next-generation sequencing; pos, positive; QNS, quantity not sufficient.
FIG 2.
FIG 2.
Concordance of LHM with G360 for the detection of tissue NGS–confirmed guideline-recommended biomarker-positive patients in metastatic nonsquamous NSCLC. ctDNA, circulating tumor DNA; ctRNA, circulating tumor RNA; G360 ctDNA, Guardant360 CDx; LHM ctDNA, LiquidHALLMARK ctDNA; LHM ctRNA, LiquidHALLMARK ctRNA; NGS, next-generation sequencing; NSCLC, non–small cell lung cancer.
FIG 3.
FIG 3.
(A) Biomarker prevalence and (B) overlap of biomarkers detected for each assay in the LIQUIK study. ctDNA, circulating tumor DNA; ctRNA, circulating tumor RNA; G360 ctDNA, Guardant360 CDx; LHM ctDNA, LiquidHALLMARK ctDNA; LHM ctRNA, LiquidHALLMARK ctRNA; NGS, next-generation sequencing.
FIG 4.
FIG 4.
Progression-free survival of (A) patients treated with targeted therapy versus nontargeted therapy in the evaluable cohort and (B) patients treated with targeted therapy based on matched biomarker finding in LHM ctDNA, G360 ctDNA, and Tissue NGS. ctDNA, circulating tumor DNA; G360 ctDNA, Guardant360 CDx; LHM ctDNA, LiquidHALLMARK ctDNA; NGS, next-generation sequencing.
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