Clinical utility of next-generation sequencing-based ctDNA testing for common and novel ALK fusions. (September 2021)

• Record Type: Journal Article
• Authors: Mondaca, Sebastian; Lebow, Emily S.; Namakydoust, Azadeh; Razavi, Pedram; Reis-Filho, Jorge S.; Shen, Ronglai; Offin, Michael; Tu, Hai-Yan; Murciano-Goroff, Yonina; Xu, Chongrui; Makhnin, Alex; Martinez, Andres; Pavlakis, Nick; Clarke, Stephen; Itchins, Malinda; Lee, Adrian; Rimner, Andreas; Gomez, Daniel; Rocco, Gaetano; Chaft, Jamie E.; Riely, Gregory J.; Rudin, Charles M.; Jones, David R.; Li, Mark; Shaffer, Tristan; Hosseini, Seyed Ali; Bertucci, Caterina; Lim, Lee P.; Drilon, Alexander; Berger, Michael F.; Benayed, Ryma; Arcila, Maria E.; Isbell, James M.; Li, Bob T.;
• Is Part Of: Lung cancer. Volume 159(2021)
• Page Start: 66
• Page End: 73
• Publication Date: 2021-09
• Subjects: ALK anaplastic lymphoma kinase -- ctDNA circulating tumor DNA -- EML4 echinoderm microtubule-associated protein-like 4 -- FDA Food and Drug Administration -- FISH fluorescence in situ hybridization -- NGS next-generation sequencing -- IHC immunohistochemistry -- NSCLC non-small cell lung cancer -- PFS progression-free survival -- PON1 Paraoxonase 1 -- TAT turnaround time -- TTD time-to-treatment discontinuation -- VAF variant allele fraction; Liquid biopsy -- Circulating tumor DNA -- Next generation sequencing -- ALK fusion; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2021.06.018
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: Liquid biopsy for plasma ctDNA NGS is capable of partner agnostic detection of ALK fusions. A subset of patients can be matched to ALK-directed therapy based on plasma ctDNA testing. PON1, a novel ALK fusion partner, was detected in plasma in a lung cancer patient. Abstract: Objectives: Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) can detect ALK fusions, though data on clinical utility of this technology in the real world is limited. Materials and Methods: Patients with lung cancer without known oncogenic drivers or who had acquired resistance to therapy (n = 736) underwent prospective plasma ctDNA NGS. A subset of this cohort ( n = 497) also had tissue NGS. We evaluated ALK fusion detection, turnaround time (TAT), plasma and tissue concordance, matching to therapy, and treatment response. Results: ctDNA identified an ALK fusion in 21 patients (3%) with a variety of breakpoints and fusion partners, including EML4, CLTC, and PON1, a novel ALK fusion partner. TAT for ctDNA NGS was shorter than tissue NGS (10 vs. 20 days; p < 0.001). Among ALK fusions identified by ctDNA, 93% (13/14, 95% CI 66%–99%) were concordant with tissue evaluation. Among ALK fusions detected by tissue NGS, 54% (13/24, 95% CI 33%–74%) were concordant with plasma ctDNA. ctDNA matched patients to ALK-directed therapy with subsequent clinical response, including four patients matched on the basis of ctDNA results alone due to inadequate or delayed tissue testing. Serial ctDNA analysis detected MET amplification ( n = 2) and ALK G1202R mutation ( n = 2) as mechanisms of acquired resistance to ALK-directed therapy. Conclusion: Our findings support a complementary role for ctDNA in detection of ALK fusions and other alterations at diagnosis and therapeutic resistance settings.