Longitudinal Tracking of ALK-Rearranged NSCLC From Plasma Using Circulating Tumor RNA and Circulating Tumor DNA

Authors

Simon Heeke
Saumil Gandhi
Hai T Tran
Vincent K Lam
Lauren A Byers
Don L Gibbons
Carl M Gay
Mehmet Altan
Mara B Antonoff
Xiuning Le
Janet Tu
Maliazurina B Saad
Michelle Pek
Jonathan Poh
Kao Chin Ngeow
Anne Tsao
Tina Cascone
Marcelo V Negrao
Jia Wu
George R Blumenschein
John V Heymach
Yasir Y Elamin

Publication Date

4-1-2025

Journal

JTO Clinical and Research Reports

Abstract

Background: Although the administration of tyrosine-kinase inhibitors in ALK-rearranged NSCLC has revolutionized precision medicine, the detection of gene rearrangements from liquid biopsies remains challenging. RNA-based detection has revealed promising sensitivity for rearrangement detection and thus we hypothesize that a liquid biopsy assay analyzing circulating tumor RNA (ctRNA) in addition to circulating tumor DNA (ctDNA) will improve detection. Furthermore, we hypothesize that the detection of gene fusions at baseline will correlate with clinical outcomes.

Methods: We retrospectively analyzed 86 plasma samples from 33 patients enrolled in the BRIGHTSTAR clinical trial assessing local consolidative therapy (LCT) and brigatinib in patients with stage IV or recurrent NSCLC and confirmed ALK rearrangement (NCT03707938) using a targeted next-generation sequencing assay that analyzes ctDNA to detect gene rearrangements and mutations in 80 genes and ctRNA to detect gene arrangements in 36 genes.

Results: ALK rearrangements were detected in 15 of 28 patients (54%) at baseline, of which eight were detected in both ctDNA and ctRNA. ALK rearrangements were detected in two patients pre-LCT, exclusively in ctRNA, but cleared completely post-LCT. The detection of ALK fusion at baseline was associated with significantly worse progression-free survival (p = 0.033). Plasma cell-free DNA concentrations for patients with detectable ALK rearrangements at baseline were significantly higher than for those without detectable gene fusions (12.3 ng/mL versus 20.2 ng/mL, p = 0.0046).

Conclusions: The inclusion of ctRNA in liquid biopsies increased detection of ALK rearrangements and detection at baseline was associated with significantly worse progression-free survival highlighting the added benefit of ctRNA.

Keywords

ALK, NSCLC, Liquid biopsy, ctRNA, ctDNA

DOI

10.1016/j.jtocrr.2025.100795

PMID

40160974

PMCID

PMC11952838

PubMedCentral® Posted Date

1-6-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes